- Email: [email protected]
Further Contributions to the Pertussis Vaccine Debate
1113
though, unlike Dudgeon, they included a personal or family history of neurological disorder (50), obstetric or perinatal problems (18), and febrile illness (12). The data were "very unsatisfactory for epidemiological purposes". All the same, "The epidemiological evidence as a whole leaves little doubt that pertussis vaccine is associated with an increased incidence of convulsions. The longer-term implication of in their series
Public Health Further Contributions to the Pertussis
Vaccine Debate WITHIN the lifetimes of most doctors now in practice the annual death toll of whooping cough in the U.K. was to be measured in hundreds. As late as 1947 the total was 1225. A decade later the pattern was very different. All the same pertussis vaccination as a national policy has not been a complete success. First, there were the problems with Bordetella pertussis serotypes, countered by altered vaccine formulations. Then there was the difficulty of interpreting changes in notification and case fatality rates against a background of spectacular reductions in the pre-vaccine era. As Prof. D. L. Miller and his team point out in a study published earlier this week: "The immunisation programme against
pertussis
has
certainly
had
a
less
convincing impact
on
the
disease than those against diphtheria and poliomyelitis, which have been virtually eliminated from the country". In thel970s the pertussis vaccine debate has been focused more on the safety issue, and the account by Professor Miller and colleagues of the National Childhood Encephalopathy Study (NCES) is the largest of six contributions issued in an unusual collation by the Department of Health and Social Security.’ In their policy on pertussis vaccination the Health Department are advised by the Joint Committee on Vaccination and Immunisation (JCVI) and by the Committee on Safety of Medicines (CSM). The CSM established two panels to examine adverse reactions to whooping cough vaccine. These were chaired by Prof. J. A. Dudgeon (Institute of Child Health) and by Dr T. W. Meade (MRC Epidemiology and Medical Care Unit, Northwick Park). The book also contains a report on the whooping cough epidemic of 1977-79 and commentaries by the CSM and the JCVI. ADVISORY PANEL ON SERIOUS REACTIONS TO VACCINES
The Dudgeon panel reported in June, 1978, the account being revised last December. They looked at 50 well documented cases of purported serious adverse reactions to pertussis antigen containing vaccines. 34 cases were thought to be possibly related to immunisation-13 of chronic epilepsy, 13 of acute encephalopathy, and 8 of infantile spasms (West’s syndrome). On 7 occasions (21%) injections were contraindicated because of reactions to an earlier dose. The verdict is tentative: "In the children with chronic epilepsy and, to a lesser extent, with acute encephalopathy, the timing of the reactions in relation to immunisation was such that an association seemed possible, but the strength of the evidence varied from case to case and was more convincing in some than in others. In the children with chronic epilepsy, for example, convulsions occurring shortly after each of 2 or 3 injections were particularly suggestive of a causal relationship." In the infantile spasms group, evidence of an association with immunisation seemed weaker, there often being considerable delay between immunisation and the onset of the spasms at an age when infantile spasms unrelated to immunisation
are
likely.
these convulsions is not, however, clear. The APVDC/AR series provides no conclusive evidence of an association between pertussis vaccine and brain damage. On the other hand, the possibility of a causal association can by no means be excluded. The APVDC/AR series gave the Panel the very strong impression that DTP vaccine was often responsible for the neurological events which followed." Dr Meade and his colleagues calculate that "The frequency of brain damage apparently attributable to DTP in 1970-74 may have been about 1 in 53 000 previously healthy children".
NATIONAL CHILDHOOD ENCEPHALOPATHY STUDY
The NCES was
set
up in
1976, and its report attempts to answer
vaccine cause brain damage in children and, if it does, how often? The study team is not the only group among those contributing to the book to avoid the risk/benefit question. A case/control approach was preferred, on practical grounds, over a cohort study, and the report covers the first 1000 cases, in the three years ended June 30, 1979, a case being defined as acute neurological illness requiring hospital admission in a child aged 2-36 months. For each case 2 controls, matched for age and area of residence, were selected from the community. 26 cases (2 -6%) and 30 controls (15%) had been immunised with DTP vaccine within 7 days before admission (or the date on which controls were the same age). This gives a relative risk of I -99 (p<0 05). For 7 days or less before onset the corresponding figures were 3-5% and 1-7% (RR= 2 · 4; p<0-001). For 72 hours the relative risks were 3 -0 and 2 - 6, respectively, both significant. This study, with which nearly every paediatrics, infectious diseases, and neurosurgery consultant in England, Scotland, and Wales cooperated, showed that: "Of the 35 DTP vaccine-associated cases 32 were regarded as neurologically normal before their illness and 21 of these recovered completely. There were only nine cases (3 with minor defects and 6 with major defects) in which no alternative explanation for their condition was found. The estimated attributable risk was 1 in 110 000 immunisations for previously normal children irrespective of eventual clinical outcome and 1 in 310 000 for those with evidence of subsequent two
questions-Does pertussis
neurological damage." It is concluded that: "(a) Most cases of acute and potentially damaging neurological illness in early childhood are attributable to causes other than immunisation. (b) Such illnesses occur more frequently within 7 days, and particularly within 72 hours, after DTP vaccine and within 7 to 14 days after measles vaccine than would be expected by chance. Most affected children made a complete recovery. (c) Taking account of possible alternative explanations of the clinical findings in cases associated with DTP and of the fact that similar cases occur after DT vaccine, it seems likely that permanent damage as a result of pertussis immunisation is a very rare event and attribution of a cause in individual cases is precarious."
PARENTAL ACCOUNTS OF ADVERSE REACTIONS OTHER STUDIES
The Meade panel handled material notified to the CSM largely by the Association of Parents of Vaccine Damaged Children, and they concentrated on 229 cases from 1970-74. Like the Dudgeon team they note the high frequency of contraindications, 48% (110 cases) Department of Health and Social Security. Reports from the
Committee
on
Safety of
Medicines and the Joint Committee on Vaccination and Immunisation. London: H M. Stationery Office. 1981 Pp. !84..E6.90.
A frustrating omission is the Public Health Laboratory Service’s surveillance study of vaccine reactions in the North West Thames region. This study began over six years ago, before the NCES. The Meade panel would clearly have found the PHLS data helpful. However, "In spite of repeated requests, no up-to-date results were made available to the Panel, nor was permission given to quote some preliminary findings which were provided." Some useful data may
1114 also come from a cohort study, of 13 000 children born in 1970, set up, for another purpose, by Prof. N. R. Butler (University of
Bristol). VERDICT OF THE COMMITTEE ON SAFETY OF MEDICINES
that their conclusions related to the period CSM concludes: the 1970-74, "No scientifically unassailable link has been established between DTP immunisation and serious neurological illness but we have come to the conclusion on the basis of all the present evidence that there is a prima facie case that such a link may exist. We would also agree that the evidence suggests that the vaccine causes convulsions in some children ... After careful consideration of the data we believe it would be unwise to accept the figures [provided by the Meade panel] as estimates of the incidence of brain damage without further evidence". Both advisory panels had noted that in some cases immunisations had been given in the presence of contraindications."... we recommend that the Health Departments should detail and publicise further the contra-indications associated with immunisation and consider making available to the medical and nursing professions and to the parents more information on the benefits and risks involved."
Stressing
.
STATEMENT BY THE JOINT COMMITTEE ON
VACCINATION AND IMMUNISATION
The JCVI estimates from the NCES that the risk of brain damage following whooping cough vaccination could be about 1 in 310000 injections. For a child given a full course the risk might be 1 in 100 000. "Studies during the whooping cough epidemic of 1977-79 when 102 500 cases were notified and 27 children died confirm that the vaccine protects children against this prolonged and exhausting illness which often requires treatment in hospital and may itself cause severe respiratory disease and brain damage." On this committee falls the onus of risk/benefit calculations. The Joint Committee on Vaccination and Immunisation have considered all the points and have "confirmed their advice published in 1974 and 1977 recommending the use of whooping cough vaccine as part of the basic course of immunisation in childhood." The book reminds readers of the contraindications to pertussis vaccine, which are:
"History of seizures, convulsions, or cerebral irritation in the neonatal period. History or family history of epilepsy or other diseases of the central nervous system. Children with developmental neurological defects. Any febrile illness, particularly respiratory, until the patient has fully recovered. Any severe local or general reaction to a preceding dose. A personal or family history of allergy has in the past been regarded as a contraindication to vaccination but there is now a substantial body of medical opinion which no longer considers this to be so. Nevertheless doctors should use their own discretion in the individual case." GOVERNMENT RESPONSE
,
The Government has accepted the advice of the JCVI, and letter, enclosing the comments of the JCVI and the CSM, has gone to all general practitioners and others. The Minister for Health, Dr Gerard Vaughan, has said: "The reports are quite clear that the advantages in terms of protection for most children outweigh the risks". On May 12 he announced that a campaign to encourage uptake of vaccination would begin later this year. Dr Vaughan has also asked for a progress a
report
on
research into
a more
effective vaccine.
Medicine and the Law Revoking of Product Licence: Appeal Fails THE licensing authority established under the Medicines Act 1968 proposed to revoke product licences issued to the applicants in respect of the manufacture of two fixed combination drugs, ’Motival’ and ’Motipress’, which were designed to treat combined states of anxiety and depression. In accordance with the provisions of section 29 and paragraph 2 of schedule 2 to the Medicines Act 1968, the licensing authority consulted the committee on the review of medicines, who, having reason to think that it might have to advise the licensing authority to revoke the licences on the grounds that the drugs could no longer be regarded as safe and efficacious within the meaning of section 28(3)(g), notified the applicants of that fact by a letter dated July 2, 1979, giving five reasons for Its provisional view. The applicants availed themselves of the opportunity of making written and oral representations to the committee dealing with each of the five reasons. Notwithstanding the representations, the committee advised the licensing authority to revoke the licences. They informed the applicants of their decision by a letter dated May 12,1980, which repeated the grounds and reasons set out in the previous letter.The applicants applied for judicial review to quash the committee’s advice on the following grounds: (i) that they were given no opportunity to deal with matters adverse to them which had been insufficiently set out in the letter of July 2 and at the hearing of the oral representations; (ii) that their representations had received inadequate consideration; and (iii) that the committee’s reasons for its advice were insufficient. Mr Justice WEBSTER said that with regard to the first ground, paragraph 2 of schedule 2 to the Medicines Act 1968 required no more than that the committee should notify a licence holder that it might have to advise the licensing authority that a product licence ought to be suspended, varied, or revoked on one or more of the grounds mentioned in paragraph 1 of the schedule; and the grounds relied upon should be particularised, as, for example, in the present case, by reference to, or recitation of, the provisions of section 28(3)(g). The appropriate rules of natural justice required that the hearing of the oral representations should be conducted fairly in all the circumstances. But the general requirements of fairness were likely to fall at the very lowest end of the scale in terms of the degree of formality or particularisation required. It was, however, an essential element of fairness that the applicants should have a reasonable opportunity of presenting their case. It was not necessary that every matter adverse to the applicants which might affect the committee’s decision should be put to them before or during the hearing; but it was necessary that they should be made aware of the substance of the case which they were likely to have to meet. That requirement would rarely be satisfied by a mere recital of, or reference to, the grounds specified in section 28(3), unless the circumstances were such that the licence holder could be taken to know the substance of the case from that recital or reference. The letter of July 2 gave sufficient notice to the applicants of the general nature of the case they had to meet to enable them to present their case, and, in the circumstances, there was no failure by the committee to put the substance of the case to the applicants, and the first ground therefore failed. In respect of the second ground, the applicants were entitled to have their written and oral representations properly considered. As a matter of procedure the representations were considered by the committee. But the applicants contended that it could be inferred that the representations had not been considered to a significant or material extent because the committee had a closed mind, or that it misunderstood the facts or the representations. The court refused to draw the inference that because the reasons given in the two notifying letters were precisely the same, the committee had such a closed mind that it was not open to persuasion by the applicants’ representations; all that might be inferred was that it was not in fact persuaded by them. In the circumstances, the court was unable to draw the conclusion that the findings of the committee showed that
though, unlike Dudgeon, they included a personal or family history of neurological disorder (50), obstetric or perinatal problems (18), and febrile illness (12). The data were "very unsatisfactory for epidemiological purposes". All the same, "The epidemiological evidence as a whole leaves little doubt that pertussis vaccine is associated with an increased incidence of convulsions. The longer-term implication of in their series
Public Health Further Contributions to the Pertussis
Vaccine Debate WITHIN the lifetimes of most doctors now in practice the annual death toll of whooping cough in the U.K. was to be measured in hundreds. As late as 1947 the total was 1225. A decade later the pattern was very different. All the same pertussis vaccination as a national policy has not been a complete success. First, there were the problems with Bordetella pertussis serotypes, countered by altered vaccine formulations. Then there was the difficulty of interpreting changes in notification and case fatality rates against a background of spectacular reductions in the pre-vaccine era. As Prof. D. L. Miller and his team point out in a study published earlier this week: "The immunisation programme against
pertussis
has
certainly
had
a
less
convincing impact
on
the
disease than those against diphtheria and poliomyelitis, which have been virtually eliminated from the country". In thel970s the pertussis vaccine debate has been focused more on the safety issue, and the account by Professor Miller and colleagues of the National Childhood Encephalopathy Study (NCES) is the largest of six contributions issued in an unusual collation by the Department of Health and Social Security.’ In their policy on pertussis vaccination the Health Department are advised by the Joint Committee on Vaccination and Immunisation (JCVI) and by the Committee on Safety of Medicines (CSM). The CSM established two panels to examine adverse reactions to whooping cough vaccine. These were chaired by Prof. J. A. Dudgeon (Institute of Child Health) and by Dr T. W. Meade (MRC Epidemiology and Medical Care Unit, Northwick Park). The book also contains a report on the whooping cough epidemic of 1977-79 and commentaries by the CSM and the JCVI. ADVISORY PANEL ON SERIOUS REACTIONS TO VACCINES
The Dudgeon panel reported in June, 1978, the account being revised last December. They looked at 50 well documented cases of purported serious adverse reactions to pertussis antigen containing vaccines. 34 cases were thought to be possibly related to immunisation-13 of chronic epilepsy, 13 of acute encephalopathy, and 8 of infantile spasms (West’s syndrome). On 7 occasions (21%) injections were contraindicated because of reactions to an earlier dose. The verdict is tentative: "In the children with chronic epilepsy and, to a lesser extent, with acute encephalopathy, the timing of the reactions in relation to immunisation was such that an association seemed possible, but the strength of the evidence varied from case to case and was more convincing in some than in others. In the children with chronic epilepsy, for example, convulsions occurring shortly after each of 2 or 3 injections were particularly suggestive of a causal relationship." In the infantile spasms group, evidence of an association with immunisation seemed weaker, there often being considerable delay between immunisation and the onset of the spasms at an age when infantile spasms unrelated to immunisation
are
likely.
these convulsions is not, however, clear. The APVDC/AR series provides no conclusive evidence of an association between pertussis vaccine and brain damage. On the other hand, the possibility of a causal association can by no means be excluded. The APVDC/AR series gave the Panel the very strong impression that DTP vaccine was often responsible for the neurological events which followed." Dr Meade and his colleagues calculate that "The frequency of brain damage apparently attributable to DTP in 1970-74 may have been about 1 in 53 000 previously healthy children".
NATIONAL CHILDHOOD ENCEPHALOPATHY STUDY
The NCES was
set
up in
1976, and its report attempts to answer
vaccine cause brain damage in children and, if it does, how often? The study team is not the only group among those contributing to the book to avoid the risk/benefit question. A case/control approach was preferred, on practical grounds, over a cohort study, and the report covers the first 1000 cases, in the three years ended June 30, 1979, a case being defined as acute neurological illness requiring hospital admission in a child aged 2-36 months. For each case 2 controls, matched for age and area of residence, were selected from the community. 26 cases (2 -6%) and 30 controls (15%) had been immunised with DTP vaccine within 7 days before admission (or the date on which controls were the same age). This gives a relative risk of I -99 (p<0 05). For 7 days or less before onset the corresponding figures were 3-5% and 1-7% (RR= 2 · 4; p<0-001). For 72 hours the relative risks were 3 -0 and 2 - 6, respectively, both significant. This study, with which nearly every paediatrics, infectious diseases, and neurosurgery consultant in England, Scotland, and Wales cooperated, showed that: "Of the 35 DTP vaccine-associated cases 32 were regarded as neurologically normal before their illness and 21 of these recovered completely. There were only nine cases (3 with minor defects and 6 with major defects) in which no alternative explanation for their condition was found. The estimated attributable risk was 1 in 110 000 immunisations for previously normal children irrespective of eventual clinical outcome and 1 in 310 000 for those with evidence of subsequent two
questions-Does pertussis
neurological damage." It is concluded that: "(a) Most cases of acute and potentially damaging neurological illness in early childhood are attributable to causes other than immunisation. (b) Such illnesses occur more frequently within 7 days, and particularly within 72 hours, after DTP vaccine and within 7 to 14 days after measles vaccine than would be expected by chance. Most affected children made a complete recovery. (c) Taking account of possible alternative explanations of the clinical findings in cases associated with DTP and of the fact that similar cases occur after DT vaccine, it seems likely that permanent damage as a result of pertussis immunisation is a very rare event and attribution of a cause in individual cases is precarious."
PARENTAL ACCOUNTS OF ADVERSE REACTIONS OTHER STUDIES
The Meade panel handled material notified to the CSM largely by the Association of Parents of Vaccine Damaged Children, and they concentrated on 229 cases from 1970-74. Like the Dudgeon team they note the high frequency of contraindications, 48% (110 cases) Department of Health and Social Security. Reports from the
Committee
on
Safety of
Medicines and the Joint Committee on Vaccination and Immunisation. London: H M. Stationery Office. 1981 Pp. !84..E6.90.
A frustrating omission is the Public Health Laboratory Service’s surveillance study of vaccine reactions in the North West Thames region. This study began over six years ago, before the NCES. The Meade panel would clearly have found the PHLS data helpful. However, "In spite of repeated requests, no up-to-date results were made available to the Panel, nor was permission given to quote some preliminary findings which were provided." Some useful data may
1114 also come from a cohort study, of 13 000 children born in 1970, set up, for another purpose, by Prof. N. R. Butler (University of
Bristol). VERDICT OF THE COMMITTEE ON SAFETY OF MEDICINES
that their conclusions related to the period CSM concludes: the 1970-74, "No scientifically unassailable link has been established between DTP immunisation and serious neurological illness but we have come to the conclusion on the basis of all the present evidence that there is a prima facie case that such a link may exist. We would also agree that the evidence suggests that the vaccine causes convulsions in some children ... After careful consideration of the data we believe it would be unwise to accept the figures [provided by the Meade panel] as estimates of the incidence of brain damage without further evidence". Both advisory panels had noted that in some cases immunisations had been given in the presence of contraindications."... we recommend that the Health Departments should detail and publicise further the contra-indications associated with immunisation and consider making available to the medical and nursing professions and to the parents more information on the benefits and risks involved."
Stressing
.
STATEMENT BY THE JOINT COMMITTEE ON
VACCINATION AND IMMUNISATION
The JCVI estimates from the NCES that the risk of brain damage following whooping cough vaccination could be about 1 in 310000 injections. For a child given a full course the risk might be 1 in 100 000. "Studies during the whooping cough epidemic of 1977-79 when 102 500 cases were notified and 27 children died confirm that the vaccine protects children against this prolonged and exhausting illness which often requires treatment in hospital and may itself cause severe respiratory disease and brain damage." On this committee falls the onus of risk/benefit calculations. The Joint Committee on Vaccination and Immunisation have considered all the points and have "confirmed their advice published in 1974 and 1977 recommending the use of whooping cough vaccine as part of the basic course of immunisation in childhood." The book reminds readers of the contraindications to pertussis vaccine, which are:
"History of seizures, convulsions, or cerebral irritation in the neonatal period. History or family history of epilepsy or other diseases of the central nervous system. Children with developmental neurological defects. Any febrile illness, particularly respiratory, until the patient has fully recovered. Any severe local or general reaction to a preceding dose. A personal or family history of allergy has in the past been regarded as a contraindication to vaccination but there is now a substantial body of medical opinion which no longer considers this to be so. Nevertheless doctors should use their own discretion in the individual case." GOVERNMENT RESPONSE
,
The Government has accepted the advice of the JCVI, and letter, enclosing the comments of the JCVI and the CSM, has gone to all general practitioners and others. The Minister for Health, Dr Gerard Vaughan, has said: "The reports are quite clear that the advantages in terms of protection for most children outweigh the risks". On May 12 he announced that a campaign to encourage uptake of vaccination would begin later this year. Dr Vaughan has also asked for a progress a
report
on
research into
a more
effective vaccine.
Medicine and the Law Revoking of Product Licence: Appeal Fails THE licensing authority established under the Medicines Act 1968 proposed to revoke product licences issued to the applicants in respect of the manufacture of two fixed combination drugs, ’Motival’ and ’Motipress’, which were designed to treat combined states of anxiety and depression. In accordance with the provisions of section 29 and paragraph 2 of schedule 2 to the Medicines Act 1968, the licensing authority consulted the committee on the review of medicines, who, having reason to think that it might have to advise the licensing authority to revoke the licences on the grounds that the drugs could no longer be regarded as safe and efficacious within the meaning of section 28(3)(g), notified the applicants of that fact by a letter dated July 2, 1979, giving five reasons for Its provisional view. The applicants availed themselves of the opportunity of making written and oral representations to the committee dealing with each of the five reasons. Notwithstanding the representations, the committee advised the licensing authority to revoke the licences. They informed the applicants of their decision by a letter dated May 12,1980, which repeated the grounds and reasons set out in the previous letter.The applicants applied for judicial review to quash the committee’s advice on the following grounds: (i) that they were given no opportunity to deal with matters adverse to them which had been insufficiently set out in the letter of July 2 and at the hearing of the oral representations; (ii) that their representations had received inadequate consideration; and (iii) that the committee’s reasons for its advice were insufficient. Mr Justice WEBSTER said that with regard to the first ground, paragraph 2 of schedule 2 to the Medicines Act 1968 required no more than that the committee should notify a licence holder that it might have to advise the licensing authority that a product licence ought to be suspended, varied, or revoked on one or more of the grounds mentioned in paragraph 1 of the schedule; and the grounds relied upon should be particularised, as, for example, in the present case, by reference to, or recitation of, the provisions of section 28(3)(g). The appropriate rules of natural justice required that the hearing of the oral representations should be conducted fairly in all the circumstances. But the general requirements of fairness were likely to fall at the very lowest end of the scale in terms of the degree of formality or particularisation required. It was, however, an essential element of fairness that the applicants should have a reasonable opportunity of presenting their case. It was not necessary that every matter adverse to the applicants which might affect the committee’s decision should be put to them before or during the hearing; but it was necessary that they should be made aware of the substance of the case which they were likely to have to meet. That requirement would rarely be satisfied by a mere recital of, or reference to, the grounds specified in section 28(3), unless the circumstances were such that the licence holder could be taken to know the substance of the case from that recital or reference. The letter of July 2 gave sufficient notice to the applicants of the general nature of the case they had to meet to enable them to present their case, and, in the circumstances, there was no failure by the committee to put the substance of the case to the applicants, and the first ground therefore failed. In respect of the second ground, the applicants were entitled to have their written and oral representations properly considered. As a matter of procedure the representations were considered by the committee. But the applicants contended that it could be inferred that the representations had not been considered to a significant or material extent because the committee had a closed mind, or that it misunderstood the facts or the representations. The court refused to draw the inference that because the reasons given in the two notifying letters were precisely the same, the committee had such a closed mind that it was not open to persuasion by the applicants’ representations; all that might be inferred was that it was not in fact persuaded by them. In the circumstances, the court was unable to draw the conclusion that the findings of the committee showed that