Call for Public Comment on Paper: Study Designs for the Safety Evaluation of Different
Childhood Immunization Schedules.
By Martin Kulldorff, Ph.D.
IOM Committee on Assessment of Studies of Health Outcomes Related to the
Recommended Childhood Immunization Schedule.
The Center for Vaccine Ethics and Policy (CVEP) is pleased to comment on the paper above.
1. Scope of Paper and IOM Committee Charter
We note from the IOM Committee website the activity description below
[http://www.iom.edu/Activities/PublicHealth/ChildhoodImmunization.aspx accessed 31 July 2012]
Activity Description
The IOM will conduct an independent assessment surrounding the feasibility of studying health
outcomes in children who were vaccinated according to the CDC recommended schedule and
those who were not (e.g. children who were unvaccinated or vaccinated with an alternate
schedule). The IOM will review scientific findings and stakeholder concerns related to the safety of
the recommended childhood immunization schedule. Further, the IOM will identify potential
research approaches, methodologies, and study designs that could inform this question, including
an assessment of the potential strengths and limitations of each approach, methodology and
design, as well as the financial and ethical feasibility of doing them. A report will be issued in mid2012 summarizing the IOM's findings and conclusions.
We find the specific focus of the Kulldorf paper on the study of adverse events to be very important, but
are concerned that it is not complemented by other papers which address questions of efficacy and
effectiveness, and which address the design of research involving children with an intervention of known
and proven safety and efficacy.
Specifically, on p.32, Kulldorf is seemingly dismissive of the need to consider such studies noting that “…If
a study (on adverse events) does not find an excess risk, (and) there is no need to worry about vaccine
efficacy…”
CVEP believes that perceptions about vaccine safety (particularly adverse events) are a key driver in
parental decisions about whether to follow the CDC recommended childhood immunization schedule,
vaccinate under an alternative schedule, or simple not to vaccinate. These perceptions are ideally based
on scientific evidence, but, unfortunately, not always.
But we assert that safety is not the sole driver of such schedule decisions. CVEP is concerned that “vaccine
hesitant parents” are also concerned about the effectiveness and efficacy of immunizations under the
recommended schedule – both regarding specific vaccines, and the schedule overall in terms of timing
and number of immunizations.
Therefore, because any study with more than minimal risk involving children is not viewed as acceptable
by current regulations or prevailing ethical standards, the efficacy of vaccines must play a key role in
research design, albeit in conjunction with safety and adverse events overall.
The Center for Vaccines Ethics and Policy is a joint program of the NYU Medical School Division of Medical Ethics,
the Wistar Institute Vaccine Center, the Vaccine Education Center of the Children’s Hospital of Philadelphia.
www.centerforvaccineethicsandpolicy.org
1
This section of the paper concludes “…While outside the scope of this paper, all these factors must be
considered in a joint cost-benefit analysis before revising the recommended vaccine schedule if and when
there is a finding of a vaccine schedule-dependent adverse event.”
We urge the IOM Committee to consider this broader context in moving forward with its work.
2. Ethical Considers
We observe that the paper treats ethical considerations on pp.35-36 in a somewhat cursory fashion.
While CVEP agrees that a key ethical issue in observational studies, data mining and other similar research
designs is patient confidentiality, we believe there are other important ethical considerations that need to
be explicitly addressed. These include the consent of those whose data may be used and the privacy
protections that may limit or prohibit such use in specific situations, which are not uniform across the
research strategies discussed.
The discussion around ethical issues in randomized trials, or other designs which may vary the timing,
number, or other aspects of immunizations for children involved, merits more discussion in terms of levels
of acceptable risk where children are involved.
In particular, the nature of the informed consent that will be obtained on behalf of study subjects requires
more detailed consideration. Randomization may be ethical when a study is done in the context of
equipoise. That is hardly true of the existing proven vaccine schedule. To study variations of that
schedule or to randomize is to subject children to very real risk. Any study will require both careful
informed consent strategy, and perhaps even quizzing of parents to insure comprehension. Also, some
attention to the nature of the risks of a non-standard schedule, compensation for illness or injury related
to any study, and some determination of a DSMB mediated end point that would bring the study to a halt
should more illness be seen in one arm or another of a trial.
We are also concerned about the discussion around herd immunity and randomized trials on p.35 and are
startled by the discussion concluding with:
“…If vaccination in one arm is delayed for a much longer time period, or not given at all, it may
reduce herd immunity. This may put children that are not participating in the study at increased
risk for the disease, and this can be especially serious for immunologically compromised children
for whom a vaccination is contraindicated. To minimize the negative effect on herd immunity,
such randomized trials should be spread out geographically, so that there are at most a few
additional unvaccinated children in any given location. In that way, non-participating children will
not be at an increased risk of the disease, and equally important, those children randomized to
the delayed vaccination will still have some protection against the disease from herd immunity.”
We believe that a more robust analysis of the ethical issues associated with exposing third parties -including infants, the immune deficient, the elderly and other high risk groups – to persons on nonstandard vaccine schedules. There may be real and significant liability issues. There also may be a need
to obtain consent from the community or group where any such study is being done as is done in
emergency research.
The Center for Vaccines Ethics and Policy is a joint program of the NYU Medical School Division of Medical Ethics,
the Wistar Institute Vaccine Center, the Vaccine Education Center of the Children’s Hospital of Philadelphia.
www.centerforvaccineethicsandpolicy.org
2
Summary
Understanding the impact of non-standard immunization schedules on children and third parties is an
important research question. Undertaking a randomized trial to answer such a question raises ethical
challenges that may well prove prohibitive given the state of knowledge about vaccination.
Corresponding author of this comment:
David R. Curry, MS
Executive Director
Center for Vaccine Ethics and Policy
david.r.curry@centerforvaccineethicsandpolicy.org
267.251.2305
Arthur L. Caplan, Ph.D.
Drs. William F and Virginia Connolly Mitty Chair
Head, Division of Medical Ethics
NYU Langone Medical Center
Arthur.Caplan@nyumc.org
Robert I. Field, JD, MPH, PhD
Professor of Law
Earle Mack School of Law at Drexel University
Professor of Health Management and Policy
Drexel University School of Public Health
rif24@drexel.edu
The Center for Vaccines Ethics and Policy is a joint program of the NYU Medical School Division of Medical Ethics,
the Wistar Institute Vaccine Center, the Vaccine Education Center of the Children’s Hospital of Philadelphia.
www.centerforvaccineethicsandpolicy.org
3