2. New Round of MMR - Vaccine Media Reports/ Spitzer

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2. New Round of MMR - Vaccine Media Reports/ Spitzer

Continued from previous post

Patja, Peltola and others.

A front page story in The Times of London alleging that Patja

“cleared” MMR as a determinant of AuS was prototypical of

misinterpretations of epidemiological studies and particularly of the

Finnish Project to the public. There have been many reports in all the lay

media suggesting similar conclusions. Manufacturers and the government have

taken the same line. Curiously the government did not issue any formal

statement in relation to the Finnish study, but they did issue a statement

on 12 January, 2001 (from the Medicines Control Agency). Its conclusion is:

“MMR remains the safest way to protect our children.”

A Finnish report evaluates serious adverse events after MMR

vaccination during a prospective follow-up of 14 years (The Ped Inf Dis J ,

2000, 19; 12:1127-34). 1.8 million individuals received nearly 3 million

doses of MMR between 1982 and 1996. 173 potential serious adverse effects

were evaluated. These adverse effects had been reported by a passive

surveillance system Another original paper from Finland, by Kielinen and

others, appearing shortly before (Eur Child & Adolesc Psych, 2000, 9:

162-67) is relevant. The Patja-Peltola Finnish project may have been big but

it cannot rule in or rule out risks of autism nor any other major disease.

It is important to stress that the Finnish project was passive surveillance

in which underreporting is in general serious, typically 80% to 90%, seldom

lower than 50%. One misses 50% to 80 & of actual cases. Passive surveillance,

pioneered by the British Yellow Card system and emulated world-wide, was

designed to raise warning flags on safety. The system was never intended to

be used the other way round, to confirm safety. Warnings from passive

surveys are generally followed by hypothesis-testing and controlled

epidemiological studies such as case control or cohort analytic designs. In

the Finnish project I find no evidence that the study was set up to be

sensitive to AuS, nor that the surveyors or the reporters of events looked

for autism events at any time.

With the Kielinen findings it is easy to demonstrate pronounced

underreporting in Patja-Peltola. The cumulative incidence (analogous to

prevalence) of autistic syndromes in Northern Finland is 13.9 (CI95

12.0-15.7) per 10,000. Conservatively taking the lower boundary of the

confidence interval (12.0 per 105), even if there had been no vaccination

among the 1.8 million individuals and even if there were no association

between MMR and autism, there should have been at least 216 cases of autism

in the 1.8 million individuals surveyed. If one had focused on classic

autism alone the number would be 79. If the study were capable of detecting

autism, it is inconceivable that at least a handful of events of autism

should not emerge in the Finnish survey. Curiously the word ‘autism’ never

appears in the abstract of the paper, or in the methods section and is only

mentioned once, briefly, in the discussion of the paper. Conversely the

mnemonic MMR never appears in the Kielinen article.

A large-scale study as was done in Finland is not automatically well

designed or adequately reported because of its size. Firstly, there were no

controls, and this was accepted as a limitation by the authors. Yet there

was no discussion about the shortcomings of such uncontrolled surveys.

Secondly, there is no indication in the report about the length of follow-up

per individual. Fourteen years was the length of the project yet; the range

and the median of follow-up per child are crucial in interpreting the

findings. Thirdly, there is no information given in the paper about the

nature or content of the briefings to health care personnel before the study

started, in relation to the types of reactions and the inclusion of autism

as a reportable side effect.

Such briefings affect subsequent reporting of adverse events

especially since those reporting an adverse event usually make subjective

decisions. It was noted that review of clinical reactions reported after MMR

were made with reference to the medical notes and also to the known

incubation times of the diseases measles, mumps and rubella, to decide if

they could be causally related to the administration of the MMR vaccine.

This may explain why AuS events were not reported here at all. In such a

large study, we would expect many more diseases and symptoms to be observed

within one month of MMR vaccination, by chance alone. Passive reporting,

where the event reporter must decide if an event is linked with vaccination,

is unlikely to detect rare, delayed or novel adverse events.

Fourthly, it is even less likely that delayed events would be linked

with vaccination. Autistic syndromes (AuS) have an insidious onset with

significant diagnostic delay. The early symptoms and signs with a closer

temporal relationship to vaccination, may be poorly defined and similar to

those exhibited by those who were excluded from follow-up in this paper. In

AuS, mood and behavioral change may be the first sign, i.e. the ‘zero time’

for the natural history of an AuS. Clear-cut deterioration or failure to

develop usually may not manifest until many months later. Would vague early

observations be reported in the Finnish project? Lastly, the ages at

vaccination varied from 14 months to adulthood, with members of the Defense

Forces, health care personnel and older children also receiving the

vaccination. However, there is no breakdown of numbers vaccinated and side

effects reported into categories of age. Given that autism among subgroups

appears to be the result of damage occurring during a specific, limited

“window of vulnerability”, it would have been helpful to have a precise

figure for the numbers of children who actually could have been at risk. Any

assertion that the Patja-Peltola paper “clears” MMR is unfounded. The

Finnish Project cannot rule out and cannot rule in MMR as a risk factor for

AuS.

and others.

Commissioned by the Medicines’ Control Agency in the U.K., this study

has probably been the most cited article to substantiate safety of MMR until

now. [ B, E, Farrington CP, Petropoulos MC, Favot-Mayou I, Li

J, & Waight PA, 1999, MMR vaccine and autism: no epidemiological evidence

for a causal association. Lancet; 353: 2026-2029]. Its publication is an

earlier one, but a comment on the current situation would not be complete

without a critical note about the North Thames project. studied

medical records of 498 prevalent cases of autistic syndrome disorders (AuS)

in eight health districts. The study reported the number of patients by year

of birth (1982-1996) seeking to identify a temporal trend. The study and its

report are seriously, if not fatally flawed, for these reasons, among

others:

· Complete ascertainment of all cases of AuS in the eight districts

uncertain.

· The authors make statements about an increasing incidence of AuS

over time from a prevalent group.

· Imprecise categorization of ‘zero time’ for the cases.

· Inadequate classification of the various diagnoses within the AuS

spectrum, notably unreliable categorization of regressive manifestations.

· Failure to correct for ‘catchup components’ of the immunization

campaign.

· An incorrect analytic method was used. The case series method used

by (similar to the case crossover method) applies primarily to acute

events and transient exposures for diseases with a well defined natural

history. (Regressive autism, for instance, has anything but such a natural

history.) One does not expect AuS to develop acutely or immediately after an

exposure to MMR; the onset of autism is typically insidious, highly variable

and may occur even years after immunization.

· Failure to discriminate between types of MMR vaccine (Pluserix,

Immravax and MMR-II) may have masked a step-up in cases in 1988 due to

diagnostic overshadowing. Pluserix and Immravax were both withdrawn due to

problems with the Urabe mumps component leading to higher rate of aseptic

meningitis.

Paradoxically, the paper, which is incorrectly interpreted as

demonstrating safety, provides much better evidence in the opposite

direction consistent with MMR associated with some AuS categories. Moreover,

an uncontrolled study is uninterpretable as the basis to demonstrate a link

between MMR and AuS or to dismiss it aside unless the findings were dramatic

and very clear.

To summarize views on an epidemic of AuS, on prevalence, which appears

to be rising, on incidence and what it all means: Fombonne and Kaye come to

differing conclusions. Kaye was the only one to publish age-adjusted

incidence. No one has tracked subsets of the spectrum of autistic disorders

allowing the ‘lumped’ data to mask potentially important profiles in

relevant subsets of autistic children. Although all we can say with

certainty is that autism (combined groups) appear to have become more common

since the introduction of MMR, any reasoning concluding that the increases

in frequency are probably real is more persuasive to me at this point than

arguments that seek to explain away reported steep rises in cumulative

incidence. Four-fold, seven-fold and ten-fold rises in prevalence are

remarkable.

A war of words should not continue. It would be a major disservice to

society and especially to children and families affected by AuS if the

current struggles of scientific and regulatory warlords became the status

quo. There will never be any winners if such a “war” were limited to

clashes of opinions grounded on questionable assumptions, on statistically

underpowered projects, and on incorrectly designed studies with accompanying

misinterpretation of findings to the public. I have to be persuaded that

anyone is acting in bad faith. We are overdue for an alliance that will

confront unanswered questions about the role of MMR and other risk factors

in the aetiology of AuS. Answers will emerge quickly. I propose the

following research priorities for the next sixty months:

· Investigation in the laboratory and the clinic such as the work

conducted by Wakefield in London, O’Leary in Dublin and others should be

adequately supported. Replication should be done in the USA and Canada.

Scientists exploring hypotheses unpopular to the establishment should not be

forced to spend a great deal of their time as fundraisers. Laboratory

research and clinical investigation should have priority in the MMR-AuS

controversy; the ‘silver bullets’ that will resolve unknowns will most

likely emerge from there.

· Three to five carefully designed incidence studies of AuS should be

conducted in different countries or regions. The geographic areas must have

had different entry dates of MMR to their markets. Precise ascertainment of

incidence trends in areas where prevalence studies have already been done is

desirable.

· Two active surveillance projects patterned after Phase IV

simplified cohort studies. The studies should be compatible in definitions

and methods and, combined, should have high statistical power to avoid Type

II errors when seeking to establish safety. If at all possible they should

be controlled. They should be done urgently. Cost should not offer

impediments considering the hundreds of millions of MMR doses sold worldwide

If one based sample sizes on a model of two cohorts under comparison, given

the baseline population rate of AuS of 5 per 10,000 in the appropriate age

brackets, specifying a relative risk of 1.5 that should not be missed, an

alpha of 0.05 and power of 90% would require 450,000 persons per comparison

group. For the combined safety studies, the same order of magnitude would be

required, not less than 500,000 new subjects. Again, given the sales volume

of MMR worldwide, the profits and the relative ease in categorizing both

exposure and outcome, the numbers are not logistically or financially

insurmountable. If more than 500,000,000 doses have been sold to date,

active surveillance would involve less than 0.001% of exposed children. The

cost would be approximately that of the lifetime care of 200 autistic

children eligible for state support.

Two major case control studies, one based on a computerized database

and one with concurrent accrual of new cases.

The best way to remain in the dark about safety is not to look for it.

One way not to look is to underpower the studies but pretend to be looking

is to study very small samples. Some authors write that the rarity of the

outcome makes it difficult to derive statistically definitive findings.

Given the rarity of AuS, hundreds of thousands of children must be followed.

The reluctance of regulators to require rigorous safety studies and the

unwillingness of manufacturers to conduct them is noteworthy. Most

importantly, whether one conducts active surveillance safety projects or

case control studies, with a controlled design or without, the length of

follow up after immunization is critically important.

A follow -p of three to six weeks from MMR immunization to look for

the occurrence of AuS negates any opportunity to discover an association if

present. My colleagues and I at McGill University, in collaboration with

British clinical experts, are nearing conclusion of a study of the natural

history of 493 British patients with AuS who were also exposed to MMR. The

source of data for each child is the complete medical record, that is, the

depository of all GP notes, entries from community resources, and

specialists’ reports. (The records, each spanning several years, are

generally many inches thick.) Because adequate length of follow up is so

important in any active safety study, preliminary findings of our study are

given here. [spitzer WO, et al. The natural history of autistic syndromes

in British children exposed to MMR. In preparation.] Among 372 eligible

children (all criteria met, abstracting done, data clean, double-coding and

double-entry reconciled) the median delay from first exposure to MMR to the

earliest manifestations of AuS recorded by a professional clinician (zero

time) was 1.1 yearsb and the range was from 33 days to 7.2 years. The median

delay between MMR exposure and formal diagnosis was 2.6 years and the range

6 months to 11.8 years.

Only definitive safety studies of active surveillance with a

pre-determined sample size and with an adequate length of follow-up can give

evidence about the safety of a product. Thus, whilev understanding and

supporting Professor Fletcher’s opinion that granting a license may have

been premature for MMR, I would have preferred a conditional license until

valid safety studies were completed in the light of these concerns. Proper

drug safety studies cannot be implemented at all with uncommon or unexpected

adverse events until a new product is marketed.

Autism is such a serious outcome that at least one controlled

epidemiological study that explores aetiology should be done. In the 18

months I have been studying the MMR/AuS controversy I have also met many of

the affected children and their families. As a former clinician and as a

public health doctor I have been gradually convinced that the aggregate

manifestations of autism are an outcome at least as serious as death.

Despite the stoic, indeed heroic conviction of most parents, despite their

invincible optimism, autistic children act as dead spirits in ostensibly

healthy bodies (except for gastrointestinal complications) resulting in a

very long terminal condition. The families cannot mourn and come to closure

about the tragedy. Families of a child who actually died can. One wonders

what the position of the authorities might be if the possible adverse event

of a vaccine were postulated to be premature death? A controlled study is

clearly justified.

As this comment is released to the written record, a group of

epidemiologists and biostatisticians is in the early phases of protocol

formulation for The Intercontinental Case Control Study of MMR and Autistic

Syndromes. At the moment we anticipate the need of at least 3,000 new cases

of autism and 6,000 unaffected controls, in 13 centers from 9 candidate

countries across three continents. The full detailed protocol will be

published in the peer-reviewed press later in 2001 to allow international

constructive critique before going to the field in any country. Final

results should be published by the end of 2004.

I assert that I am a strong supporter of vaccination in general; it is

the most important pillar of effective primary prevention in the history of

public health.

We would not wish to replicate the Japanese experience with MMR. In

Japan, loss of public confidence in vaccination per se against mumps,

measles and rubella after the sudden withdrawal of their MMR vaccine which

had caused aseptic meningitis led to low uptake of vaccination against

measles and significant mortality in outbreaks of wild strain infection.

In prudence, I also believe that each new vaccine should be

scrutinized for safety in the post-marketing period, one by one. I continue

agnostic, but today the general burden of scientific evidence makes it

difficult to set aside an MMR/autism link. It is for those completely

convinced of MMR’s safety, especially those profiting from the hundreds of

millions of doses of MMR sold, to finance the research that could set aside

legitimate concerns. Sponsorship must be undertaken by an entity without

vested interests or publicized prior opinions. Many scientists who are

concerned about the unanswered questions are not crusaders, including

myself. I have no family members with autism. I am a consultant to affected

families in the UK, when asked, pro bono. I am very worried by autism as an

adverse event. I would be delighted to be proven wrong and to have my

concerns minimized or dispelled by the highest standard of laboratory

research, by well designed clinical studies, by valid safety projects and by

rigorous aetiologically oriented epidemiology. Until then, it is premature

to offer any assurance about the safety of the measles-mumps-rubella

vaccine.

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