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THIMEROSAL-CONTAINING VACCINES
23
policy, there are clear limits on this element of the charge. For example, it would
exceed the committee's authority to recommend a change in the licensure, sched-
uling, or administration of a vaccine. If the committee concluded that the scientific
evidence or other important factors justified such action, it could recommend con-
vening the appropriate advisory groupies) to examine the question.
THE STUDY PROCESS
The committee held an initial organizational meeting in January 2001. CDC
and NIH presented the committee's charge at the meeting, and the committee
conducted a general review of immunization safety concerns and determined its
methodology for assessing causality. This approach would be used for the hy-
potheses to be considered at subsequent meetings. A web site (www.iom.edu/
imsafety) and a listserv were created to facilitate communication with the com-
mittee and provide the public access to information about its work. The commit-
tee's first report, Immunization Safety Review: Measles-Mumps-Rubella Vaccine
and Autism (IOM, 2001), is summarized in Appendix A.
To evaluate the hypothesis on thimerosal-containing vaccines and neurode-
velopmental disorders, the committee collected information from several sources.
An extensive review was performed of the published, peer-reviewed scientific
and medical literature pertinent to the hypothesis. A request was also sent through
the project's listserv for information regarding specific adverse outcomes that
may be related to thimerosal exposure and the biological mechanisms that may
explain their hypothesized relationship, the committee reviewed the resulting
submissions. In addition, a scientist was commissioned to prepare written an-
swers to questions from the committee regarding the toxicity of ethylmercury
(Magos, 2001a). This document was made available on the project's website for
public review, and critiques of the answers were reviewed during the committee's
deliberations. (The committee emphasizes that the commissioned material does
not represent the views of the committee, only those of the author.)
At an open scientific meeting in July 2001 (see Appendix B), academic and
independent researchers, scientists from federal agencies, and representatives of
child-health and vaccine-safety advocacy groups gave presentations and offered
comments. The formal presentations reviewed the knowledge regarding thimero-
sal-containing vaccines and the toxicology of ethyl- and methylmercury. Unpub-
lished data shared with the committee through presentations and personal com-
munications helped inform the committee's conclusions and recommendations.
THE FRAMEWORK FOR ASSESSING CAUSALITY
The Immunization Safety Review Committee has adopted the framework
for assessing causality developed by the committees previously convened by the
IOM (1991a, 1994a) to address questions of vaccine safety. Assessments begin
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IMMUNIZATION SAFETY RE VIE W
from a position of neutrality regarding the specific vaccine safety hypothesis
under review. That is, there is no presumption that a specific vaccine (or vaccine
component) does or does not cause the adverse event in question. The weight of
the available evidence determines whether it is possible to shift that neutral po-
sition toward causality ("the evidence favors acceptance of a causal relation-
ship") or away from causality ("the evidence favors rejection of a causal rela-
tionship"~. The committee does not conclude that the evidence favors rejecting
causality merely if the evidence toward causality is inadequate. Table 1 de-
scribes the five categories that summarize the direction and strength of the evi-
dence for causality. The table shows the differences in the wording of the cau-
sality categories in the 1991 and 1994 IOM vaccine safety reports. The wording
was revised in the 1994 report because the IOM had found that some people
misinterpreted the 1991 language. The types and strength of evidence required
to determine a specific level of causal association were the same for the two
reports. The Immunization Safety Review Committee is using the wording
adopted in 1994.
The sources of evidence considered by the committee in its plausibility as-
sessment include epidemiological studies, reports of individual cases or series of
cases, and studies related to biological plausibility. Epidemiological studies
carry the most weight in a causality assessment, these studies measure health-
related exposures or outcomes in a defined sample of subjects and make infer-
ences about the values of those exposures or outcomes, or the associations
among them, in the population from which the study sample was drawn. Epide-
miological studies can be categorized as observational (survey) or experimental
(clinical trial), and as uncontrolled (descriptive) or controlled (analytic). Among
these various study designs, experimental studies generally have the advantage
of random assignment to exposures and therefore carry the most weight in as-
sessing causality. Uncontrolled observational studies are important but are gen-
erally considered less definitive than controlled studies.
Case reports and case series are reviewed, although they are generally in-
adequate by themselves to establish causality. Despite the limitations of case
reports, the causality argument for at least one adverse event (the relationship
between vaccines containing tetanus toxoid and Guillain-Barre syndrome) was
strengthened most by a single, well-documented case report on recurrence of the
adverse event following re-administration of the vaccine, a situation referred to
as a"rechallenge" (IOM, 1994a).
Evidence regarding biological plausibility is also reviewed. Biological plau-
sibility exists on a spectrum, ranging from not plausible to established. The
committee has not developed a formal rating system for biological plausibility,
because an agreed upon hierarchy of evidence required for assessments of bio-
logical plausibility does not exist, nor does an associated terminology (Weed
and Hursting, 1998~. Individual researchers and organizations discuss this con-
cept differently. It is generally agreed, however, that biological plausibility is a
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THIMEROSAL-CONTAINING VACCINES
25
domain of intellectual and research inquiry, requires less stringent standards
than proof-of-principle for exploring ideas and possible connections, is usually
in itself insufficient to warrant huge investments in research and development,
and is clearly insufficient to describe inferences of causality. While evidence
regarding biological plausibility can never prove causality, it can be used to
support other kinds of evidence and is useful for generating hypotheses, which
might be addressed by additional research. Proof-of-principle in biomedical re-
search is a more stringent standard by which a biological relationship is judged
sufficiently strong to conclude with certainty that agent A (protein, cell, drug, or
the like) can lead to result B (biochemical reaction, cell function, symptom re-
lief, or the like). Such conclusions may serve as the foundation upon which sub-
sequent research seeking to test causality is based. Conclusions about causality
have been discussed in other sections of the report and require evidence from
human studies. This evidence is, with only rare exceptions, a body of consistent
and well-controlled epidemiological research.
Published reports that have been subjected to a rigorous peer review process
carry the most weight in the committee's assessment. Unpublished data and
other reports that have not undergone peer review have value, and they are often
considered by the committee, they could be used, for example, in support of a
body of published literature with similar findings. If the committee concluded
that the unpublished data were well described, had been obtained using sound
methodology, and presented very clear results, the committee could report, with
sufficient caveats in the discussion, how those data fit with the entire body of
published literature. But only in extraordinary circumstances could an unpub-
lished study refute a body of published literature. In general, the committee can-
not rely heavily on unpublished data in making its plausibility assessment be-
cause they have not been subjected to a rigorous peer review process, and
therefore must be interpreted with caution.
The committee acknowledges that its approach differs from the state of the
art for evidence-based reviews of clinical practices in medicine, which does not
include consideration of unpublished or non-peer-reviewed information (U.S.
Preventive Services Task Force, 1996~. However, the Immunization Safety Re-
view Committee was convened specifically to assess topics that are usually of
immediate and intense concern. In some cases, the committee's review will take
place when data are only beginning to emerge. Thus, given the unique nature of
this project, the committee thought it was important to review and consider un-
published information. The committee did not perform primary or secondary
analyses of unpublished data, however. In reviewing unpublished material, the
committee applied generally accepted standards for assessing the quality of sci-
entific evidence, as described above. (All unpublished data reviewed by the
committee and cited in this report are available in the form reviewed by the
committee through the public access files of the National Academies, 202-334-
3543, www.national-academies.org/publicaccess.)
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IMMUNIZATION SAFETY RE VIE W
TABLE 1 Summary Categories and Levels of Evidence Regarding
Causality
Category IOM, l 991 a IOM, 1 994a
No evidence No evidence
bearing on a bearing on a
causal relation causal relation
Evidence The evidence is
insufficient to inadequate to
indicate a accept or reject a
causal relation causal relation
Level of Evidence
3
No case reports or
epidemiological studies
identified.
One or more case reports
or epidemiological studies
were located, but the evi-
dence for the causal rela-
tion neither outweighs nor
is outweighed by the evi-
dence against a causal
relation.
Evidence does The evidence
not indicate a favors rejection
causal relation of a causal
relation
Only evidence from epi-
demiological studies can
be used as a basis for pos-
sible rejection of a causal
relation. Requires a rigor-
ously performed epidemi-
ological study (or meta-
analysis) of adequate size
that did not detect a sig-
nificant association be-
tween the vaccine and the
adverse event.
Evidence is The evidence The balance of evidence
consistent favors acceptance from one or more case
with a causal of a causal reports or epidemiological
relation relation studies provides evidence
for a causal relation that
outweighs the evidence
against such a relation.
Evidence The evidence
indicates a establishes a
causal relation causal relation
Epidemiological studies
and/or case reports provide
unequivocal evidence for a
causal relation.
Representative terms from entire chapter:
biological plausibility
