Vaccine 25 (2007) 5671–5674
Editorial
The development of standardized case definitions and guidelines
for adverse events following immunization夽
1. A global collaboration for standardization of case
definitions and guidelines of adverse events following
immunization
Because safety cannot be measured directly, but can only
be inferred indirectly by the relative presence or absence
of multiple adverse events following immunization (AEFI),
the standardized understanding of AEFI through a common
“vocabulary” to allow for comparability of AEFI data is a
key element in the scientific assessment of AEFI. Medical
dictionaries for regulatory affairs [1–3] as well as case def-
initions [4] for adverse drug reactions have been developed
and implemented. There have also been a few pioneering
efforts by the World Health Organization, the U.S. Food and
Drug Administration (FDA), and other public health organi-
zations to develop case definitions for use in immunization
safety [5–7]. However, because only a few definitions have
been developed and they have not reached widespread use,
vaccine safety data from different studies and sources cannot
be compared [8–11].
The case definitions presented in this issue (and pre-
vious as well as following issues) of Vaccine are part of
a series of newly developed standardized case definitions
and guidelines for AEFI to fill these gaps. The guidelines
for data collection, analysis, and presentation additionally
enhance comparability of immunization safety data, as the
classification of an AEFI based on a case definition is nec-
essary but not sufficient to allow for comparability of data.
The case definitions and guidelines are being developed
by voluntary international scientific working groups under
the auspices of the Brighton Collaboration with the over-
sight of an elected steering committee, and with staff (the
“secretariat”) at the Centers for Disease Control and Pre-
vention (CDC), Atlanta, USA and the University Children’s
夽 Disclaimer: The findings and conclusions in this paper are those of the
authors and do not necessarily represent the views of the Centers for Disease
Control and Prevention or the Food and Drug Administration.
0264-410X/$ – see front matter. Published by Elsevier Ltd.
doi:10.1016/j.vaccine.2007.02.063
Hospital, Basel, Switzerland. The Brighton Collaboration
(http://www.brightoncollaboration.org) named after the city
where the idea for this global endeavor was first conceived
during an international vaccine meeting, has as its overall
goal enabling the standardized collection and assessment of
immunization safety data to improve comparability of data
across different data sources. The Brighton Collaboration
consists of various scientific stakeholders interested in immu-
nization safety (e.g., scientific, regulatory, academic, clinical
care, and vaccine-producing groups). All activities surround-
ing the development, evaluation, and implementation of these
immunization safety standards are conducted by the Brighton
Collaboration, and have previously been described within
their scientific framework in greater detail [8,9,12].
1.1. Intended uses of Brighton Collaboration case
definitions and guidelines
These standardized definitions and guidelines are intended
to serve as a tool to investigators of prelicensure and postli-
censure vaccine safety studies as an aid in the development
of study protocols and data collection forms, and to enable
standardized assessment and presentation of data collected
in clinical trials, epidemiologic studies, and in AEFI surveil-
lance systems both in resource-poor and resource-rich study
settings.
To allow for applicability in study settings with differing
resources and study questions, Brighton Collaboration case
definitions are classified according to diagnostic certainty
with which to categorize the clinical information of an AEFI
for standardization purposes, from the highest complexity
(Level 1) of needed information and certainty to the
lowest (Level 3). Methodological considerations regarding
the three-level format of our case definitions have been
discussed previously [8,12]. The different levels of certainty
specifically do not address possible causal relationships
between an immunization and an AEFI. In fact, it is recog-
nized by the Brighton Collaboration and should generally be
5672 Editorial / Vaccine 25 (2007) 5671–5674
emphasized that an adverse event that follows administration
of an inactivated component or live vaccine may be tem-
porally associated with, but is not necessarily the result of,
administration of a vaccine. The time post-immunization is,
therefore, typically not part of the case definition of an AEFI.
The guidelines for data collection, analysis, and presen-
tation of AEFI data are offered as a useful and practical
standardized data collection and assessment tool rather than
as guidelines for primary reporting of an AEFI to a surveil-
lance system or study monitor. Given that regulatory and
other public health or professional organizations already have
begun to endorse or use our case definitions and guide-
lines, it is important to emphasize that the guidelines are
not suggested as a requirement for data collection, analysis,
or presentation, but as a means to allow for data compa-
rability based on sound scientific evidence. Because the
guidelines were developed to complement the case defini-
tion, both need to be used in the collection and analysis
of immunization safety data. Depending on the study ques-
tion, additional information also may, of course, be collected,
analyzed, and presented as deemed necessary by the investi-
gators. Obviously, the implementation of all guidelines might
not be possible in all settings; for example, the availability of
information may vary depending upon resources, geographic
region, and whether the source of information is a prospective
clinical trial, a post-marketing surveillance or epidemiologic
study, or an individual report of an AEFI.
In general, the content of the guidelines is primarily
based on current clinical, regulatory, and literature-informed
understanding of a given AEFI, and routine aspects of collect-
ing, analyzing, and presenting vaccine safety data are taken
into consideration, e.g., information on the time to onset of
an AEFI post-immunization. The guidelines are separated
into three sections – data collection, analysis, and presen-
tation – to follow the chronologic sequence of conducting
a study. While specific guidelines are being developed for
each AEFI defined, all of them aim to be in accordance
with general drug safety guidelines from other international
organizations, i.e., the general International Conference on
Harmonization of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH) [13] guidelines and
the Council for International Organizations of Medical Sci-
ences (CIOMS) [14] form for reporting of drug adverse events
– as well as with existing general guidelines for presentation
and publication of randomized controlled trials, systematic
reviews, and meta-analyses – i.e., Consolidated Standards
of Reporting Trials (CONSORT), Improving the Quality of
Reports of Meta-analyses of Randomized Controlled Trials
(QUORUM), and Meta-analysis of Observational Studies in
Epidemiology (MOOSE), respectively [15–17].
Neither the case definitions nor the guidelines are intended
to be used for diagnosis in the clinical setting, or to define
management of ill children or adults, i.e., they are not
designed to replace medical text books or good clinical
judgment, which comes from a combination of medical
knowledge and experience, and is typically tailored to an
individual patient; this cannot be accomplished by any given
set of standardized criteria or guidelines. Further, clinicians
encountering patients with any potential AEFI should fol-
low their respective practice guidelines for diagnosis and
treatment.
1.2. Process for developing case definitions and
guidelines
The process for development of the Brighton Collabo-
ration case definitions and guidelines has been described
previously in greater detail [8,9], and the specific composition
of each working group, the reference group (see below), and
the steering committee can be reviewed on the Brighton Col-
laboration website (http://www.brightoncollaboration.org).
Briefly, the steering committee first prioritizes work on a case
definition of an AEFI based on its frequency, severity, and
public health importance. Then, subject matter experts are
solicited to volunteer to participate in a given working group
through announcements at scientific meetings, professional
websites or mailing lists, including the Brighton Collabora-
tion website and e-mail list, and referrals by other scientists.
Diverse scientific and geographic backgrounds are balanced.
Each working group assigns a team leader and a coordinator
(typically a member of the secretariat), who are responsi-
ble for the logistics, agenda and minutes of conference calls,
summarizing the literature, implementing and analyzing
web-based surveys asking for feedback on draft documents,
and drafting the case definition and guidelines. Using the
literature and their professional expertise on the topic, work-
ing groups usually hold bi-weekly or monthly teleconference
calls and participate in regular e-mail exchanges over the
course of 1–2 years to select and review the pertinent medi-
cal literature and decide on the criteria for case definition and
guidelines. The literature search is typically conducted by a
search professional, who also conducts systematic searches
for the Cochrane Collaboration (http://www.cochrane.org/
index0.htm). Additional information, such as definitions
developed for study protocols or text books possibly missed
by the literature search is sought through working group
members. Next, a larger group of scientists (“reference
group”) with backgrounds comparable to those of the
working group members is invited through similar distri-
bution mechanisms as well as by referral from working
group members to comment on the usefulness, applica-
bility, and scientific soundness of draft documents via
surveys posted for 1–3 months on the Brighton Collabo-
ration website. Comments received are addressed in detail
by the respective working group in additional conference
calls and e-mail discussions, and the survey results and
subsequent discussions are posted on the Brighton Col-
laboration website. Finally, the steering committee reviews
the documents, which then undergo routine clearance pro-
cesses in each of the organizations of the working group
members who author the publications. Recently, a newly
formed vaccine working group of CIOMS has taken on
 Editorial / Vaccine 25 (2007) 5671–5674
an additional review of already developed Brighton Col-
laboration case definitions and guidelines for possible
endorsement and to aid in further distribution as well as
translation into different languages (http://www.cioms.ch/
frame current programme.htm). Review of each definition
with its accompanying guidelines is planned on a regular
(i.e., every 3–5 years) basis, or more often if needed.
1.3. Overview of progress made in the Brighton
Collaboration since 2000
The following section briefly describes the progress made
by the Brighton Collaboration towards its four objectives
since its official launch in Fall 2000. The first objective is to
establish a global collaboration of professionals and organi-
zations concerned with immunization safety. Since 2000, the
Brighton Collaboration has grown from five participants in
5 countries to over 670 participants from over 70 countries,
participant in working groups, the reference group, and/or
implementing or evaluating these newly developed defini-
tions and guidelines. An additional 130 investigators have
expressed interested in staying informed about the progress
in the Collaboration via our e-mail distribution list.
The second objective is the development of standardized
case definitions and guidelines. With the tremendous input
from 234 working group members and 120 reference group
participants, six documents have already been published in
this journal [18–23], 18 documents have been completed for
publication, and several more documents are currently under
development.
Implementation and evaluation of these newly developed
standardized case definition and guidelines – the third and
fourth objectives – have been described elsewhere [9], suf-
fice to say here that evaluation of selected case definitions
in different settings resulted in positive feedback about their
applicability, sensitivity, and specificity by investigators in
clinical research and AEFI surveillance settings [24–27]. Fur-
ther formal evaluation studies of additional case definitions
as well as feedback on the implementation of the case def-
initions and guidelines are encouraged by all investigators
using or reviewing the definitions and guidelines. Because
widespread implementation is key to achieving data com-
parability, investigators of immunization safety studies in
various settings are encouraged to use these standards as
appropriate. As of March 2006, several organizations are
endorsing or recommending our definitions including the
American Academy of Pediatrics, CIOMS for selected doc-
uments recently reviewed, the European Medicines Agency,
FDA, and the World Health Organization. In addition, over
370 scientists from >50 countries have downloaded previ-
ously published documents from the Brighton Collaboration
website.
Finally, it should be stressed that, with the exception of
the staff in the secretariat, which is responsible for the overall
implementation of all aspects of the process of the Brighton
Collaboration, and some additional coordination work by
5673
working group team leads or coordinators in selected work-
ing groups, all other participants volunteer their time and
expertise. We wish to express our sincere gratitude to all
participants for their thoughtful, substantial, and motivating
contributions.
Acknowledgements
The authors would like to thank Tanja Popovic and Shawna
L. Mercer at the Centers for Disease Control and Prevention,
Atlanta, U.S. for their helpful comments and suggestions on
this manuscript.
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