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	Vaccine Trials By Paddy Doyle God Squad August 23 2010 http://www.paddydoyle.com/vaccine-trials/ The letter below deals with Vaccine Trials carried out on babies and children in institutional setting in Ireland during the 1960’s and 1970’s. Commission to Inquire into Child Abuse (C.I.C.A) Vaccine Trials Inquiry Arbitration Centre, The Distillery Building, 145-151 Church Street, Dublin 7. Telephone: (01) 8726888 Fax: (01) 872 6806 Mr. Patrick Doyle Address: Dublin. 17th July 2003 Vaccine Trials Dear Mr. Doyle. I wish to confirm that we have on file a questionnaire completed by you and furnished to the Commission to Inquire into Child Abuse (‘the Commission’). The contents thereof have been carefully noted. The Commission has been requested by Dail Eireann to inquire, through its Vaccine Trials Division (‘the Division’), into 3 vaccine trials that are known to have taken place in various institutions in the State in the 1960s and 1970s. The first of these trials took place in 1960/1961 in 4 Mother-and Baby Homes, 1 Baby Home, and 1 Industrial School in the State. The purpose of the trial, in general terms, was to measure the effectiveness of a four-in-one vaccine against diphtheria, tetanus, whooping cough and polio. The general practice at the time was to give a tree in one vaccine against the first three diseases, and to give the polio vaccine separately. The second of the known vaccine trials took place between 1968 and 1970. It was carried out in and Industrial School in Dublin, and also involved children in the Midlands who were living at home. In general terms, the purpose of this trial was to assess the effectiveness of a rubella vaccine when administered nasally rather than by injection. The third vaccine trial into which the Division has been statutorily mandated to inquire into took place in 1973. The subjects of this trial were children living at home in Dublin, as well as children residing in 5 institutions. In general terms, the purpose of this trial was to compare the reactions of children who were given commercially-available batches of 3 in 1 vaccines to the reactions of children who were given a modified vaccine of equivalent efficacy but of a lesser potency. The Division’s preliminary investigations into the aforementioned trials is ongoing. It is only now that the Division is in a position to confirm, based on the information that it currently has, that you were not involved in any of the aforementioned trials. The Commission is also mandated to inquire, through the Division, into any other vaccine trial that was conducted in an institution in the State between January 1, 1940 and December 31, 1987, following an allegation by a person that he or she as a child in that institution was a subject thereof. I note from your questionnaire that you were resident in an institution during the relevant periods. On the basis of its enquiries to date the Division has found no evidence that a vaccine trial took place in the institution in which you were resident. There is therefore no evidence to suggest that you were ever a participant in a vaccine trial. I wish to assure you, however, that should the Division discover evidence of a vaccine trial having been conducted in such institution, and of our involvement therein, it will contact you immediately. Your details have been recorded and will remain on file. I hope this letter clarifies matters for you. If you have any further queries, please do not hesitate to contact the Division. Yours sincerely, Robert Kerr, Solicitor to the Vaccine Trials Divisions This letter sent to me and to many other people who were institutionalised during their childhood is far from satisfactory. The language contained in it is vague and there seems to be a willingness to accept that vaccine trials only took place in five institutions in the state. The last paragraph of the letter, informs recipients that the Commission to Inquire into Child Abuse – Vaccine Division – “the Division” “on the basis of its enquiries to date the Division has found no evidence that a vaccine trial took place in the institution in which you were resident. There is therefore no evidence to suggest that you were ever a participant in a vaccine trial”. Are we to believe that because “the Division” “found no evidence” of vaccine trials, that none took place. Who is to say that “evidence” is not being withheld by both drug companies and institutions? The letter then continues with the assurance “that should “the Division” discover evidence of a vaccine trial having been conducted in such institutions, and of your involvement therein, it will contact you immediately. Your details have been recorded and will remain on file”. ( I am aware that I was not the only person to receive this letter – the chances are that many hundreds were posted to individuals who felt that they were the “victims of vaccine trials”. I did telephone “the Division” and sought clarification of some aspects of their investigation. It is my view that the following questions need to be answered: How would a young child between the age of say, four and ten years know what was being injected into them or what it was they were being asked to swallow. Does “the Division” really believe the Multi National Drug companies will really come forward with their “hands up” and admit to having conducted drug trials. It is well known that large drug companies never volunteer such information. It is my view that “the Division” is naive in believing that such information will be easily forthcoming. Can we really expect that religious orders and others in whose care children were placed are going to admit that they did allow drug trials to be carried out in their institutions – I very much doubt it. Most people are now familiar with the cover-up regarding sexual, psychological and emotional abuse, which was an every day occurrence in institutions all over Ireland. Can we realistically expect that admissions of other abuses will be admitted to? I think not! “The Division” did offer to send me a copy of a report entitled: Report on 3 Clinical Trials involving babies and children in institutional settings 1960/’61, 1970 and 1973 (This report is stamped with the official stamp of the Commission to Inquire into Child abuse and is dated 04 June 2002) I have transcribed the report as part of this important debate. Many other questions need to be asked and regarding the vaccination of children in “care” Questions such as: How many children were exposed to drug trials or even experimental surgery once they had been admitted to hospital. While these questions are not within the remit of the Commission to Inquire into Child Abuse, perhaps they should be included in the Commissions Terms of Reference. It appears to many people who were institutionalised and abused that little or nothing is happening to speed up the Inquiry or Compensation process through the Residential Institutions Redress Board R.I.R.B. The patience of any individual is not something that is infinite. Questions need to be asked and answers must be given. Paddy Doyle, July, 2003. NB. This Document was forwarded to me from the Commission to Inquire into Child Abuse. Because I was not able to locate the report on the Irish Government website, it was necessary for me to type the report in full. I have remained true to the original in every respect, however if you do find any serious errors please do let me know where they occur and I will do my best to rectify them as soon as possible. Paddy Doyle Report on 3 Clinical Trials involving babies and children in institutional settings 1960/’61, 1970 and 1973 Introduction 1. One of the greatest contributions to human health this century has been the reduction, and in some cases, the elimination of disease and death due to infections diseases. A number of factors have contributed to this phenomenon, not least being the widespread use of vaccines. Vaccines against a range of serious diseases such as diphtheria, pertussis, polio and measles which have been developed and introduced into comprehensive, population based vaccination programmes around the world. Ireland has been to exception and over many decades, vaccines have been incorporated into a national programme on the basis of a schedule recommended by the Department of Health and Children and delivered by the Health Boards. Such vaccines have been developed in the main, by commercial companies in accordance with the evolving standards governing the conduct of laboratory and clinical research and have been licenced and brought to general use. 2. In May 1991, three vaccine trials that had been undertaken in the 1960s and 1970s were brought to the attention of the Minister for Health. Two of these trials were the subject of published articles in peer review journals and the third was unpublished. These particular trials have become the subject of public discussion over the past number of years because some of the children who took part in these trials were resident in Mother and Baby homes and children’s homes around the country and questions have been raised as to the ethical propriety of these trials. These trials initially became the subject of media interest in 1991 on foot of which the then Minister for Health answered questions in the Dail on 7th May 1991. There was subsequent interest in these trials by way of correspondence between a former resident of a childrens’ home in Dublin and the then Minister in 1993 and finally in media reports in July 1997. This was followed by a statement from the Minister for Health in the Dail on 9th July 1997, in the course of which he promised to make enquiries into the matter following which he would consider what was the most appropriate action to take. The trials in question are as follows: Trial 1 Hillary, IB, Meenan, PB, Goffe, AP, Knight, GT, Kanarek, Ad and Pollock, TM: Antibody response in infants to the poliomyelitis component of a quadruple vaccine. Br. Med J 1962; I: 1098 This trial in which fifty eight infants resident in five childrens’ homes in Ireland took part sought to compare the poliomyelitis antibody response after vaccination with a quadruple vaccine (Diptheria, Pertussis Tetanus (DTP) and Polio combined) with the standard vaccines in use at the time which consisted of DTP and Polio administered separately and at different sites. Trial 2 Hillary, IB: Trials of intra nasally administered rubella vaccine. J Hyg Camb. 1971; 69: 547-553 In this trial sixty-nine children resident in a children’s’ home in Dublin had blood taken of whom twelve were subsequently administered intranasal rubella vaccine. In the same trial, twenty-three children living at home were administered this vaccine. The purpose of the trial was to investigate whether there was a propensity for intranasal administered vaccine to spread to susceptible contacts and to estimate antibody levels and acceptability of the intranasal techniques of vaccination. Diphtheria, Tetanus Pertussis Trial (DTP) 1973 Not published. This trial in which fifty three children in Mother and Baby homes and children’s’ homes in Dublin and sixty five children living at home in Dublin were administered vaccine to compare the *reactogenicity of the commercially available batches of Trivax vaccine and Trivax AD vaccine, with a vaccine of equivalent efficacy but of lesser potency. *Reactogenicity: Events that are considered to have occurred in direct relationship to the vaccination. These events may be local or systemic. Issues for Consideration These trials, although they were undertaken over a period of thirteen years, had a number of factors in common. These were: The vaccines used were all manufactured by the same company, Burroughs Wellcome referred to in the rest of the report as Wellcome. The researchers* were members of the staff or either the Wellcome company of the Department of Medical Microbiology, University College Dublin (UCD) and, in the case of Trial 3, the Eastern Health Board. Participants in all three trials included babies and children resident in Mother and Baby homes and children’s residential homes in Ireland. In considering the trials, the number of issues need to be clarified and addressed. These are: 1. What were the statutory controls relating to the importation and use of the vaccines used in the trials and were these complied with? 2. What were the statutory controls relating to the conduct of clinical trials and were they complied with? 3. What were the ethical standards which governed such trials, particularly in relation to the principle of consent, and were these complied with? 4. Were the participants exposed to any, or additional risk, by reason of these vaccines? (.) It is proposed to describe, in so far as it is possible, the relevant context and background within which these trials took place, how the individual trials themselves were conducted, and then to deal with each of the issues identified (1-4) above as they apply to each individual trial. Professor PN Meenan, one of the researchers, was also a consultant Bacteriologist to the Department of Health and as such was an advisor on whether therapeutic substances to be licenced under the therapeutic Substances Act, 1932 were of appropriate quality and safety Background and Context A matter which it would be useful to consider is the manner in which such issues as the consent of participants in scientific trials, while alluded to in published documents such as the Nuremberg Code, were actually dealt with by researchers in their published work. It is not possible in this document to undertake a definitive review of the historical development of the principles underlying scientific research, particularly that of consent. However, there are certain indications in the literature of the environment existing in the 1950s ‘60s and ‘70s in relation to these matters. In a 1987 review article in the New England Journal of Medicine, David J Rothman (1) traces the history of “ethics and Human Experimentation” in the USA. He makes a number of important points concerning the development of ethical approaches to human research and contends that in the decades after World War 11, such research was governed to a large degree as a “utilitarian ethic”, i.e. the benefits to the many which flowed from experiments could be seen as justification for the lack of a full appreciation of the rights of some subjects, particularly in regard to obtaining their consent for participation in such research. He suggests that such an ethic continued to underpin research for many years and while “numerous international codes defined ethical standards for human experimentation, most notably the Nuremberg Code, the issue did not command much attention”. Also, he is of the opinion that “before the 1970s the Code itself was infrequently cited or discussed in medical journals”. In the UK, Pappworth (2), in a review article in the British Medical Journal in 1990, reviewed progress in relation to ethics and research in that country and cities many references to the subject from the 1950s, ‘60s and ‘70s, the decades which are of relevance to the trials under considerations here. He reflects a situation in which influential and important institutions such as the Medical Research Council and various authors and journals drew attention to the necessity for the application of proper ethical standards in the conduct of research. This was accompanied by responses and actions from researchers which did not appear to suggest that they approached this issue with the rigour which was being recommended. An example was a response form a senior medical figure in the House of Lords in 1973 to a proposal to legislate for the introduction of ethics committees to supervise research inn the NHS, “the provision of these ethical committees is no a suitable subject for legislation. We should leave things as they are and trust in the good sense and responsibility of the doctors”. It is difficult to discern in the Irish medical literature anything to suggest that these issues and the concerns surroundings them were being articulated in Irish medical research circles during the 1950s, ‘60s and ‘70s. During that period and up to 1978, with the establishment of the Medical Council, Irish medicine and its practitioners took their lead on ethics from the UK General Medical Council and it was not until 1987 that the Control of Clinical Trials Act gave legislative underpinning to the conduct of clinical trials and systematically addressed the issue of informed consent. It is probably fair to say that like much of the rest of the medical and research world, Irish doctors and researchers did not view their responsibilities in this regard with the same perspective which has been brought to bear in more recent times with the development of concepts which take into account patient rights to a far greater degree and are informed not only by medical and scientific concerns but also by legal, philosophical, social science and public policy principles. A matter of particular interest which has been raised in relation to these trials is whether it was appropriate to use as subjects babies and children who were in institutional settings. The matter is not discussed in the available protocols, the published articles or any further documents provided by the researchers. The only reference to this issue which has been located is in a Department of Health memorandum written in 1962 some time after Trial 1 was completed. A request from a researcher for permission to carry out a trial on another vaccine in a Mother and Baby Home in Dublin was turned down by the Minister on the basis that the selection of this group as participants was open to objection. The nature of the objection is not specified. There is no evidence available to show whether or not the objection of the participation of such children in clinical trials was ever communicated by the Department to researchers in this field, at any time. Trial 1 Hillary, IB, Meenan, PN, Goffe, AP, Knight, GT, Kanarek, AD and Pollock, TM: Antibody response in infants to the poliomyelitis component of a quadruple vaccine. BR, Med J 1962; I; 1098 This trial was the subject of an article in the British Medical Journal in April 1962. It sought to compare the poliomyelitis antibody response after vaccination with a quadruple vaccine (Diphtheria, Pertussis, Tetanus (DTP) and Polio combined) with the standard vaccines in use at the time which consisted of DTP and Polio administered separately and at different sites. Fifty-eight infants resident in five Mother and Baby homes in Ireland took part in the trial. Twenty-eight were administered the quadruple vaccine and thirty the triple vaccine and Polio separately. Subsequently, six infants did not have appropriate blood samples taken and were excluded from the analysis. Four of these had received the quadruple vaccine and two the standard vaccine. The results of the analysis following the administration of the vaccines demonstrated some evidence of a lower antibody response to one component of the Polio vaccine in those who received the quadruple vaccine as compared to the other group indicating that it may not have been as effective a vaccine as the standard vaccine in use at the time. A number of months later, sixteen of those who have received the quadruple vaccine and twenty from the standard group received booster doses of Polio vaccine which further increased their antibody levels. The response of those infants who received the standard vaccines was again greater than those who received the quadruple vaccine. The conclusion was that, until a more satisfactory quadruple vaccine was produced, infants should be immunised initially with DTP and Polio separately and then given a booster does of Polio vaccine six to twelve months later. (2) The institutions in which this trial took place are not named in the article but Professor Hillary, one of the investigators, indicated to the Department of Health and Children the names of the institutions in which she thought these may have taken place. (3) In the case of one of these, the Sacred Heart Home and Hospital, Bessboro, Cork the Southern Health Board has located individual patient records for the period 1959 5o 1963 and these have been examined by a Medical Officer of the Board. This was a Mother and Baby Unit which provided ante-natal, delivery and post-natal care for single mothers and their babies up to the age of two years, or, until the baby was adopted. The local health authority or county council paid for individual residents. In addition, there was some funding from the health authority for overheads. These records indicate that seventy-eight infants received vaccinations. However, as the trial commenced in December 1960 and concluded in November 1961, it is clear that only some of these infants could have been included in the trial. Of these seventy-eight infants, twenty-three started and twenty completed a course of quadruple vaccine. These infants were between two and eleven months at the time of the first vaccination. Seven of this group are recorded as having received a booster dose of Polio some months later which accords with the description given in the article. Professor Hillary’s name is included in these particular seven records but otherwise there is no doctor’s name or signature, batch number or name of manufacturer included in any of the other records. On the basis of this information, particularly the description of the quadruple vaccine given, it seems reasonable to infer that some or all of the twenty children who completed the course of vaccination were part of the trial. However, this is not explicitly stated on any of the records. Fifty five infants were recorded as having received a course of Diphtheria, Tetanus and Pertussis (DTP0 only or DTP and Polio separately. Again there is no doctor’s signature or batch number but, on a number of the records, the name of the vaccine “Trivax” is noted. It is not indicated in any of the records of these fifty five infants that these vaccinations were administered as part of a trial so there is no way of knowing how man, if any, of these children were participants in the trial. It is clear, however, that those who received only DTP could not have been involved. (4) Health Boards were not in existence at the time this trial took place and were only established in 1971. The Health Boards for the areas in which other locations for this trial may have been situated have not been able to discover any original documentation which would confirm that such trials actually took place. It is, there, not possible to make any comment on what may have happened in the other four homes in which the trials were said by Professor Hillary to have taken place. (5) The Wellcome company which was involved in the trial and whose quadruple vaccine was used, have indicated that, despite extensive searches of their archives, they are unable to locate any source documentation which would provide any further information on this trial. Discussion The issues identified for consideration are now addressed. The Applicable Statutory Controls Relating to the Importation and Use of Vaccines Used in the Trial The Therapeutic Substances Act, 1932 was the only legislation governing the manufacture or importation of vaccines at the time this trial was conducted. The Act provided for the granting by the Minister of Health of manufacturing, import and research licences in respect of therapeutic substances, including vaccines. Furthermore, the Act also provided that “import permits” might be granted to medical practitioners to enable them personally, as such practitioners, to import such substances as might on occasion be necessary. It appears that the quadruple vaccine used in this trial was prepared specifically for the purpose of the trial by Wellcome in the UK and was not part of a commercial batch. It would, therefore, not have been covered by any commercial import licence held at that time by Wellcome under the Therapeutic Substances Act, 1932. However the components of the vaccines used were already in use in the state in products i.e. DTP and Polio vaccines for which the company had import licences at the time. The trial protocol indicates that the vaccines were to be sent from the UK to Professor Meenan, Professor of Medical Microbiology at UCD. Professor Meenan had a Research Licence no. 216 which was granted to him in July 1958, was personal to him, was renewed every two years and enabled him “to import for the purpose of scientific research at the Department of Microbiology as applied to medicine University College Dublin, or in such other place or places as the said Minister may from time to time authorise, any therapeutic substance he may require”. While the file relating to Professor Meenan’s research licence is available, a thorough search for the files associated with the operational aspects of the licence, going back over 40 years, has been unsuccessful. The files do, however, indicate that the requirement to apply to the Minister for permission to use vaccines outside UCD as well recognised and, on at least two occasions, Professor Meenan sought authorisation under the terms of his licence to undertake research in locations other than University College Dublin. Professor Hillary has indicated that she was unaware of the existence of this licence and, therefore, of the requirement to have ministerial sanction for research outside UCD. No document relevant to Trial 1 has been located in the Department, despite and exhaustive search In a discussion held with Professor Meenan, he indicated that he had o documentation in his possession relating to this particular trial nor had he any personal recollection of the trial and the circumstances surrounding it. There is, therefore, no information available which can establish whether or not the statutory requirements regarding the importation and use of these vaccines in this trial were fully complied with. (2) Statutory Controls relating to Clinical Trials There were no statutory controls relating to the conduct of clinical trials at the time of this trial. Such controls were first introduced when the Control of Clinical Trials Act 1987 was enacted by the Oireachtas (Irish Parliament) (3) Ethical Standards Relating to Clinical Trials The relevant ethical framework within which this trial would have been considered would have consisted in the first instance of the ethical guidelines which governed professional conduct as were published, monitored and applied by the General Medical Council (GMC London) The GMC has indicated that there was no specific guidance relating to the conduct of clinical trials in these guidelines. The Nuremberg Code (1947) laid down ten standards to which physicians must conform in carrying out experiments on humans. Two standards are of particular relevance to this trial and it is proposed to consider these in examining the propriety of the trials referred to in this report. For the purpose of the report, these will be referred to as Standard 1 and Standard 2. Standard 1 The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature. (Nuremberg Code, 1947) This clearly means that any trials undertaken should have a clear objective relevant to an identified and serious health problem and that the methods undertaken to investigate the problem and to achieve the objective should be reasonable and proportionate. In relation to this standard, infectious diseases, including Polio, were a major cause of ill health and death in the ‘50s and ‘60s worldwide. The improvement in the effectiveness of vaccines and the development of more effective combinations of vaccines were highly desirable objectives and research such as that described in this article was being conducted worldwide. In relation to the specific vaccines used, and particularly the major studies published in reputable journals in the USA and Canada. It is fair to say that the objectives of this study, and the nature of the public health problems being investigated, were such as to seem reasonable when judged by this standard. Standard 2 The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject, there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs, or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity (Nuremberg Code, 1947) This clearly sets out the rights of the subjects in clinical trials and the ethical obligations of the researchers towards these subjects as regards obtaining consent for participation in such trials. Because the subjects in this trial were infants, an effective consent could not have been given by the subjects and could only have been given by parents or legal guardians. In a public statement of 9th July 1997, Professor Hillary says that the researchers received the consent of some of the parents of the infants involved in the trial. In subsequent communications, Professor Hillary has asserted that she requested and received the permission of both the management and Medical Officer of the home in Bessboro to carry out a trial and she understood that all the parents whose infants were participants were informed either by her or the manager of the nature of the vaccination being undertaken and they gave their consent on that basis. There is a statement in the published article in the Medical Officers in the homes gave their permission to carry out the trial on infants under their care. This is the only reference to consent in the article. The question of consent is not addressed in the trial protocol. In the home in Bessboro, Cork, the mothers of the infants would also have been resident there but there is no written evidence to indicate whether the mothers’ consent was sought or obtained for their childrens’ participation in this trial. Further, there is no documentation available in Bessboro which describes the arrangements made between the management and the researchers for the conduct of this trial. In principle, it appears to be the case that the authorities in whose care children were placed and who, in the absence of parents or guardians, were in loco parentis, were entitled to give consent for medical treatment (including vaccination) on behalf of the children in circumstances where, in their judgement, that treatment was in the child’s interest. It is not clear, however, that such authority would extend to giving consent to an intervention which, while it would confer certain benefits on the child by way of protection against a number of infectious diseases, was clearly a clinical trial, the outcome of which or the level of benefit accruing to the child could not be predicted. It is also unclear what standing, if any, medical officers attached to childrens’ homes had to give consent. In the course of the Department’s enquiries, information and opinion was requested from the editorial department of the British Medical Journal on the ethical aspects of this investigation and they have indicated as follows: In 1961/’62 there were no established ethics committees and the Journal editors made their own judgements about ethics. The policy was to refer papers intended for publication to a clinical or scientific review referee but the editors also sent papers about which they had ethical concerns to an ethics referee. Unfortunately, in relation to this particular paper, the Journal does not have any records available and the present deputy editor is unaware of what precisely was done in relation to the paper. Therefore, the opportunity to examine an independent, contemporaneous assessment of all aspects of this trial is not available. It has not been possible to discover any subsequent published communication to the British Medical Journal offering any opinions on the ethical propriety of these trials which communication is likely to have arisen is there was any objection to them. In the event, it is likely the one of two things happened: the editors did not have concerns about the ethics of the trial and thus did not refer it to an ethics referee or they did refer it to an ethics referee to consideration and accordingly it can be inferred that, if such occurred, the ethics referee had no objection to the trial. The fact that the study was published would indicate that, irrespective of which of the above procedures was adopted, the British Medical Journal editors considered that the authors’ ethical obligations were discharged to the point where they felt it was appropriate to publish the paper. The editorial department suggests that it is likely that the Journal’s assessment would have taken account of the fact that Polio was a devastating disease at the time, that the aims of the particular study seemed to be not unreasonable and that quadruple vaccine had been used in the USA3 and Canada4. Therefore, it did not appear as though this was an untried and highly experimental regime and the rationale for testing it made sense. Risk/additional Risk to Infants Involved DTP and Polio vaccines were already in use in the immunisation programme in Ireland. Quadruple vaccine was a combination of these and should theoretically not be considered a risk to those vaccinated. A number of studies in which quadruple vaccine was used were reported in the literature prior to this trial and did not demonstrate any level of increased risk to those who partook in those trials. In this particular trial, no adverse reactions, either local or general, were reported after the first or third injections. Sixteen of twenty-five infants from a single home were reported in the article as having developed vomiting, diarrhoea and pyrexia after the second immunisation which symptoms lasted a few days and was followed by complete recovery. The authors did not consider this outbreak was caused by the immunisation procedure as a number of other infants who were not vaccinated were ill with similar symptoms. However, thirty-six infants had subsequent booster doses of Polio vaccine because their Polio antibody response was considered to be inadequate in both quadruple vaccine and standard vaccine groups. Because a number of the children left the children’s’ homes in the months following primary immunisation, it is not clear from the published study whether all infants with an inadequate antibody response to these vaccines were followed up and received appropriate boosters to bring their antibodies to a satisfactory level. It was not the practice to follow-up infants who had been vaccinated for any prolonged period of time apart from those thirty six infants who received booster doses of Polio vaccine some months after the trial, no further follow-up was carried out on the participants in this trial. In the 1970s, there were reports suggesting that some children may have been brain damaged as a result of DTP (3-in-1) vaccination. An expert group was established by the then Minister for Health to investigate these reports. As a result of these investigations, the expert group found that, on the balance of probability, a small number of children might have suffered brain damage as a result of the vaccination. Enquiries have been made to establish if any of the children on whose behalf claims of vaccine related damage were made, have been vaccinated in this trial or in any of the trials referred to. An examination of the Department’s records in this regard reveals that none of the children on whose behalf claims were made received their vaccinations in any of these trials. Trial 2 Hillary, IB: Trials of intra-nasally administered rubella vaccine. J Hyg Camb. 1971; 69: 547-553 This trial comprises of two parts. In Dublin, sixty-nine children ranging in age from two to eighteen years resident into a children’s home had blood taken to establish their Rubella antibody status. Eleven of these children who were antibody negative and one child who had Rubella antibodies were administered Rubella vaccine via the intranasal route. Six remaining children who were negative for Rubella antibodies were retained as indicators of vaccine transmission. Five of the eleven susceptible vaccines subsequently developed Rubella antibodies following administration of the vaccine and none of the six contacts developed antibodies as a result of being in contact with those previously vaccinated. At the same time and as part of the same study, twenty three girls in a semi-rural area in the Irish Midlands were also administered intranasal Rubella vaccine and vaccine virus transmission studies were carried out on a further thirty children (eleven girls and nineteen boys.) The purpose of the trial was to investigate, inter alia, whether there was a propensity for intranasally administered vaccine to spread to susceptible contacts which, in the general population, might have detrimental consequences, especially to pregnant woman. There was no evidence of vaccine virus transmission in the study and a number of other questions were identified which were suggested as possible subjects for further study in this area. The name of the childrens’ home is not mentioned in the published article. The principal author, Professor Hillary, indicated to the Department of Health and Children the name of an institution in Dublin where she thought it may have been carried out. The Eastern Health Board has investigated this but has indicated that there are no records available which would confirm it. The Wellcome company has indicated that there is no original source material relating to this study in its archives and so it has not been possible to identify the home in which this trial took place. Discussion The issues relating to this trial are similar to those already raised in relation to the first mentioned trial. The Applicable Statutory Controls Relating to the Importation and Use of Vaccines Used in the Trial. The therapeutic Substances Act, 1932 is again the applicable statute. As in the previous trial, the vaccine was specially prepared for the trail by Wellcome research laboratories and, therefore, would not have been the subject of a commercial import licence held by Wellcome under the Act of the time. There is no information in the Department’s records to indicate that the vaccine was imported under the Act to any trial researcher as individual medical practitioners nor of any application from the author of the article to the Minister for permission to use the vaccine in locations other than at the Department of Medical Microbiology in UCD.(University College, Dublin. Therefore, there is no documentary evidence available to demonstrate that the statutory requirements in respect of the importation and use of the vaccine used in this trial were fully complied with. Statutory Controls Relating to Clinical Trials There were no statutory controls relating to the conduct of clinical trials at the time of this trial. Such controls were introduced with the enactment of the Control of Clinical Trials Act 1987. Ethical Standards Relating to Clinical Trials As in Trail 1, the General Medical Council ethical guidelines and the Nuremberg Code were relevant here. In addition, the report of the Medical Research Council of the UK for 1962-’63 addressed this issue in a document entitled Clinical Research. Included in the report were the following observations: “That it is both considerate and prudent to obtain the patient’s agreement before using a novel procedure is not more than a requirement of good medical practice”. “In general, therefore, the propriety of procedures intended to benefit the individual – whether these are directed to treatment, to prevention or to assessment – are determined by the same considerations as govern the care of patients.” “In general, the patients participating in them should be told frankly that two different procedures are being assessed and their co-operation invited.” Finally, the Declaration of Helsinki (1964), which was initially adopted by the 18th World Medical Assembly Helsinki in Finland, now also informed doctors’ approach to biomedical research. The two standards identified as being of particular importance in the examination of the propriety of Trial 1 are re-emphasised in the Declaration of Helsinki i.e. proportionality and consent. “Biomedical research involving human subjects cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk of to the subject.” The Declaration was particularly explicit in relation to the issue of informed consent and it draws attention to the obligations of physicians when the subject of a trial is a minor. “In case of legal incompetence, informed consent should be obtained from 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. Whenever the minor child is in fact able to given consent, the minor’s consent must be obtained in additional to the consent of the minor’s legal guardian.” These two issues are not discussed as they pertain to Trial 2 using the same criteria as were applied in relation to Trial 1 Standard 1 Rubella infection with its attendant complication of Congenital Rubella Syndrome (mental handicap and other problems in the new-born) was regarded at the time as a serious and preventable disease. Research on the development of a vaccine had been carried out in many locations and reported in the literature. Clinical trials on this subject then would have been appropriate and acceptable. However, it is clear that the major objective of this trial was to assess whether there was any measurable degree of vaccine virus transmission for vaccinated to unvaccinated children. It does not appear as though the intervention was directed primarily towards the provision of any appreciable benefit to the children who were assessed to determine if such vaccine virus transmission had occurred but was rather directed towards the identification of a particular property of the vaccine. Standard 2 As regards consent, while the authors mention in the article that permission was given by the parents of the children from the Midlands involved in the study, no such statement is made in relation to the childrens’ home. It has not been possible to locate a copy of the original trial protocol so it is impossible to say if there was any reference to informed consent contained in it. There is no documentation available therefore, to allow the conclusion to be drawn as to whether consent was obtained on behalf of all the participants in this trial resident in the childrens’ home. Additional Risk to Infants Involved Reports of vaccination of children with Rubella vaccine had appeared in the literature on a number of occasions prior to the publication of this study with no indication of any identifiable adverse risk to the subjects. In this particular study, two children who were vaccinated developed palpable most auricular glands which lasted for three and a half days and one developed a cough which lasted for two days. Otherwise, there were no documented adverse reactions. It is interesting to note that, in the period between the completion of this study and its publication, Rubella vaccine identical to that used in the trial was licenced and became widely available from the company concerned albeit for administration by the subcutaneous route as opposed to the intranasal route used in this trial. There is no record that these children were followed up in later life and their subsequent medical history is unknown. Trial 3 Diphtheria, Tetanus, Pertussis Trial (DTP) 1973 (unpublished) This study, the results of which were not published in a peer-reviewed journal, was carried out during 1973 in Dublin. The purpose of the trial was to compare the reactogenicity of the commercially available batches of Trivax vaccine and Trivax AD vaccine, with that of modified equivalent vaccines. In these modified vaccines, the Pertussis, (Whooping Cough), component was replaced with a component obtained by a modified method of culturing, Bordella Pertussis (the Whooping Cough organism). This modification was to enable the numbers of organisms per vaccine does to be decreased and thus the safety of the vaccine to be theoretically increased. In the trial, four vaccine products were used as follows: Trivax Vaccine (DTP), Trivax AD Vaccine (DTP/AD), New DTP plain and new DTP absorbed. The context in which this trial was undertaken was presented in the Wellcome company’s public statement in July 1997 as one in which Wellcome was responding to a request from the Eastern Health Board through its deputy Chief Medical Officer to investigate an apparent increase in the incidence of adverse reactions to the DTP vaccine, then in use in the Eastern Health Board Immunisation Programme. Professor Hillary, in her public statement of 17th July 1997 appears to confirm this. However, examination of the documentation provided by Wellcome shows that, while what appears to be the Eastern Health Board’s initial correspondence with Dr. Griffith in Wellcome is dated August 1973, the trial itself was apparently in progress earlier in 1973. It appears that a number of blood samples for use in the trial were taken as early as February 1973. Further, a letter of no objection to the trial and to the utilisation of the modified vaccines had been given to Wellcome in April 1973 by Dr. A Scott of the National Drugs Advisory Board on foot of the submission of a protocol specifically for this trial from Wellcome Laboratories prior to this. The documentation in relation to the trial itself provided by Wellcome and the letter from Dr. Colgan, head of the Medical Department of Glaxo-Wellcome of 10th December 1997, does not clarify how this apparent discrepancy in the recorded chronology of events came about. In addition, the Eastern Health Board has been unable to locate any documentation setting out formally the basis on which the Board agreed to co-operate with Wellcome in this study. It is, therefore, not possible to fully describe the rationale of this trial. One hundred and eighteen children took part in the trial. Fifty-three of the children were in children’s’ homes in the Dublin area and were all administered the modified DTP vaccine in these homes. The other sixty-five children were all living at home and were administered their vaccines at immunisation clinics run by the Eastern Health Board. Sixty one of these sixty five children were given the DTP vaccine which was identical with that in use in the Eastern Health Board Immunisation Programme at the time and four were administered the modified vaccines. It is not clear why four of the sixty five children in the community setting were administered the modified vaccines when the other sixty one children attending the Immunisation Clinics were given the vaccine identical to the standard one in use. The trial protocol called for the children to be assessed the day after the immunisation for evidence of any reaction to the vaccine and this was done in respect of the one hundred and eighteen children. The results of the trial were not published but an internal document from Wellcome which was made available by the company showed that, while they consider that there were some differences between the various vaccines in terms of their reactogenicity, overall, the date did not support a change to a new vaccine. Details of all the available clinical information relevant to this trial containing names, home addresses, institutional addresses, dates of vaccination and reactions recorded on the one hundred and eighteen children in the trial, have been made available by Wellcome and the Eastern Health Board to the Department of Health and Children. Of the fifty three children who were identified as living in childrens’ homes in the Dublin area, twenty were in St Patrick’s Home, nineteen in Madonna House, seven in Cottage Home, six in Bird’s Nest Home and one in Bohernabreena. Of these fifty-three children, at the time of vaccination, two had Spina Bifida, one had Downs Syndrome and one had a facial bone disorder. All the other sixty-five children involved in the study had home addresses in the Dublin area. Again, the Therapeutic Substances Act 1932 would have been the relevant statutory instrument. According to the protocol, all vaccines for the trial were manufactured in the Wellcome Research Laboratories in the UK and would, therefore, not have been covered by the commercial licence held by Welcome under the Act. There is no record of applications having been made to the Minister for import permits for named doctors for these products nor is there any record of an application to the Minister to utilise these products at any location other than the location specified under any research licence held at the time. There is not sufficient information to confirm that the statutory requirements in respect of the importation and use of the vaccines used in this trial were full complied with. Statutory Controls relating to Clinical Trials There were no statutory controls relating to the conduct of clinical trials at the time of this trial, the national Drugs Advisory Board expressed no objection to the use of the modified product in the trial in accordance with the protocols submitted to the Board of Wellcome Laboratories. This was conveyed in a letter from the Medical Director of the National Drugs Advisory Board to Wellcome Research Laboratories on the 6th April 1973. Ethical Standards relating to Clinical Trials The relevant ethical considerations were still those comprehended by the ethical guidelines of the General Medical Council, the Nuremberg Code, the Declaration of Helsinki and the statement of the Medical Research Council previously referred to. In applying the standards used in assessing the propriety of trials 1 and 2 to this trial, the following observations can be made. Standard 1 The prevention and control of infectious diseases was still considered to be of major public health importance at the time of this trial. The use of effective and safe vaccines was a major element of disease control and, given the minimisation of adverse reactions was a major factor in the acceptance of the vaccines by the general population, research which would result in the production of vaccines which had a lower incidence of reaction and were, therefore, considered to be safer, was an appropriate and reasonable subject to clinical trials. Standard 2 As the subjects of this clinical trial were minors, the requirement for consent would have reverted to their parents or guardians. There is no reference to consent in the trial protocol made available by the company. In the case of the children who were vaccinated in Eastern Health Board clinics, and subsequently visited by a health professional in their homes to assess the level of reaction, it seems reasonable to infer that consent was given by parents for this to be done. In relation to the children living in the childrens’ homes, the situation is less clear. In her statement of 15th July 1997, Professor Hillary indicates that the children were presented to her by the medical officers of the homes who were responsible for the assessment of their health and their suitability for vaccination. Correspondence from the Cottage Home for little Children in Dun Laoghaire and the Mrs Smyly’s Homes (Bird’s Nest) in Dun Laoghaire to the Eastern Health Board in relation to this trial, indicates that these homes believed that the vaccines administered to their residents were those which were in routine use in the Eastern Health Board Immunisation Programme in 1973. It appears from the correspondence that, in the case of Mrs Smyly’s Homes, while the Medical Officer was aware that a trial was taking place, he stated that he believed that the children in this home were being given the standard vaccines and were being used for comparison with other children being given the modified vaccines elsewhere. In the case of the Cottage Home, the Chairman of the Committee of Management stated that he was satisfied that at no time were trials carried out on children in this home and that only standard vaccines in the routine use were administered to these children. The documentation provided by Wellcome, however, appears to show that in fact it was the modified vaccines which were administered to the children in these two homes in the context of a clinical trial. In the light of these assertions, it is unclear as to whether effective consent was obtained in relation to the participation of the children in these two homes in this trial. The Eastern Health Board has been unable to locate any documentation relating to the issue of consent in the other children’s homes mentioned as having participated in this trial. Risk/Additional Risk to Infants Involved The use of the vaccines which were identical with those already in use in the Immunisation Programme would not have posed any extra risk on those who received them. As regards the modified vaccines, they were produced by a method which reduced the number of organisms per dose without lowering its potency below the required level. Theoretically, therefore, the level of risk attaching to the administration of this particular vaccine should have been lower than that attaching to the standard vaccine. In analysing the outcome of the trial, the internal Wellcome document noted some differences in the reactogenicity of the various vaccines and noted that the new plain vaccine was the least reactogenic of all while the existing plain vaccine was the most reactogenic. However, it is noteworthy that, of the fifty three children who received their vaccinations in the childrens’ homes, twelve were over eighteen months of age and, of these, eight were over two years compared to six children out of sixty four in the community being over eighteen months. This was a much later age for primary vaccination than that recommended at the time and, in its internal analysis of this trial, the company draws attention to this fact. Indeed, it concludes that the age of the participants in the trial from the childrens’ home may be one of a number of reasons why the data on reactogenicity in the trial could be questioned to the point where it could be considered to be unreliable. If this were so, one would ask why a trial with such an inherent methodological flaw was undertaken at all. Summary 1.In the case of the three clinical trials involving the use of childhood vaccines that were brought to the attention of the Minister, the vaccines in each trial were manufactured by Wellcome laboratories and subsequently used in these trials. The research institutions involved in the trials were Welcomme laboratories in the UK and, the Department of Medical Microbiology in University College Dublin and, in Trial 3, the Eastern Health Board. 2. These vaccines were administered to a total of two hundred and eleven children in Ireland, one hundred and twenty three of whom were resident in children’s’ homes in various parts of Ireland. 3. As these were clinical trials, a number of issues have been raised as being important in the assessment of the propriety of these trials. 4.The Therapeutic Substances Act, 1932 was the statute governing the importation and use of vaccines in these trials. It has not been possible to locate or identify documentation which would confirm whether or not the legal requirements of this Act were complied with respect of these three trials. In respect of Trial 3, the modified vaccines used and the protocol for the trial itself were the subject of a letter of no objection from the National Drugs Advisory Board under a voluntary, non-statutory code of approvals in place at the time. As the subjects of these trials were children, effective consent to their participation in the trials could only have been given by their parents or guardians. The requirement for such consent to be obtained was clearly understood by researchers and articulated in a number of documents available to the research community at the time. As regards Trial 1. There is no documentation available which describes any arrangements arrived at with management or parents for the conduct of this trial. Professor Hillary was asserted that the management, medical officers and mothers were aware of the nature of the trial and gave their consent on that basis. As regards Trial 2, there is no information available which can clarify one way or another, whether consent was obtained for the participation in this trial of those children who were resident in the childrens’ home mentioned because there are no records. As regards Trial 3, the question of consent is unclear. Available correspondence seems to indicate that the Medical Officer of some of the homes may not have been aware that residents of those homes were being given the vaccines prepared for the trial in use at the time. Professor Hillary asserts that she sought and received permission to use these newer vaccines in the homes as part of a clinical trial. It is not the practice to follow-up vaccinated children for other than very short periods and the participants in these trials were not followed up in the longer term. Current Controls Relating to Clinical Trials The current situation in relation to the conduct of clinical trials is now significantly different from that which existed at the times of the trials referred to in this Report. In particular, the Control of Clinical Trials Act, 1987 introduced strict regulatory controls on the conduct of clinical trials in Ireland. Under the Act, a person now proposing to conduct a clinical trial must first seek and be granted the permission of the Irish Medicines Board before undertaking the trial. In addition so much permission, the approval of an appropriate ethics committee must also be obtained. The Act also provides a range of protections for persons participating as volunteers in clinical trials, including a requirement of informed consent. References 1.Rothman, David J. (1987) Ethics and Human Experimentation. New England Medical Journal, 317:19,1195-1199 2. Pappworth, M.H. (1990) Human Guinea Pigs – A History. British Medical Journal, 301, 1456-60 3. Bordt, D.E., Whalen, J.W., Boyer, P.A. Pursell, A.R., and Staffieri, F.P. (1960. Poliomyelitis Component in Quadruple Antigen: Controlled Clinical Study of Enhanced Response of Children. Journal American Medical Association, 174, 1166 4. Wilson, R.J., Moss, G.W.O., Potter, F.C., and MacLeod, D.R.E (1960). Diptheria and Tetanus Toxoids Combined with Pertussis and Poliomyelitis Vaccines: Clinical Trial of a Quadruple Antigen. Canadian Medical Association Journal, 81, 450 Nuremberg Code Directives for Human Experimentation NUREMBERG CODE The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonable to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject. ______________________ Reprinted from Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10, Vol. 2, pp. 181-182.. Washington, D.C.: U.S. Government Printing Office, 1949.
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