causality assessment aefi
SEA-Immun-88
Distribution: General
Causality assessment of adverse
events following immunization
Report of an intercountry workshop
18–20 February 2014, Bangkok, Thailand
© World Health Organization 2014
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Contents
Page
Acronyms .............................................................................................................. v
Executive summary ............................................................................................... vi
1.
Background ................................................................................................... 1
2.
Methodology and objectives .......................................................................... 4
3.
Proceedings ................................................................................................... 7
Annexes
1.
List of participants ....................................................................................... 15
2.
Agenda ........................................................................................................ 18
3.
Summary country profile, status of AEFI and performances of vaccine
pharmacovigilance systems .......................................................................... 19
4.
Case Study AEFI investigation report ............................................................ 24
5.
Eight AEFI case reports with findings of working group and summary of
plenary discussions ...................................................................................... 26
6.
Questionnaire to assess usefulness of causality algorithm tools to
participants ................................................................................................. 52
7.
Plenary discussions ...................................................................................... 58
iii
Acronyms
AEFI - Adverse Events Following Immunization
NIP - National Immunization Programmes
NRA - National Regulatory Authorities
EPI - Expanded Programme on Immunization
LIC - Low-Income Countries
VPD - Vaccine Preventable Diseases
NCL – National Control Laboratory
CIOMS - International Organizations of Medical
HMIS - Health Management Information System
SIDS - Sudden Infant Death Syndrome
LMIC - Low and Middle-Income Countries
v
Executive summary
The World Health Organization (WHO) Regional Office for South-East Asia
organized an intercountry workshop on causality of adverse events
following immunization (AEFI) from 18 to 20 February 2014 in Bangkok,
Thailand, as part of the regional strategy to support countries to strengthen
national vaccine safety surveillance and AEFI monitoring systems. Since
2008, WHO has provided training support to national regulatory authorities
(NRAs) and national immunization programmes (NIPs) in the South-East
Asia Region to strengthen capacity to detect, report and investigate AEFI.
WHO training material is utilized in all countries to conduct training
programmes. These programmes are adapted to local needs by national
immunization programmes and national regulatory authorities and National
AEFI committees for peripheral level immunization service delivery and
may be translated into local languages in some countries. WHO provided
follow-up support to some countries to establish national AEFI committees
and their secretariats, update national guidelines, implement pilot projects
to test and validate notification forms and investigation templates, and to
standardize data analysis and reporting. The countries of the South-East
Asia Region have thus experienced enhanced reporting of AEFI cases for
which the causes were not always understood. This resulted in unnecessary
concerns and disrupted routine immunization programme for some
vaccines in some countries.
As part of the strategy to address this risk of loss of public confidence
in the immunization programmes, the countries in the South-East Asia
Region strengthened their national AEFI committees with new members
with expertise in neurology, forensic specialists, paediatricians,
epidemiologists and professors in teaching hospitals. WHO proposed to
organize this intercountry workshop involving 29 vaccine experts from ten
countries in the South-East Asia and Western Pacific Regions to review,
discuss and analyse selected cases of AEFI for the period 2011–2013. WHO
country offices were instrumental in mobilizing national AEFI committee
members to identify specific AEFI case reports for discussion. Six out the ten
participating countries provided a total of 23 AEFI case reports. Not all
cases submitted could be reviewed because of time constraints and so nine
cases were short-listed and anonymized for the purpose of this workshop.
In addition to South-East Asia Region countries, Viet Nam in the WHO
Western Pacific Region participated in the workshop.
vi
The workshop provided a platform for experts in each country to
share their experiences and report on their performances in an open forum
with presentations using standardized templates. The new definitions for
AEFI and vaccine pharmacovigilance were presented and discussed in
plenary sessions. The WHO revised causality assessment methodology was
further tested in the process of reviewing selected cases and participants’
opinions on the usefulness of the tool were collected through a
questionnaire developed during the workshop. Participants appreciated the
opportunities to discuss with experts from different fields and learned a
great deal by working on AEFI case reports in the Region. All countries
acknowledge the need for further collaborative initiatives like this workshop
in the field of vaccine pharmacovigilance and developed a set of
recommendations to foster increased cooperation among countries in the
Region and beyond.
vii
1.
Background
The Expanded Programme on Immunization (EPI) was established in 1974
at a time when only 5% of the world’s children were protected by
vaccination against six diseases, that is, polio, diphtheria, tuberculosis,
pertussis, measles and tetanus. Today, that figure is 83%, with some lowincome countries (LICs) reaching 99% immunization coverage.
Consequently, some vaccine preventable diseases (VPDs) are today on the
verge of eradication. The challenge for immunization programmes
throughout the world has become to maintain high immunization coverage
with VPDs disappearing from the collective memory. Vaccines are the safest
medicines with very rare serious adverse events following immunization
(AEFI). Although, serious AEFI are in the range of 1 per million doses, public
tolerance is much lower than for medicines because vaccines are given
mostly to infants who are healthy at the time the vaccine is administered. In
addition, vaccines are provided to children less than one year of age, a
vulnerable age in many LICs. A country with an infant mortality of 50 per
1000 live births may expect 14 deaths of children below one year every
day. As vaccination is routinely provided, those deaths could be attributed
to the vaccine when in fact they are coincidental and are due to
underlining diseases which were not diagnosed at the time of the
vaccination. Thus, it is essential to sustain public confidence in
immunization to establish surveillance systems that detect and report AEFI
in the national immunization programme (NIP), experts committees able to
conduct scientific AEFI causality assessments and ministry of health capacity
to address vaccine safety concerns.
The World Health Organization (WHO) has a long history of technical
support to build the national capacity of Member States in the South-East
Asia Region to monitor AEFI. In 2003, the WHO Regional Office for SouthEast Asia established the Global Training Network (GTN) centre in
Colombo, Sri Lanka to provide training on AEFI monitoring to South-East
Asia Region Member States and to other WHO regions. The GTN centre in
Sri Lanka was instrumental in providing training on AEFI monitoring to
national regulatory authority (NRA) and EPI representatives of the countries
of the South-East Asia Region.
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Report of an intercountry workshop
Meanwhile, NRAs have initiated capacity-strengthening activities to
meet international/WHO standards for vaccine safety, quality and efficacy.
In the South-East Asia Region countries, national expertise increased and
new requirements emerged to further expand the basic AEFI course in
order to meet training requirements with new more complex vaccines and
additional experts added to the national AEFI committees. The WHO
course content of the basic AEFI training package was revised to cater to the
needs of national AEFI committees as they were being established by
NRAs/national control laboratories (NCLs) and NIPs with pharmacists,
experts in allergies, forensic specialists, professors in immunology, etc. who
were not always knowledgeable about their national vaccine safety
surveillance system.
To further support AEFI causality assessment, the revised AEFI training
material was tested in 2012 in Myanmar and Nepal with participants from
national AEFI committee members, NRA representatives and EPI managers.
In Myanmar1, the training methodology was adapted to maximize time for
participants to breakup in small groups to conduct formal causality
assessment of selected AEFI cases. Analyses of cases were reviewed in small
working group sessions using the WHO 2012 revised causality assessment
methodology for causality association and the findings were debated in
plenary sessions to reach consensus on the conclusions of the committee
about the causal association of the vaccine with the symptoms.
Since 2008, the Regional Office for South-East Asia has conducted 11
training workshops on AEFI monitoring in eight countries of the South-East
Asia Region, that is, Bangladesh, Bhutan, Democratic People’s Republic of
Korea, India, Indonesia, Nepal, Myanmar and Sri Lanka. The Regional
Office for South-East Asia support toward training on AEFI 2 is a twopronged approach to address needs in the NRA capacity strengthening
programme
(1)
for vaccine pharmacovigilance and the building of national AEFI
committee with national AEFI experts to periodically review cases
________________________
1
Report on the Training Workshop on Adverse Events Following Immunizaton 26–30 April 2012, Nay Pyi Taw,
Myanmar. Report available within Regional Office for South-East Asia/FHR/IVD library.
2
Adverse Events Following immunization in the South East Region 2008–2010; Report on WHO support to
training programme.
2
Causality assessment of adverse events following immunization
of AEFI and to respond scientifically to serious AEFI cases and
concerns of vaccine safety and;
(2)
to improve the detection and reporting of AEFI, including to
update monitoring guidelines and implement pilot projects with
enhanced AEFI surveillance systems to validate notification forms
and reporting mechanisms.
Consequently, AEFI cases which were neither detected nor reported
before AEFI strengthening activities have started to be increasingly detected
and reported to national AEFI committees. Several countries have established
surveillance systems that not only detect serious AEFI cases which result in
hospitalization but also detect minor AEFI cases.
In the South-East Asia Region, the countries are introducing or have plans
to introduce new vaccines in their NIPs; therefore, programme managers along
with regulators and the members of national AEFI committees, and other
national vaccine safety stakeholders in South- East Asia, identified the need to
strengthen procedures to investigate and analyse AEFI cases in a systematic and
scientific manner in order to provide timely and accurate responses to address
errors to help immunization providers and the public at large. Strengthened
procedures will also address vaccine safety concerns.
Countries in the WHO Western Pacific Region identified similar training
needs following recent allegations concerning vaccine safety that resulted in
temporary suspension of specific immunization programmes until further
findings could reject a causal association with the vaccine in question. The
South- East Asia and Western Pacific Regions share the same suppliers for most
of the vaccines for their NIPs, making vaccine safety a cross regional issue
requiring mechanisms to share information and analyse cases for causality
assessments. In this connection, both regions have been cooperating to
undertake joint efforts and to initiate joint activities on vaccine safety
surveillance and AEFI monitoring when possible. Regional and intercountry
workshops agendas are designed to address training needs in the two regions.
As of 2009, all countries in the Regional Office for South-East Asia,
except Maldives and Timor-Leste, had established a national AEFI committee
to review and analyse AEFI cases on a periodic basis. Thus the time was ripe
for an intercountry workshop on causality assessment to share learning and
discuss experiences with the currently recommended tools and processes.
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Report of an intercountry workshop
This intercountry workshop on causality of AEFI conducted in
Bangkok, Thailand, from 18 to 20 February 2014 was primarily aimed at
countries with an established surveillance system (to detect and report AEFI)
supported by a national AEFI committee that meets regularly to conduct
AEFI causality assessments. The session plan of the standard WHO five day
advanced course on AEFI monitoring, investigation and causality assessment
was adapted to a three-day agenda focusing predominately on causality
assessment. The training methodology emphasized working group sessions
to stimulate discussions and exchange of experience and also to create a
work environment similar to a meeting of an AEFI causality assessment
committee which would meet to review and to determine causes of
selected cases of AEFI. The 29 participants were from Bangladesh, Bhutan,
India, Indonesia, Maldives, Nepal, Sri Lanka, Thailand and Timor- Leste in
the South-East Asia Region and Viet Nam in the West Pacific Region. They
included representatives of national AEFI committees, NRAs and NCLs, EPI
managers, hospital paediatricians and professors from university and
medical institutes and two WHO country office representatives from India
and Nepal. (See Annex A for List of participants.) The intercountry
workshop was facilitated by Professor Noni MacDonald, Professor of
Paediatrics, Dalhousie University, Halifax, Canada; Dr Ananda
Amarasinghe, Consultant epidemiologist, Epidemiology Unit, Ministry of
Health, Sri Lanka; Dr Madhava Ram Balakrishnan, Medical Officer,
Quality, Safety and Standards, WHO Geneva and Mr Stephane Guichard,
Regional Adviser, Vaccine Supply and Quality, WHO Regional Office for
South-East Asia.
2.
Methodology and objectives
2.1
Objective
The main objective of the workshop was to build regional capacity to
assess AEFI with the following specific objectives:
4
to review selected AEFI cases from 2011–2013 in the WHO
South-East Asia and Western Pacific regions using WHO revised
the methodology for causality assessment;
to identify critical AEFI cases of common interest for countries of
the South-East Asia and Western Pacific regions (serious and
Causality assessment of adverse events following immunization
non-serious AEFI) to standardize terminology and case
definitions to enable comparison and also signal detection by
aggregating data from several countries;
to streamline AEFI data collection procedures by introducing
core variables and data analysis methods;
to apply the new WHO causality assessment tool in different
country settings, in order to strengthen its wider application; and
to set the prerequisites for sustainable regional collaboration to
share vaccine safety data of regional and global importance.
The agenda was spread over three days with the first day centred on
sessions for country presentations by national counterparts to inform the
participants about the status of vaccine pharmacovigilance system in their
countries and activities to strengthen detection, reporting and analysis of AEFI
cases (The agenda of the intercountry workshop is shown in Annex B)
2.2
Methodology
Prior to the workshop, the countries were contacted by the WHO Regional
Office and country offices to provide a standard presentation template to
report on the current status of vaccine safety surveillance systems, activities
of the national AEFI committee and current constraints and opportunities.
Initially, countries presented their situation analysis, enabling participants to
gain understanding of the various country scenarios. Then the audience was
updated on the recent Council for International Organizations of Medical
Sciences (CIOMS) definitions and the concepts of vaccine
pharmacovigilance in order to facilitate harmonization of procedures and
data-sharing and data mining. Definitions and classifications of AEFI were
updated by the CIOMS/WHO working group established in November
2005 3 to develop general definitions strictly focused on vaccine
pharmacovigilance and to contribute to the development review evaluation
and approval of definitions on AEFI as developed by the Brighton
Collaboration process and to their dissemination.
________________________
3 http://vaccinepvtoolkit.org/vaccine-wp/wp-content/uploads/2013/12/report_working_group_on_vaccine_LRCIOMS-WHO-WG.pdf
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Report of an intercountry workshop
The second day was devoted to the review of selected cases for AEFI
causality assessment. Participants were divided into three groups. Each group
was given three AEFI cases which had occurred in the South-East Asia Region
between 2011 and 2013. Several weeks before the meeting, chairmen of the
national AEFI committees in the South-East Asia and Western Pacific Regions
were contacted by WHO country offices to provide a minimum of five AEFI
investigation reports. A total of 23 AEFI investigation reports were provided by
six of the 10 countries represented at this workshop. Each AEFI investigation
report was then anonymised by removing names of the case and other
identifiers including name of institutions and addresses. Once the cases had
been anonymised, nine were selected by the facilitators. Selection criteria
included cases with well-documented reports and cases with AEFI known to be
linked to vaccines. The cases were then numbered from 1 to 9 and each
working group received three of these case reports to review and to present
the outcomes of their analysis in plenary. Two groups managed to review all
their assigned cases with one group reviewing only two cases. The participants
therefore, analysed eight cases and presented their findings in the plenary
sessions.
On the third day, following presentations on vaccine pharmacovigilance
global initiatives, the workshop provided a platform for participants to discuss
and provide comments on the different tools recently developed by WHO to
conduct causality assessment, including the revised causality assessment
methodology, the AEFI core variables, sample reporting forms and supporting
materials available on the web. It was an opportunity to have representatives
from national AEFI committees, NCLs and NRAs meet together to discuss
important questions, such as the need to (1) establish a regional/biregional
group of experts to respond to serious AEFI cases which could have public
health impacts that occur in countries with limited capacity; (2) analyse
regional data with particular interest in signal detection; (3) explore how to
sustain national vaccine pharmacovigilance systems and to increase
involvement of academicians and medical colleges and institutes involved in
postmarketing vaccine safety surveillance; and (4) discuss what countries saw
as the regional needs for monitoring AEFI and maintaining public confidence in
immunization programmes.
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Causality assessment of adverse events following immunization
3.
Proceedings
3.1
Vaccine pharmacovigilance systems
Nine countries from the South-East Asia and one from Western Pacific
regions presented their AEFI surveillance and causality assessment systems.
Annex 3 summarizes country profile, status and performance of the vaccine
pharmacovigilance systems in each country.
Of the 10 countries, only Maldives and Timor-Leste do not have yet an
established AEFI surveillance system with a national AEFI committee. Of four
vaccine-producing countries, Thailand reported more than 1000 AEFI cases.
Indonesia in the last three years has significantly improved its capacity to detect
AEFI with more than 18 000 reports in 2013. The two other vaccineproducing countries, that is, India and Viet Nam respectively reported 536
cases and 31 cases in 2013, highlighting significant under-reporting occurring
under these systems. During the plenary discussions, India explained that the
figures included only severe AEFI; the nonserious AEFI are monitored through
the health management information system (HMIS) and were not included in
the India presentation.
Nepal and Sri Lanka are among countries that procure vaccine directly
except for pentavalent DPT-HepB-Hib vaccine which is procured through
UNICEF. Nepal, with its nascent system, reports fewer than 30 AEFI cases a
year, whereas Sri Lanka has a well-established AEFI system and reports more
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Report of an intercountry workshop
than 6400 cases per year. In the other countries that procure vaccine through
UNICEF, that is, Bangladesh, Bhutan and Timor-Leste, the capacity of the
surveillance systems to detect and report AEFI varies widely. Bangladesh, which
has plans to produce vaccines itself, has shown significant progress with more
than 2200 cases reported per year. The other three countries report only
serious cases, that is, hospitalizations and deaths. In 2013, Bhutan reported 16
cases, Maldives no cases and Timor-Leste one case. These countries have
relatively small populations and may not have a serious AEFI at all for several
years. Thus, it may not be sustainable for them to maintain a full-fledged
system with national AEFI committee to detect very rare events and then carry
out causality assessment on serious AEFI, and a rapid response system might be
more suitable. However, these countries as well as all the others were
encouraged to monitor nonserious AEFI which could help to detect
programmatic errors and/or signals.
Progress is most significant in the capacity of the countries to analyse AEFI
data. The cornerstone of vaccine pharmacovigilance is the national AEFI
committee that collects, consolidates, reviews and analyses AEFI data to
conduct causality assessment. All participating countries except Maldives and
Timor-Leste have established a national AEFI committee. India is the only
country that has a secretariat for the national AEFI committee, officially
established in 2012. All the national AEFI committees were reorganized in the
last three years to address the increasing number of AEFI to be reviewed
because of improvement in AEFI surveillance systems. The national AEFI
committees, however, do not meet regularly in all countries, which results in a
substantial number of serious cases not being reviewed in a timely fashion. In
2013, India managed to review 30% of serious cases while Bangladesh
reviewed only 27%. On the other hand, the national AEFI committees of
Indonesia, Nepal, Thailand and Viet Nam managed to review all the serious
AEFI cases reported in 2013.
Out of 10 countries, four listed poor quality of data as a major constraint
and three mentioned high staff turnover. Finally, six countries reported
difficulties in sending the investigation team to the field within 24 hours and
their lack of training in AEFI field investigation.
The country presentations were followed by a series of lectures to review
causality assessment. Dr Madhava Ram Balakrishnan presented the revised
WHO causality assessment methodology including the revised CIOMS
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Causality assessment of adverse events following immunization
definition of AEFI. The latter raised concerns among the participants, especially
with the term “unfavourable”.
AEFI is defined as any untoward medical occurrence which follows
immunization and which does not necessarily have a causal relationship with
usage of a vaccine. The adverse event maybe an unfavourable or unintended
sign, abnormal laboratory finding, symptom or disease.
Several participants noted that the term “unfavourable” was not easily
translated, is a negative of a positive term and is not clear in its meaning.
Several participants raised the question of what is an “unfavourable or
unintended sign” compared to a sign. An abnormal laboratory finding,
symptom or disease was understood. Why was a sign dealt with differently?
Some participants proposed “an abnormal laboratory finding, symptom, sign or
disease”. One participant noted that the revised definition was more difficult to
explain at the working level compared to the previous definition. Participants
also argued that the term AEFI is too negative for the NIP and that they would
prefer a more neutral terminology, such as “vaccine safety surveillance”. Dr
Madhava Ram Balakrishnan said he would raise the concern about
“unfavourable” with the CIOMS.
Professor Noni MacDonald then discussed causality assessment: AEFI
case definitions and case scenarios (formerly Module G in the advance course)
followed by a new lecture on common fallacies and pitfalls (Module C) with
emphasis on anaphylaxis and sudden infant death syndrome (SIDS). The latter
was well received with many comments on pitfalls; more topics might be
included, such as misinterpretation of data, confusion with academic jargon,
etc. This was followed by Dr Ananda Amarasinghe’s presentation on the
systematic review of the vaccine safety database. This piqued the interest of
several participants and engendered good discussions.
3.2
Case studies
The participants worked on a case study (see Annex 4) through the WHO
revised causality assessment methodology. The approach to causality
assessment process for the case raised a number of issues, both clinical and
methodological. For example, the term “valid diagnosis” was found
confusing by some. Which diagnosis to choose – death, thrombocytopenia,
etc.? How should the different “diagnoses” be worked through – all on one
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Report of an intercountry workshop
form or several forms? Is the purpose of conducting AEFI causality
assessment solely to determine if the vaccine was associated with the
symptoms? Several noted that anxiety rose if only that is done as many then
ask why the child died. There may be a need to review what the parent
/media/politician is concerned about even if that is not a “medically
relevant diagnosis” upon review of the case. Queries were also raised about
some of the terminology on the WHO form as well as the process.
This was followed by a review of eight cases from the countries that had
been anonymized both to patient as well as to country and institutions (nine
AEFI cases were prepared for review, but due to time constraint, eight were
reviewed). Three working groups were carefully formed in order to contain
clinical expertise as well as a wide country mix. Out of the eight selected AEFI
reports reviewed in working group session, one case had onset in 2006, one in
2011, three in 2012, one in 2013 and two cases in 2014. The ages ranged
from one day to 18 months. The eight AEFI reports involved seven serious AEFI
cases with hospitalization; two cases recovered.
All groups worked enthusiastically with lively discussions and full
participation. The findings of the assessment were presented by the
representative of each working group. During the plenary discussions,
comments and insights made for lively audience participation.
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Causality assessment of adverse events following immunization
3.3
Format of the revised causality assessment methodology
More issues were raised about the format of the revised causality
assessment methodology and the applicability of some of the Brighton
definitions. The eight AEFI case histories and the salient features of
discussions are summarized in Annex 5. In several instances, participants
from other countries noted they had seen cases similar to the one
discussed. Many participants commented on how very helpful this session
was for not only increasing their knowledge about AEFI causality
assessment, but also on account of the breadth of the discussions and
different views of the cases in the groups. All saw this as a very valuable
exchange of experiences.
Given the comments about the WHO form and process for causality
assessment, a questionnaire was developed for the participants to specifically
comment on the usefulness of each section of the revised causality assessment
methodology and process (Annex 6). Out of 20 questionnaires distributed, 17
were returned by participants. Among the respondents, 82% felt that the
eligibility step was useful. However, 35% felt that some wording not always
easy to understand. Likewise, 82%, 71% and 82% indicated that the causality
question, event checklist and algorithm respectively were helpful. Only 18%
indicated that there were some situations where the event checklist did not
work, and 61% and 71% respectively expressed satisfaction at the approaches
used for the classification and summarizing the logic of classification.
Suggestions for making the methodology more user-friendly were made
by 35% of respondents. They included:
provision of more details on the indeterminate steps B1 and B2
particularly the differences;
addition of sections on feedback, recommendations and
corrective actions;
recommendations from the committee to prevent the event from
occurring in future; and
inclusion of an instruction page on how to fill the form, ensuring
that it covers the key definitions and terms used.
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Report of an intercountry workshop
Suggestions for improving causality assessment in the countries
included:
3.4
training for expert committee members, paediatricians or other
members;
training on critical cases of causality assessment through the
WHO collaborating centres, Brighton collaboration etc;
training on communication issues, especially in rumoured cases;
guidance on special considerations before immunization;
standardized verbal autopsy; and
special studies.
Vaccine safety and pharmacovigilance assessment tools
Dr Ananda Amarasinghe described vaccine safety and pharmacovigilance
assessment tools to review vaccine safety postmarketing surveillance
performance at the subnational levels. Many countries acknowledged a lack
of proper use of vaccine safety data for evidence-based practice and the
need to focus on improving critical reviews of database and vaccine safety
data analysis at different administrative levels. This session not only
generated much interest but also led to a number of questions. The
experience of using field data for analysis and interpretation in Sri Lanka
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Causality assessment of adverse events following immunization
provided an example of good practices for postmarketing surveillance of
vaccines.
3.5
Global vaccine pharmacovigilance initiatives
The different tools and resources available for vaccine pharmacovigilance
were demonstrated and the methods for accessing them were discussed by
Dr Madhav Ram Balakrishnan.
3.6
Vaccine adverse event information management System
Dr Ajit Pal Singh gave a brief overview of International Vaccine Institute in
Seoul, Korea and then reviewed the rationale for and how to use the
VAEIMS (Vaccine Adverse Event Information Management System). The
screen shot examples came from Sri Lanka which is piloting the programme
in the Region. This covered learning from the workshop, gaps, concerns
and potential solutions. The participants discussed the benefit of inviting
representatives of the vaccine industry in the intercountry workshop on
causality of AEFI, and felt that inviting industry might be helpful to enhance
understanding of AEFI issues. In Annex 7 an overview of the discussions are
provided. A key and strong recommendation was that such intercountry
workshops on causality assessment of AEFI take place in the Region every
12 to 28 months. The next discussion covered the potential for publication
of an article about this process (rationale, methods) with summary of the
eight cases and summary of recommendations from the meeting, that is,
more than just a meeting report. Permission to use the anonymized cases
will be sought and a title for the group volunteering to be on the writing
committee.
Recommendations and follow-up
(1)
The major constraints of the national vaccine pharmacovigilance
are lack of planning for regular reviews of AEFI cases through a
committee of experts and the poor quality of investigation,
affecting data quality and causality assessments.
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Report of an intercountry workshop
14
(2)
Countries are encouraged to advocate to the respective ministries
of health for additional resources to support the ongoing
functioning of the post-marketing vaccine safety surveillance and
to establish AEFI secretariat, particularly in vaccine-producing
countries.
(3)
Guidelines to assist NIPs to plan for serious AEFI field
investigations and promptly respond to AEFI should be developed
(4)
The WHO revised causality assessment methodology and CIOMS
AEFI definition should be reviewed based upon suggestions from
the homework questionnaire and concerns raised by end users at
the meeting. The questionnaire might be revised based on
responses for use in assessing causality using the WHO revised
causality assessment methodology in other settings.
(5)
An informal technical working group should be set up to initiate
development of regional guidelines to plan serious AEFI field
investigation and to adapt WHO verbal autopsy to fit AEFI case
clinical needs.
(6)
Several small-scale studies were identified to improve and
document signal detection; for example(1) to approach pediatric
societies in the Region to see if they could develop a practical set
of questions and observations for detection of infants with
clinically significant congenital heart disease for referral but not to
let this impede immunization; (2) to develop a small survey to
identify to what extent the NRA is involved in AEFI monitoring in
each of the participating countries in this forum and which
strategies countries have used to increase involvement; (3) to
explore development of a practical tool AEFI definition, time
interval, rates AEFI with different vaccines used in the Region and
(4) how immunization and AEFI can be better incorporated into
teaching at medical and nursing schools in the Region.
(7)
A formal review of Brighton definitions should be undertaken to
develop definitions at levels that will work in settings where there
is no equipment and limited health worker training (for example,
outside a clinical trial in an LIC context)
(8)
An article about the methods, findings, and recommendations
from the workshop should be prepared for publication.
Causality assessment of adverse events following immunization
Annex 1
List of participants
Bangladesh
Dr Shafiqur Rahman
Deputy Director and Programme Manager EPI
and Surveillance
EPI Headquarter
DGHS, Mohakhali,
Dhaka
Dr Md. Shafiqul Islam
Associate Professor
Department of Epidemiology
National Institute of Preventive and Social
Medicine (NIPSOM)
Mohakhali
Mr A A Salim Barami
Director (cc)
Directorate General of Drug Administration
and Deputy Chief, NCL
Dhaka
Dr Rahma Dewi Handari
Staff of Sub Directorate of Surveillance and
Risk Analyses of Therapeutic Products
Sub Directorate of Surveillance and Risk
Analysis of Therapeutic Product (PV unit)
National Agency of Drug and Food Control
Jakarta
Dr Sherli Karolina
Staff of Immunization Sub Directorate
Ministry of Health
Jakarta
Maldives
Ms Aishath Thimna Latheef
Public Health Programme Manager
Health Protection Agency
Ministry of Health
Malé
Bhutan
Nepal
Mr Tshewang Dorji Tamang
Senior Programme Officer
Department of Public Health
Ministry of Health
Thimphu
Dr Neelam Adhikari
Chairperson, AEFI Committee Nepal
Consultant Pediatrician
B & B Hospital, Gwarku
Patan, Kathmandu
India
Dr Shyam Raj Upreti
EPI Chief,
Child Health Division,
Teku, Kathmandu
Dr Ajay Khera
Deputy Commissioner (CH & I)
Ministry of Health & Family Welfare
New Delhi
Indonesia
Dr Hingky Hindra Irawan Satari
Head of National Committee of AEFI
National Committee of AEFI, Indonesia
Departemen IKA FKUI-RSCM
Jakarta Pusat
Sri Lanka
Dr Pathiraja Dissanayakelage Sriyani
Dissanayake
Deputy Director
Medical Technology & Supplies
(Cosmetic Devices & Drug Regulatory
Authority)
Colombo
15
Report of an intercountry workshop
Dr Duminda Samarasinghe
Consultant Paediatric Cardiologist
Lady Ridgeway Hospital for Children
Colombo
Thailand
Clinical Professor Dr. Suchitra Nimmanitya
Consultant
Department of Disease Control
Ministry of Public Health
Nonthaburi
Dr Pornsak Yoocharoen
Medical Officer, Senior Professional Level
Bureau of General Communicable Diseases
Department of Disease Control
Ministry of Public Health
Nonthaburi
Dr Nguyen Thi My Hanh
Officer
Division of Vaccine, Biological and Biosafety
General Department of Preventive Medicine
Ministry of Health
Hanoi
WHO Headquarters, Geneva
Dr Madhav Balakrishnan
Medical Officer, Safety and Vigilance (SAV)
Regulation of Medicines and other Health
Technologies (RHT)
Department of Essential Medicines and
Health Products (EMP)
Health Systems and Innovation (HIS)
WHO South-East Asia Regional Office,
New Delhi, India
Miss Kanoktip Thiparat
Public Health Technical Officer – Professional
Level
Bureau of Epidemiology
Department of Disease Control
Ministry of Public Health
Nonthaburi
Mr Stephane Guichard
Regional Adviser
Vaccine Supply and Quality
Miss Pattreya Pokhagul
Pharmacist – Professional Level
Health Product Pharmacovigilance Center
Technical and Policy Administration Division
Food and Drug Administration
Ministry of Public Health
Nonthaburi
WHO country offices
Timor-Leste
Mrs Liliana dos Santos Varela
Official VPD Surveillance
Department of Epidemiological Surveillance
Ministry of Health
Dili
Viet Nam
Dr. Nguyen Lien Huong
EPI Staff
National Expanded Programme on
Immunization (EPI)
National Institute of Hygiene and
Epidemiology
Hanoi
16
Ms Aunyawan Thavinkaew
WHO Country Office, Thailand
Ministry of Public Health
Nonthaburi
Dr Sujeet Kumar Jain
AEFI and VPD Surveillance Focal person
WHO Country Office for India – NPSP
New Delhi, India
Dr Santosh Gurung
New Vaccines Officer
Programme for Immunization Preventable
Diseases
WHO Country Office for Nepal
Kathmandu
Facilitators
Dr Ananda Amarasinghe
Consultant Epidemiologist
Epidemiology unit
Ministry of Health
Colombo, Sri Lanka
Causality assessment of adverse events following immunization
Professor Nora Noni Elisabeth Macdonald
Professor of Paediatrics
Dalhousie University
IWK Health Centre
Halifax, Nova Scotia
Canada
Dr Suchada JiamSiri
Medical Officer
EPI Programme
Bureau of General Communicable Diseases
Ministry of Public Health
Nonthaburi, Thailand
Observers
Mrs Teeranart Jivapaisarnpong
Director, Institute of Biological Products
Department of Medical Sciences
Ministry of Public Health
Nonthaburi, Thailand
Mr Pramote Akarapanon
Senior Pharmacist
Biological Products Section
Bureau of Drug Control
Food and Drug Administration
Ministry of Public Health
Nonthaburi, Thailand
Mrs Prapassorn Thanaphollert
Acting Director
Bureau of Drug Control
Food and Drug Administration
Ministry of Public Health
Nonthaburi, Thailand
Ms Werayarmarst Jaroenkunathum
Chief of Vaccine Section
Institute of Biological Products
Department of Medical Sciences
Ministry of Public Health
Nonthaburi, Thailand
Mrs Porpit Varinsathien
Public Health Technical Officer
Bureau of General Communicable Disease
Department of Disease Control
Ministry of Public Health
Nonthaburi, Thailand
17
Report of an intercountry workshop
Annex 2
Agenda
Sessions
1
2
3
4
5
6
7
8
9
10
11
12
18
Objectives
Country presentations: AEFI monitoring systems, past experience in investigation
and causality assessment
Bangladesh
Bhutan
India
Indonesia
Maldives
Nepal
Sri Lanka
Thailand
Timor-Leste
Viet Nam
Revised WHO Causality Assessment Methodology
Causality assessment: AEFI case definitions and case scenarios
Common fallacies and pitfalls
Systematic review of the vaccine safety database
Review of selected AEFI cases and categorization on a specially designed WHO
causality assessment form
Assessment tools to assess vaccine safety post marketing surveillance system
Global vaccine pharmacovigilance initiatives
International Vaccine Institute Vaccine Adverse Event Information Management
System
Building sustainable country and regional vaccine pharmacovigilance and
identification of needs and next steps
Closing remarks
Annex 3
Summary country profile, status of AEFI and performances of vaccine pharmacovigilance systems
Bangladesh
Bhutan
India
Indonesia
Maldives
Nepal
Sri Lanka
Thailand
Timor-Leste
Viet Nam
Country profile
Total pop.
153 904 238
745 157
1 200 000
244 000 000
320 000
28 600 000
21 000 000
64 181 001
1 154 625
90 000 000
Child. < 1
3 478 236
14 679
26 000 000
4 600 000
5500
700 000
350 000
796 317
42 114
1 700 000
BCG, HepB
(birth dose),
DPT-HepBHib
MR
DPT (2 yrs)
Td
HPV (12 yrs)
BCG, HepB,
DPT-HepBHib, OPV,
DTP, measles,
JE (LAV), TT
Hep B (birth
dose), BCG,
OPV, DPTHepB-Hib,
measles, DT,
Td, TT
BCG, OPV,
DPT-HepBHib, measles,
MMR, TT, DT
BCG, DPTHepB-Hib,
OPV, MR, JE
BCG, DPT,
DPT-HepBHib, OPV
MMR, JE,
Rubella, DT,
TT
BCG, HepB,
OPV, MMR,
JE, DTP, Td,
DTP-HepB,
Influenza (pop
at risk HCW)
BCG, OPV,
DPT-HepBHib, measles,
TT.
BCG, DPTHepB-Hib,
DPT, OPV,
measles, TT,
cholera (2–5
yrs), typhoid
(3–5 yrs), JE
(1–5 yrs)
Date new
vaccine
introduced
-Hep B from
2003 to 2005
-Penta 2009
-MR 2012
(Sept)
-measles 2nd
dose 2012
Sept
Penta 2009
(Sept)
HPV 2010
(May)
Penta (started
2011 in 2
states with
gradual
expansion)
Td (2011)
Penta (2013)
in 4/33
provinces
2014 all
provinces
Penta (2012)
Penta (2009)
Penta (Jan
2008)
MMR Oct
2012
JE LAV
(Oct2012)
NA
Pentavallent in Penta (2010)
2012.
measles2
(2011)
DPT booster
(2011)
Coverage for
each antigen
2013
BCG: 99%
OPV3: 92%
Penta3: 92%
measles: 86%
Fully immune:
81%
2012
BCG: 94%
OPV3: 97%
DPT-HepBHib: 97%
MR1: 95%
MR2: 89%
2013
BCG: 92%
DPT3: 76%
HepB3:67%
Hib3: NA
MCV1: 88%
MCV2: 42%
2013
HepB0:83.4%
BCG: 94%
DPTHepB3:95.6%
OPV4: 95.3%
MEA: 93.5%
2013
BCG: 99.7%
DPT3: 99.4%
HepB3: 99.2%
Hib3: 99.5%
MCV1: 99.4%
MCV2: 98.6%
2013
BCG: 97%
DPT3: 92%
HepB3: 92%
Hib3: 92%
OPV3: 92%
MCV1: 88%
2012
Penta3: 99%
MMR2: 96%
JE: (99%)
2013
BCG: 100%
DPT3: 99.4%
OPV3:99.4%
HepB3:99.4%
Measles:
98.7%
JE3: 89.3%
2013
BCG: 81.6%
Penta3: 76.3%
OPV3: 76%
MEA: 69%
19
Causality assessment of adverse events following immunization
Vaccine in the BCG, DPTimmunization HepB-Hib,
schedule
OPV, MR,
measles, TT
Dates and
no.
vaccinated
SIA and NIDs
in 2012–2013
if any
20th NID Jan–Feb
2012: 44 093 255
21st NID Dec 2013:
20 630 062
Vaccine
supply
sources
Procurement
services agreement
with UNICEF,
Government
funded. Local
pharmaceutical
industry with
capacity to
manufacture
vaccines
Bhutan
India
Indonesia
Maldives
Nepal
Sri Lanka
Government of
Sri-Lanka from
WHO PQ
sources. Only
PVV supplied
by UNICEF
with GAVI
funds
Thailand
Timor-Leste
Nov 2012 Round 1
(DTP 2–36 mths):
98.3%
(DT 3–7 yrs): 100%
(Td 7–15 yrs): 100%
Jun 2013 Round 2
(DPT 2–36ms):
96.6% (DT 3–7 yrs):
97.2
(Td 7–15 yrs): 96.3%
Nov 2013 Round 3
(DPT 2–36
mths):97.3%
(DT 3–7 yrs):97.6%
(Td 7–15 yrs): 98%
Procurement Government of India
service
from local producers
agreement
mostly WHO PQ
with UNICEF.
Government
funded
All vaccine are
supplied from one
domestic producer
and are WHO PQ
UNICEF
Government
of Nepal
except PVV
through
UNICEF.
Vaccines are
all from WHO
PQ sources.
30 September 1997
and reorganized in
2012.
No committee
2004
2008
reorganized in
2008.
Government of UNICEF
Thailand from 3
local
manufacturers
and imported
from India,
Indonesia,
Korea and
Europe.
Status AEFI
Date AEFI
committee
established
Viet Nam
10 January 2004
15 July 2009
and list updated on List updated
13 March 2011
on 15 June
2012
25 January 2008 list
updated July 2013,
Secretariat of Nat’l
AEFI committee
established in 2012.
2004 and
updated in
2010
No
committee
Government
of VTN from
local
suppliers:
BCG, OPV,
DPT, HepB,
JE, oral
cholera,
typhoid,
measles and
imported
through
UNICEF
Pentavalent
Report of an intercountry workshop
20
Bangladesh
Bhutan
India
List of AEFI
committee
members
Includes 13
members
representing, EPI,
NRA, professors of
virology, pathology,
paediatricians and
professors of
medical colleges
Paediatrician,
medical
specialist,
microbiologist,
district health
officer, clinical
Lab NRA and
pharmacist
Epidemiologists/public
health specialist,
paediatrician, NRA,
microbiologist,
neurologist,
pathologist, forensic
scientist, member of
infectious diseases
surveillance, professor
in teaching
hospital/medical
colleges
Representative of
NA
Infectiologist
Indonesia Paediatric
Society (IDAI),
Indonesian Society of
Obstetrics/Gynecology
and Health Law
Association
(PERHUKI);
paediatricians from
the National Public
Hospital; Forensic
specialist, EPI
managers, NRA
technicians,
pharmacists,
representative of the
legal bureau MOH
and professors from
medical institutes.
No. of
committee
meeting
2012–2013
Irregular
2012: 2
2013: 3
Established fixed
calendar, met four
times btw August
2013 to March 2014
Core meeting twice a
year + upon request.
AEFI committee met
10 times in 2012 and
4 times in 2013 to
conduct causality
assessments
NA
Guidelines (2005)
revised in 2010 and
SOP developed in
2011.
Guideline (2005),
AEFI technical
guideline (2012); AEFI
MOH regulation
(2013)
National
guidelines
under
development
AEFI
guideline
dates and
update
Indonesia
Maldives
Nepal
Sri Lanka
Thailand
Chaired by
independent
senior
paediatrician
with
representatives
from Child
Health
Division,
Logistics &
Management
Division,
Department of
Drug
Administration,
WHO,
UNICEF and
pediatricians
Professors of
paediatrics and
microbiology
Faculty of
medicines;
virologists,
pathologists,
immunologists
Medical,
Research
Institutes, EPI
managers, NRA
representatives,
cardiologist
Children
Hospital,
Neurologist
and professors
of
pharmacology
and director of
Maternal &
Child Health
division
Epidemiologist,
paediatrician for
infectious
diseases,
paediatrician for
neurology,
neonatology,
representative
of the NCL,
associate
professor
forensic
medicine,
neuropathology,
epidemiologist
and
representative
of the NIP
2012: 3
2013: 1
2012: 4
2013:3
NA
Guidelines
2007 updated
in 2012
2003 and
updated in
2008
NA
Guidelines
2003 in
Nepalese
language in
2008
TimorLeste
NA
Viet Nam
2003 and
updated in
2013 and
2014
21
Causality assessment of adverse events following immunization
Bangladesh
Definition
to identify
serious
AEFI, i.e.
what is
reported as
serious AEFI
Death,
hospitalization,
cluster of reportable
AEFI,
parental/community
concerns
Bhutan
India
Includes death,
hospitalization,
cluster, persistent or
significant disability
/incapacity or lifethreatening condition
Indonesia
Maldives
Nepal
Severe local
Deaths and
reaction,
hospitalization
injection site
abscess
BCG
lymphadenitis
High fever
(more than 101
F) within 48
hrs
Rash
Seizures within
14 days
Encephalitis /
Meningitis
within 28 days
Encephalopathy
within 3 days
Loss of
consciousness /
shock within 48
hours
Anaphylaxis
Toxic shock
syndrome
VAPP
Hospitalization
Death
Public concerns
Sri Lanka
Thailand
Deaths,
hospitalization,
any event
believed to be
associated to
vaccine and/or
any people
concerns
Death,
hospitalization
and cases
suspected to be
associated to
vaccine, people
concerns
TimorLeste
NA
Viet Nam
Anaphylactic
shock,
intoxication
shock
syndrome,
suspected
programme
error a
Distribution: General
Causality assessment of adverse
events following immunization
Report of an intercountry workshop
18–20 February 2014, Bangkok, Thailand
© World Health Organization 2014
All rights reserved.
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Printed in India
ii
Contents
Page
Acronyms .............................................................................................................. v
Executive summary ............................................................................................... vi
1.
Background ................................................................................................... 1
2.
Methodology and objectives .......................................................................... 4
3.
Proceedings ................................................................................................... 7
Annexes
1.
List of participants ....................................................................................... 15
2.
Agenda ........................................................................................................ 18
3.
Summary country profile, status of AEFI and performances of vaccine
pharmacovigilance systems .......................................................................... 19
4.
Case Study AEFI investigation report ............................................................ 24
5.
Eight AEFI case reports with findings of working group and summary of
plenary discussions ...................................................................................... 26
6.
Questionnaire to assess usefulness of causality algorithm tools to
participants ................................................................................................. 52
7.
Plenary discussions ...................................................................................... 58
iii
Acronyms
AEFI - Adverse Events Following Immunization
NIP - National Immunization Programmes
NRA - National Regulatory Authorities
EPI - Expanded Programme on Immunization
LIC - Low-Income Countries
VPD - Vaccine Preventable Diseases
NCL – National Control Laboratory
CIOMS - International Organizations of Medical
HMIS - Health Management Information System
SIDS - Sudden Infant Death Syndrome
LMIC - Low and Middle-Income Countries
v
Executive summary
The World Health Organization (WHO) Regional Office for South-East Asia
organized an intercountry workshop on causality of adverse events
following immunization (AEFI) from 18 to 20 February 2014 in Bangkok,
Thailand, as part of the regional strategy to support countries to strengthen
national vaccine safety surveillance and AEFI monitoring systems. Since
2008, WHO has provided training support to national regulatory authorities
(NRAs) and national immunization programmes (NIPs) in the South-East
Asia Region to strengthen capacity to detect, report and investigate AEFI.
WHO training material is utilized in all countries to conduct training
programmes. These programmes are adapted to local needs by national
immunization programmes and national regulatory authorities and National
AEFI committees for peripheral level immunization service delivery and
may be translated into local languages in some countries. WHO provided
follow-up support to some countries to establish national AEFI committees
and their secretariats, update national guidelines, implement pilot projects
to test and validate notification forms and investigation templates, and to
standardize data analysis and reporting. The countries of the South-East
Asia Region have thus experienced enhanced reporting of AEFI cases for
which the causes were not always understood. This resulted in unnecessary
concerns and disrupted routine immunization programme for some
vaccines in some countries.
As part of the strategy to address this risk of loss of public confidence
in the immunization programmes, the countries in the South-East Asia
Region strengthened their national AEFI committees with new members
with expertise in neurology, forensic specialists, paediatricians,
epidemiologists and professors in teaching hospitals. WHO proposed to
organize this intercountry workshop involving 29 vaccine experts from ten
countries in the South-East Asia and Western Pacific Regions to review,
discuss and analyse selected cases of AEFI for the period 2011–2013. WHO
country offices were instrumental in mobilizing national AEFI committee
members to identify specific AEFI case reports for discussion. Six out the ten
participating countries provided a total of 23 AEFI case reports. Not all
cases submitted could be reviewed because of time constraints and so nine
cases were short-listed and anonymized for the purpose of this workshop.
In addition to South-East Asia Region countries, Viet Nam in the WHO
Western Pacific Region participated in the workshop.
vi
The workshop provided a platform for experts in each country to
share their experiences and report on their performances in an open forum
with presentations using standardized templates. The new definitions for
AEFI and vaccine pharmacovigilance were presented and discussed in
plenary sessions. The WHO revised causality assessment methodology was
further tested in the process of reviewing selected cases and participants’
opinions on the usefulness of the tool were collected through a
questionnaire developed during the workshop. Participants appreciated the
opportunities to discuss with experts from different fields and learned a
great deal by working on AEFI case reports in the Region. All countries
acknowledge the need for further collaborative initiatives like this workshop
in the field of vaccine pharmacovigilance and developed a set of
recommendations to foster increased cooperation among countries in the
Region and beyond.
vii
1.
Background
The Expanded Programme on Immunization (EPI) was established in 1974
at a time when only 5% of the world’s children were protected by
vaccination against six diseases, that is, polio, diphtheria, tuberculosis,
pertussis, measles and tetanus. Today, that figure is 83%, with some lowincome countries (LICs) reaching 99% immunization coverage.
Consequently, some vaccine preventable diseases (VPDs) are today on the
verge of eradication. The challenge for immunization programmes
throughout the world has become to maintain high immunization coverage
with VPDs disappearing from the collective memory. Vaccines are the safest
medicines with very rare serious adverse events following immunization
(AEFI). Although, serious AEFI are in the range of 1 per million doses, public
tolerance is much lower than for medicines because vaccines are given
mostly to infants who are healthy at the time the vaccine is administered. In
addition, vaccines are provided to children less than one year of age, a
vulnerable age in many LICs. A country with an infant mortality of 50 per
1000 live births may expect 14 deaths of children below one year every
day. As vaccination is routinely provided, those deaths could be attributed
to the vaccine when in fact they are coincidental and are due to
underlining diseases which were not diagnosed at the time of the
vaccination. Thus, it is essential to sustain public confidence in
immunization to establish surveillance systems that detect and report AEFI
in the national immunization programme (NIP), experts committees able to
conduct scientific AEFI causality assessments and ministry of health capacity
to address vaccine safety concerns.
The World Health Organization (WHO) has a long history of technical
support to build the national capacity of Member States in the South-East
Asia Region to monitor AEFI. In 2003, the WHO Regional Office for SouthEast Asia established the Global Training Network (GTN) centre in
Colombo, Sri Lanka to provide training on AEFI monitoring to South-East
Asia Region Member States and to other WHO regions. The GTN centre in
Sri Lanka was instrumental in providing training on AEFI monitoring to
national regulatory authority (NRA) and EPI representatives of the countries
of the South-East Asia Region.
1
Report of an intercountry workshop
Meanwhile, NRAs have initiated capacity-strengthening activities to
meet international/WHO standards for vaccine safety, quality and efficacy.
In the South-East Asia Region countries, national expertise increased and
new requirements emerged to further expand the basic AEFI course in
order to meet training requirements with new more complex vaccines and
additional experts added to the national AEFI committees. The WHO
course content of the basic AEFI training package was revised to cater to the
needs of national AEFI committees as they were being established by
NRAs/national control laboratories (NCLs) and NIPs with pharmacists,
experts in allergies, forensic specialists, professors in immunology, etc. who
were not always knowledgeable about their national vaccine safety
surveillance system.
To further support AEFI causality assessment, the revised AEFI training
material was tested in 2012 in Myanmar and Nepal with participants from
national AEFI committee members, NRA representatives and EPI managers.
In Myanmar1, the training methodology was adapted to maximize time for
participants to breakup in small groups to conduct formal causality
assessment of selected AEFI cases. Analyses of cases were reviewed in small
working group sessions using the WHO 2012 revised causality assessment
methodology for causality association and the findings were debated in
plenary sessions to reach consensus on the conclusions of the committee
about the causal association of the vaccine with the symptoms.
Since 2008, the Regional Office for South-East Asia has conducted 11
training workshops on AEFI monitoring in eight countries of the South-East
Asia Region, that is, Bangladesh, Bhutan, Democratic People’s Republic of
Korea, India, Indonesia, Nepal, Myanmar and Sri Lanka. The Regional
Office for South-East Asia support toward training on AEFI 2 is a twopronged approach to address needs in the NRA capacity strengthening
programme
(1)
for vaccine pharmacovigilance and the building of national AEFI
committee with national AEFI experts to periodically review cases
________________________
1
Report on the Training Workshop on Adverse Events Following Immunizaton 26–30 April 2012, Nay Pyi Taw,
Myanmar. Report available within Regional Office for South-East Asia/FHR/IVD library.
2
Adverse Events Following immunization in the South East Region 2008–2010; Report on WHO support to
training programme.
2
Causality assessment of adverse events following immunization
of AEFI and to respond scientifically to serious AEFI cases and
concerns of vaccine safety and;
(2)
to improve the detection and reporting of AEFI, including to
update monitoring guidelines and implement pilot projects with
enhanced AEFI surveillance systems to validate notification forms
and reporting mechanisms.
Consequently, AEFI cases which were neither detected nor reported
before AEFI strengthening activities have started to be increasingly detected
and reported to national AEFI committees. Several countries have established
surveillance systems that not only detect serious AEFI cases which result in
hospitalization but also detect minor AEFI cases.
In the South-East Asia Region, the countries are introducing or have plans
to introduce new vaccines in their NIPs; therefore, programme managers along
with regulators and the members of national AEFI committees, and other
national vaccine safety stakeholders in South- East Asia, identified the need to
strengthen procedures to investigate and analyse AEFI cases in a systematic and
scientific manner in order to provide timely and accurate responses to address
errors to help immunization providers and the public at large. Strengthened
procedures will also address vaccine safety concerns.
Countries in the WHO Western Pacific Region identified similar training
needs following recent allegations concerning vaccine safety that resulted in
temporary suspension of specific immunization programmes until further
findings could reject a causal association with the vaccine in question. The
South- East Asia and Western Pacific Regions share the same suppliers for most
of the vaccines for their NIPs, making vaccine safety a cross regional issue
requiring mechanisms to share information and analyse cases for causality
assessments. In this connection, both regions have been cooperating to
undertake joint efforts and to initiate joint activities on vaccine safety
surveillance and AEFI monitoring when possible. Regional and intercountry
workshops agendas are designed to address training needs in the two regions.
As of 2009, all countries in the Regional Office for South-East Asia,
except Maldives and Timor-Leste, had established a national AEFI committee
to review and analyse AEFI cases on a periodic basis. Thus the time was ripe
for an intercountry workshop on causality assessment to share learning and
discuss experiences with the currently recommended tools and processes.
3
Report of an intercountry workshop
This intercountry workshop on causality of AEFI conducted in
Bangkok, Thailand, from 18 to 20 February 2014 was primarily aimed at
countries with an established surveillance system (to detect and report AEFI)
supported by a national AEFI committee that meets regularly to conduct
AEFI causality assessments. The session plan of the standard WHO five day
advanced course on AEFI monitoring, investigation and causality assessment
was adapted to a three-day agenda focusing predominately on causality
assessment. The training methodology emphasized working group sessions
to stimulate discussions and exchange of experience and also to create a
work environment similar to a meeting of an AEFI causality assessment
committee which would meet to review and to determine causes of
selected cases of AEFI. The 29 participants were from Bangladesh, Bhutan,
India, Indonesia, Maldives, Nepal, Sri Lanka, Thailand and Timor- Leste in
the South-East Asia Region and Viet Nam in the West Pacific Region. They
included representatives of national AEFI committees, NRAs and NCLs, EPI
managers, hospital paediatricians and professors from university and
medical institutes and two WHO country office representatives from India
and Nepal. (See Annex A for List of participants.) The intercountry
workshop was facilitated by Professor Noni MacDonald, Professor of
Paediatrics, Dalhousie University, Halifax, Canada; Dr Ananda
Amarasinghe, Consultant epidemiologist, Epidemiology Unit, Ministry of
Health, Sri Lanka; Dr Madhava Ram Balakrishnan, Medical Officer,
Quality, Safety and Standards, WHO Geneva and Mr Stephane Guichard,
Regional Adviser, Vaccine Supply and Quality, WHO Regional Office for
South-East Asia.
2.
Methodology and objectives
2.1
Objective
The main objective of the workshop was to build regional capacity to
assess AEFI with the following specific objectives:
4
to review selected AEFI cases from 2011–2013 in the WHO
South-East Asia and Western Pacific regions using WHO revised
the methodology for causality assessment;
to identify critical AEFI cases of common interest for countries of
the South-East Asia and Western Pacific regions (serious and
Causality assessment of adverse events following immunization
non-serious AEFI) to standardize terminology and case
definitions to enable comparison and also signal detection by
aggregating data from several countries;
to streamline AEFI data collection procedures by introducing
core variables and data analysis methods;
to apply the new WHO causality assessment tool in different
country settings, in order to strengthen its wider application; and
to set the prerequisites for sustainable regional collaboration to
share vaccine safety data of regional and global importance.
The agenda was spread over three days with the first day centred on
sessions for country presentations by national counterparts to inform the
participants about the status of vaccine pharmacovigilance system in their
countries and activities to strengthen detection, reporting and analysis of AEFI
cases (The agenda of the intercountry workshop is shown in Annex B)
2.2
Methodology
Prior to the workshop, the countries were contacted by the WHO Regional
Office and country offices to provide a standard presentation template to
report on the current status of vaccine safety surveillance systems, activities
of the national AEFI committee and current constraints and opportunities.
Initially, countries presented their situation analysis, enabling participants to
gain understanding of the various country scenarios. Then the audience was
updated on the recent Council for International Organizations of Medical
Sciences (CIOMS) definitions and the concepts of vaccine
pharmacovigilance in order to facilitate harmonization of procedures and
data-sharing and data mining. Definitions and classifications of AEFI were
updated by the CIOMS/WHO working group established in November
2005 3 to develop general definitions strictly focused on vaccine
pharmacovigilance and to contribute to the development review evaluation
and approval of definitions on AEFI as developed by the Brighton
Collaboration process and to their dissemination.
________________________
3 http://vaccinepvtoolkit.org/vaccine-wp/wp-content/uploads/2013/12/report_working_group_on_vaccine_LRCIOMS-WHO-WG.pdf
5
Report of an intercountry workshop
The second day was devoted to the review of selected cases for AEFI
causality assessment. Participants were divided into three groups. Each group
was given three AEFI cases which had occurred in the South-East Asia Region
between 2011 and 2013. Several weeks before the meeting, chairmen of the
national AEFI committees in the South-East Asia and Western Pacific Regions
were contacted by WHO country offices to provide a minimum of five AEFI
investigation reports. A total of 23 AEFI investigation reports were provided by
six of the 10 countries represented at this workshop. Each AEFI investigation
report was then anonymised by removing names of the case and other
identifiers including name of institutions and addresses. Once the cases had
been anonymised, nine were selected by the facilitators. Selection criteria
included cases with well-documented reports and cases with AEFI known to be
linked to vaccines. The cases were then numbered from 1 to 9 and each
working group received three of these case reports to review and to present
the outcomes of their analysis in plenary. Two groups managed to review all
their assigned cases with one group reviewing only two cases. The participants
therefore, analysed eight cases and presented their findings in the plenary
sessions.
On the third day, following presentations on vaccine pharmacovigilance
global initiatives, the workshop provided a platform for participants to discuss
and provide comments on the different tools recently developed by WHO to
conduct causality assessment, including the revised causality assessment
methodology, the AEFI core variables, sample reporting forms and supporting
materials available on the web. It was an opportunity to have representatives
from national AEFI committees, NCLs and NRAs meet together to discuss
important questions, such as the need to (1) establish a regional/biregional
group of experts to respond to serious AEFI cases which could have public
health impacts that occur in countries with limited capacity; (2) analyse
regional data with particular interest in signal detection; (3) explore how to
sustain national vaccine pharmacovigilance systems and to increase
involvement of academicians and medical colleges and institutes involved in
postmarketing vaccine safety surveillance; and (4) discuss what countries saw
as the regional needs for monitoring AEFI and maintaining public confidence in
immunization programmes.
6
Causality assessment of adverse events following immunization
3.
Proceedings
3.1
Vaccine pharmacovigilance systems
Nine countries from the South-East Asia and one from Western Pacific
regions presented their AEFI surveillance and causality assessment systems.
Annex 3 summarizes country profile, status and performance of the vaccine
pharmacovigilance systems in each country.
Of the 10 countries, only Maldives and Timor-Leste do not have yet an
established AEFI surveillance system with a national AEFI committee. Of four
vaccine-producing countries, Thailand reported more than 1000 AEFI cases.
Indonesia in the last three years has significantly improved its capacity to detect
AEFI with more than 18 000 reports in 2013. The two other vaccineproducing countries, that is, India and Viet Nam respectively reported 536
cases and 31 cases in 2013, highlighting significant under-reporting occurring
under these systems. During the plenary discussions, India explained that the
figures included only severe AEFI; the nonserious AEFI are monitored through
the health management information system (HMIS) and were not included in
the India presentation.
Nepal and Sri Lanka are among countries that procure vaccine directly
except for pentavalent DPT-HepB-Hib vaccine which is procured through
UNICEF. Nepal, with its nascent system, reports fewer than 30 AEFI cases a
year, whereas Sri Lanka has a well-established AEFI system and reports more
7
Report of an intercountry workshop
than 6400 cases per year. In the other countries that procure vaccine through
UNICEF, that is, Bangladesh, Bhutan and Timor-Leste, the capacity of the
surveillance systems to detect and report AEFI varies widely. Bangladesh, which
has plans to produce vaccines itself, has shown significant progress with more
than 2200 cases reported per year. The other three countries report only
serious cases, that is, hospitalizations and deaths. In 2013, Bhutan reported 16
cases, Maldives no cases and Timor-Leste one case. These countries have
relatively small populations and may not have a serious AEFI at all for several
years. Thus, it may not be sustainable for them to maintain a full-fledged
system with national AEFI committee to detect very rare events and then carry
out causality assessment on serious AEFI, and a rapid response system might be
more suitable. However, these countries as well as all the others were
encouraged to monitor nonserious AEFI which could help to detect
programmatic errors and/or signals.
Progress is most significant in the capacity of the countries to analyse AEFI
data. The cornerstone of vaccine pharmacovigilance is the national AEFI
committee that collects, consolidates, reviews and analyses AEFI data to
conduct causality assessment. All participating countries except Maldives and
Timor-Leste have established a national AEFI committee. India is the only
country that has a secretariat for the national AEFI committee, officially
established in 2012. All the national AEFI committees were reorganized in the
last three years to address the increasing number of AEFI to be reviewed
because of improvement in AEFI surveillance systems. The national AEFI
committees, however, do not meet regularly in all countries, which results in a
substantial number of serious cases not being reviewed in a timely fashion. In
2013, India managed to review 30% of serious cases while Bangladesh
reviewed only 27%. On the other hand, the national AEFI committees of
Indonesia, Nepal, Thailand and Viet Nam managed to review all the serious
AEFI cases reported in 2013.
Out of 10 countries, four listed poor quality of data as a major constraint
and three mentioned high staff turnover. Finally, six countries reported
difficulties in sending the investigation team to the field within 24 hours and
their lack of training in AEFI field investigation.
The country presentations were followed by a series of lectures to review
causality assessment. Dr Madhava Ram Balakrishnan presented the revised
WHO causality assessment methodology including the revised CIOMS
8
Causality assessment of adverse events following immunization
definition of AEFI. The latter raised concerns among the participants, especially
with the term “unfavourable”.
AEFI is defined as any untoward medical occurrence which follows
immunization and which does not necessarily have a causal relationship with
usage of a vaccine. The adverse event maybe an unfavourable or unintended
sign, abnormal laboratory finding, symptom or disease.
Several participants noted that the term “unfavourable” was not easily
translated, is a negative of a positive term and is not clear in its meaning.
Several participants raised the question of what is an “unfavourable or
unintended sign” compared to a sign. An abnormal laboratory finding,
symptom or disease was understood. Why was a sign dealt with differently?
Some participants proposed “an abnormal laboratory finding, symptom, sign or
disease”. One participant noted that the revised definition was more difficult to
explain at the working level compared to the previous definition. Participants
also argued that the term AEFI is too negative for the NIP and that they would
prefer a more neutral terminology, such as “vaccine safety surveillance”. Dr
Madhava Ram Balakrishnan said he would raise the concern about
“unfavourable” with the CIOMS.
Professor Noni MacDonald then discussed causality assessment: AEFI
case definitions and case scenarios (formerly Module G in the advance course)
followed by a new lecture on common fallacies and pitfalls (Module C) with
emphasis on anaphylaxis and sudden infant death syndrome (SIDS). The latter
was well received with many comments on pitfalls; more topics might be
included, such as misinterpretation of data, confusion with academic jargon,
etc. This was followed by Dr Ananda Amarasinghe’s presentation on the
systematic review of the vaccine safety database. This piqued the interest of
several participants and engendered good discussions.
3.2
Case studies
The participants worked on a case study (see Annex 4) through the WHO
revised causality assessment methodology. The approach to causality
assessment process for the case raised a number of issues, both clinical and
methodological. For example, the term “valid diagnosis” was found
confusing by some. Which diagnosis to choose – death, thrombocytopenia,
etc.? How should the different “diagnoses” be worked through – all on one
9
Report of an intercountry workshop
form or several forms? Is the purpose of conducting AEFI causality
assessment solely to determine if the vaccine was associated with the
symptoms? Several noted that anxiety rose if only that is done as many then
ask why the child died. There may be a need to review what the parent
/media/politician is concerned about even if that is not a “medically
relevant diagnosis” upon review of the case. Queries were also raised about
some of the terminology on the WHO form as well as the process.
This was followed by a review of eight cases from the countries that had
been anonymized both to patient as well as to country and institutions (nine
AEFI cases were prepared for review, but due to time constraint, eight were
reviewed). Three working groups were carefully formed in order to contain
clinical expertise as well as a wide country mix. Out of the eight selected AEFI
reports reviewed in working group session, one case had onset in 2006, one in
2011, three in 2012, one in 2013 and two cases in 2014. The ages ranged
from one day to 18 months. The eight AEFI reports involved seven serious AEFI
cases with hospitalization; two cases recovered.
All groups worked enthusiastically with lively discussions and full
participation. The findings of the assessment were presented by the
representative of each working group. During the plenary discussions,
comments and insights made for lively audience participation.
10
Causality assessment of adverse events following immunization
3.3
Format of the revised causality assessment methodology
More issues were raised about the format of the revised causality
assessment methodology and the applicability of some of the Brighton
definitions. The eight AEFI case histories and the salient features of
discussions are summarized in Annex 5. In several instances, participants
from other countries noted they had seen cases similar to the one
discussed. Many participants commented on how very helpful this session
was for not only increasing their knowledge about AEFI causality
assessment, but also on account of the breadth of the discussions and
different views of the cases in the groups. All saw this as a very valuable
exchange of experiences.
Given the comments about the WHO form and process for causality
assessment, a questionnaire was developed for the participants to specifically
comment on the usefulness of each section of the revised causality assessment
methodology and process (Annex 6). Out of 20 questionnaires distributed, 17
were returned by participants. Among the respondents, 82% felt that the
eligibility step was useful. However, 35% felt that some wording not always
easy to understand. Likewise, 82%, 71% and 82% indicated that the causality
question, event checklist and algorithm respectively were helpful. Only 18%
indicated that there were some situations where the event checklist did not
work, and 61% and 71% respectively expressed satisfaction at the approaches
used for the classification and summarizing the logic of classification.
Suggestions for making the methodology more user-friendly were made
by 35% of respondents. They included:
provision of more details on the indeterminate steps B1 and B2
particularly the differences;
addition of sections on feedback, recommendations and
corrective actions;
recommendations from the committee to prevent the event from
occurring in future; and
inclusion of an instruction page on how to fill the form, ensuring
that it covers the key definitions and terms used.
11
Report of an intercountry workshop
Suggestions for improving causality assessment in the countries
included:
3.4
training for expert committee members, paediatricians or other
members;
training on critical cases of causality assessment through the
WHO collaborating centres, Brighton collaboration etc;
training on communication issues, especially in rumoured cases;
guidance on special considerations before immunization;
standardized verbal autopsy; and
special studies.
Vaccine safety and pharmacovigilance assessment tools
Dr Ananda Amarasinghe described vaccine safety and pharmacovigilance
assessment tools to review vaccine safety postmarketing surveillance
performance at the subnational levels. Many countries acknowledged a lack
of proper use of vaccine safety data for evidence-based practice and the
need to focus on improving critical reviews of database and vaccine safety
data analysis at different administrative levels. This session not only
generated much interest but also led to a number of questions. The
experience of using field data for analysis and interpretation in Sri Lanka
12
Causality assessment of adverse events following immunization
provided an example of good practices for postmarketing surveillance of
vaccines.
3.5
Global vaccine pharmacovigilance initiatives
The different tools and resources available for vaccine pharmacovigilance
were demonstrated and the methods for accessing them were discussed by
Dr Madhav Ram Balakrishnan.
3.6
Vaccine adverse event information management System
Dr Ajit Pal Singh gave a brief overview of International Vaccine Institute in
Seoul, Korea and then reviewed the rationale for and how to use the
VAEIMS (Vaccine Adverse Event Information Management System). The
screen shot examples came from Sri Lanka which is piloting the programme
in the Region. This covered learning from the workshop, gaps, concerns
and potential solutions. The participants discussed the benefit of inviting
representatives of the vaccine industry in the intercountry workshop on
causality of AEFI, and felt that inviting industry might be helpful to enhance
understanding of AEFI issues. In Annex 7 an overview of the discussions are
provided. A key and strong recommendation was that such intercountry
workshops on causality assessment of AEFI take place in the Region every
12 to 28 months. The next discussion covered the potential for publication
of an article about this process (rationale, methods) with summary of the
eight cases and summary of recommendations from the meeting, that is,
more than just a meeting report. Permission to use the anonymized cases
will be sought and a title for the group volunteering to be on the writing
committee.
Recommendations and follow-up
(1)
The major constraints of the national vaccine pharmacovigilance
are lack of planning for regular reviews of AEFI cases through a
committee of experts and the poor quality of investigation,
affecting data quality and causality assessments.
13
Report of an intercountry workshop
14
(2)
Countries are encouraged to advocate to the respective ministries
of health for additional resources to support the ongoing
functioning of the post-marketing vaccine safety surveillance and
to establish AEFI secretariat, particularly in vaccine-producing
countries.
(3)
Guidelines to assist NIPs to plan for serious AEFI field
investigations and promptly respond to AEFI should be developed
(4)
The WHO revised causality assessment methodology and CIOMS
AEFI definition should be reviewed based upon suggestions from
the homework questionnaire and concerns raised by end users at
the meeting. The questionnaire might be revised based on
responses for use in assessing causality using the WHO revised
causality assessment methodology in other settings.
(5)
An informal technical working group should be set up to initiate
development of regional guidelines to plan serious AEFI field
investigation and to adapt WHO verbal autopsy to fit AEFI case
clinical needs.
(6)
Several small-scale studies were identified to improve and
document signal detection; for example(1) to approach pediatric
societies in the Region to see if they could develop a practical set
of questions and observations for detection of infants with
clinically significant congenital heart disease for referral but not to
let this impede immunization; (2) to develop a small survey to
identify to what extent the NRA is involved in AEFI monitoring in
each of the participating countries in this forum and which
strategies countries have used to increase involvement; (3) to
explore development of a practical tool AEFI definition, time
interval, rates AEFI with different vaccines used in the Region and
(4) how immunization and AEFI can be better incorporated into
teaching at medical and nursing schools in the Region.
(7)
A formal review of Brighton definitions should be undertaken to
develop definitions at levels that will work in settings where there
is no equipment and limited health worker training (for example,
outside a clinical trial in an LIC context)
(8)
An article about the methods, findings, and recommendations
from the workshop should be prepared for publication.
Causality assessment of adverse events following immunization
Annex 1
List of participants
Bangladesh
Dr Shafiqur Rahman
Deputy Director and Programme Manager EPI
and Surveillance
EPI Headquarter
DGHS, Mohakhali,
Dhaka
Dr Md. Shafiqul Islam
Associate Professor
Department of Epidemiology
National Institute of Preventive and Social
Medicine (NIPSOM)
Mohakhali
Mr A A Salim Barami
Director (cc)
Directorate General of Drug Administration
and Deputy Chief, NCL
Dhaka
Dr Rahma Dewi Handari
Staff of Sub Directorate of Surveillance and
Risk Analyses of Therapeutic Products
Sub Directorate of Surveillance and Risk
Analysis of Therapeutic Product (PV unit)
National Agency of Drug and Food Control
Jakarta
Dr Sherli Karolina
Staff of Immunization Sub Directorate
Ministry of Health
Jakarta
Maldives
Ms Aishath Thimna Latheef
Public Health Programme Manager
Health Protection Agency
Ministry of Health
Malé
Bhutan
Nepal
Mr Tshewang Dorji Tamang
Senior Programme Officer
Department of Public Health
Ministry of Health
Thimphu
Dr Neelam Adhikari
Chairperson, AEFI Committee Nepal
Consultant Pediatrician
B & B Hospital, Gwarku
Patan, Kathmandu
India
Dr Shyam Raj Upreti
EPI Chief,
Child Health Division,
Teku, Kathmandu
Dr Ajay Khera
Deputy Commissioner (CH & I)
Ministry of Health & Family Welfare
New Delhi
Indonesia
Dr Hingky Hindra Irawan Satari
Head of National Committee of AEFI
National Committee of AEFI, Indonesia
Departemen IKA FKUI-RSCM
Jakarta Pusat
Sri Lanka
Dr Pathiraja Dissanayakelage Sriyani
Dissanayake
Deputy Director
Medical Technology & Supplies
(Cosmetic Devices & Drug Regulatory
Authority)
Colombo
15
Report of an intercountry workshop
Dr Duminda Samarasinghe
Consultant Paediatric Cardiologist
Lady Ridgeway Hospital for Children
Colombo
Thailand
Clinical Professor Dr. Suchitra Nimmanitya
Consultant
Department of Disease Control
Ministry of Public Health
Nonthaburi
Dr Pornsak Yoocharoen
Medical Officer, Senior Professional Level
Bureau of General Communicable Diseases
Department of Disease Control
Ministry of Public Health
Nonthaburi
Dr Nguyen Thi My Hanh
Officer
Division of Vaccine, Biological and Biosafety
General Department of Preventive Medicine
Ministry of Health
Hanoi
WHO Headquarters, Geneva
Dr Madhav Balakrishnan
Medical Officer, Safety and Vigilance (SAV)
Regulation of Medicines and other Health
Technologies (RHT)
Department of Essential Medicines and
Health Products (EMP)
Health Systems and Innovation (HIS)
WHO South-East Asia Regional Office,
New Delhi, India
Miss Kanoktip Thiparat
Public Health Technical Officer – Professional
Level
Bureau of Epidemiology
Department of Disease Control
Ministry of Public Health
Nonthaburi
Mr Stephane Guichard
Regional Adviser
Vaccine Supply and Quality
Miss Pattreya Pokhagul
Pharmacist – Professional Level
Health Product Pharmacovigilance Center
Technical and Policy Administration Division
Food and Drug Administration
Ministry of Public Health
Nonthaburi
WHO country offices
Timor-Leste
Mrs Liliana dos Santos Varela
Official VPD Surveillance
Department of Epidemiological Surveillance
Ministry of Health
Dili
Viet Nam
Dr. Nguyen Lien Huong
EPI Staff
National Expanded Programme on
Immunization (EPI)
National Institute of Hygiene and
Epidemiology
Hanoi
16
Ms Aunyawan Thavinkaew
WHO Country Office, Thailand
Ministry of Public Health
Nonthaburi
Dr Sujeet Kumar Jain
AEFI and VPD Surveillance Focal person
WHO Country Office for India – NPSP
New Delhi, India
Dr Santosh Gurung
New Vaccines Officer
Programme for Immunization Preventable
Diseases
WHO Country Office for Nepal
Kathmandu
Facilitators
Dr Ananda Amarasinghe
Consultant Epidemiologist
Epidemiology unit
Ministry of Health
Colombo, Sri Lanka
Causality assessment of adverse events following immunization
Professor Nora Noni Elisabeth Macdonald
Professor of Paediatrics
Dalhousie University
IWK Health Centre
Halifax, Nova Scotia
Canada
Dr Suchada JiamSiri
Medical Officer
EPI Programme
Bureau of General Communicable Diseases
Ministry of Public Health
Nonthaburi, Thailand
Observers
Mrs Teeranart Jivapaisarnpong
Director, Institute of Biological Products
Department of Medical Sciences
Ministry of Public Health
Nonthaburi, Thailand
Mr Pramote Akarapanon
Senior Pharmacist
Biological Products Section
Bureau of Drug Control
Food and Drug Administration
Ministry of Public Health
Nonthaburi, Thailand
Mrs Prapassorn Thanaphollert
Acting Director
Bureau of Drug Control
Food and Drug Administration
Ministry of Public Health
Nonthaburi, Thailand
Ms Werayarmarst Jaroenkunathum
Chief of Vaccine Section
Institute of Biological Products
Department of Medical Sciences
Ministry of Public Health
Nonthaburi, Thailand
Mrs Porpit Varinsathien
Public Health Technical Officer
Bureau of General Communicable Disease
Department of Disease Control
Ministry of Public Health
Nonthaburi, Thailand
17
Report of an intercountry workshop
Annex 2
Agenda
Sessions
1
2
3
4
5
6
7
8
9
10
11
12
18
Objectives
Country presentations: AEFI monitoring systems, past experience in investigation
and causality assessment
Bangladesh
Bhutan
India
Indonesia
Maldives
Nepal
Sri Lanka
Thailand
Timor-Leste
Viet Nam
Revised WHO Causality Assessment Methodology
Causality assessment: AEFI case definitions and case scenarios
Common fallacies and pitfalls
Systematic review of the vaccine safety database
Review of selected AEFI cases and categorization on a specially designed WHO
causality assessment form
Assessment tools to assess vaccine safety post marketing surveillance system
Global vaccine pharmacovigilance initiatives
International Vaccine Institute Vaccine Adverse Event Information Management
System
Building sustainable country and regional vaccine pharmacovigilance and
identification of needs and next steps
Closing remarks
Annex 3
Summary country profile, status of AEFI and performances of vaccine pharmacovigilance systems
Bangladesh
Bhutan
India
Indonesia
Maldives
Nepal
Sri Lanka
Thailand
Timor-Leste
Viet Nam
Country profile
Total pop.
153 904 238
745 157
1 200 000
244 000 000
320 000
28 600 000
21 000 000
64 181 001
1 154 625
90 000 000
Child. < 1
3 478 236
14 679
26 000 000
4 600 000
5500
700 000
350 000
796 317
42 114
1 700 000
BCG, HepB
(birth dose),
DPT-HepBHib
MR
DPT (2 yrs)
Td
HPV (12 yrs)
BCG, HepB,
DPT-HepBHib, OPV,
DTP, measles,
JE (LAV), TT
Hep B (birth
dose), BCG,
OPV, DPTHepB-Hib,
measles, DT,
Td, TT
BCG, OPV,
DPT-HepBHib, measles,
MMR, TT, DT
BCG, DPTHepB-Hib,
OPV, MR, JE
BCG, DPT,
DPT-HepBHib, OPV
MMR, JE,
Rubella, DT,
TT
BCG, HepB,
OPV, MMR,
JE, DTP, Td,
DTP-HepB,
Influenza (pop
at risk HCW)
BCG, OPV,
DPT-HepBHib, measles,
TT.
BCG, DPTHepB-Hib,
DPT, OPV,
measles, TT,
cholera (2–5
yrs), typhoid
(3–5 yrs), JE
(1–5 yrs)
Date new
vaccine
introduced
-Hep B from
2003 to 2005
-Penta 2009
-MR 2012
(Sept)
-measles 2nd
dose 2012
Sept
Penta 2009
(Sept)
HPV 2010
(May)
Penta (started
2011 in 2
states with
gradual
expansion)
Td (2011)
Penta (2013)
in 4/33
provinces
2014 all
provinces
Penta (2012)
Penta (2009)
Penta (Jan
2008)
MMR Oct
2012
JE LAV
(Oct2012)
NA
Pentavallent in Penta (2010)
2012.
measles2
(2011)
DPT booster
(2011)
Coverage for
each antigen
2013
BCG: 99%
OPV3: 92%
Penta3: 92%
measles: 86%
Fully immune:
81%
2012
BCG: 94%
OPV3: 97%
DPT-HepBHib: 97%
MR1: 95%
MR2: 89%
2013
BCG: 92%
DPT3: 76%
HepB3:67%
Hib3: NA
MCV1: 88%
MCV2: 42%
2013
HepB0:83.4%
BCG: 94%
DPTHepB3:95.6%
OPV4: 95.3%
MEA: 93.5%
2013
BCG: 99.7%
DPT3: 99.4%
HepB3: 99.2%
Hib3: 99.5%
MCV1: 99.4%
MCV2: 98.6%
2013
BCG: 97%
DPT3: 92%
HepB3: 92%
Hib3: 92%
OPV3: 92%
MCV1: 88%
2012
Penta3: 99%
MMR2: 96%
JE: (99%)
2013
BCG: 100%
DPT3: 99.4%
OPV3:99.4%
HepB3:99.4%
Measles:
98.7%
JE3: 89.3%
2013
BCG: 81.6%
Penta3: 76.3%
OPV3: 76%
MEA: 69%
19
Causality assessment of adverse events following immunization
Vaccine in the BCG, DPTimmunization HepB-Hib,
schedule
OPV, MR,
measles, TT
Dates and
no.
vaccinated
SIA and NIDs
in 2012–2013
if any
20th NID Jan–Feb
2012: 44 093 255
21st NID Dec 2013:
20 630 062
Vaccine
supply
sources
Procurement
services agreement
with UNICEF,
Government
funded. Local
pharmaceutical
industry with
capacity to
manufacture
vaccines
Bhutan
India
Indonesia
Maldives
Nepal
Sri Lanka
Government of
Sri-Lanka from
WHO PQ
sources. Only
PVV supplied
by UNICEF
with GAVI
funds
Thailand
Timor-Leste
Nov 2012 Round 1
(DTP 2–36 mths):
98.3%
(DT 3–7 yrs): 100%
(Td 7–15 yrs): 100%
Jun 2013 Round 2
(DPT 2–36ms):
96.6% (DT 3–7 yrs):
97.2
(Td 7–15 yrs): 96.3%
Nov 2013 Round 3
(DPT 2–36
mths):97.3%
(DT 3–7 yrs):97.6%
(Td 7–15 yrs): 98%
Procurement Government of India
service
from local producers
agreement
mostly WHO PQ
with UNICEF.
Government
funded
All vaccine are
supplied from one
domestic producer
and are WHO PQ
UNICEF
Government
of Nepal
except PVV
through
UNICEF.
Vaccines are
all from WHO
PQ sources.
30 September 1997
and reorganized in
2012.
No committee
2004
2008
reorganized in
2008.
Government of UNICEF
Thailand from 3
local
manufacturers
and imported
from India,
Indonesia,
Korea and
Europe.
Status AEFI
Date AEFI
committee
established
Viet Nam
10 January 2004
15 July 2009
and list updated on List updated
13 March 2011
on 15 June
2012
25 January 2008 list
updated July 2013,
Secretariat of Nat’l
AEFI committee
established in 2012.
2004 and
updated in
2010
No
committee
Government
of VTN from
local
suppliers:
BCG, OPV,
DPT, HepB,
JE, oral
cholera,
typhoid,
measles and
imported
through
UNICEF
Pentavalent
Report of an intercountry workshop
20
Bangladesh
Bhutan
India
List of AEFI
committee
members
Includes 13
members
representing, EPI,
NRA, professors of
virology, pathology,
paediatricians and
professors of
medical colleges
Paediatrician,
medical
specialist,
microbiologist,
district health
officer, clinical
Lab NRA and
pharmacist
Epidemiologists/public
health specialist,
paediatrician, NRA,
microbiologist,
neurologist,
pathologist, forensic
scientist, member of
infectious diseases
surveillance, professor
in teaching
hospital/medical
colleges
Representative of
NA
Infectiologist
Indonesia Paediatric
Society (IDAI),
Indonesian Society of
Obstetrics/Gynecology
and Health Law
Association
(PERHUKI);
paediatricians from
the National Public
Hospital; Forensic
specialist, EPI
managers, NRA
technicians,
pharmacists,
representative of the
legal bureau MOH
and professors from
medical institutes.
No. of
committee
meeting
2012–2013
Irregular
2012: 2
2013: 3
Established fixed
calendar, met four
times btw August
2013 to March 2014
Core meeting twice a
year + upon request.
AEFI committee met
10 times in 2012 and
4 times in 2013 to
conduct causality
assessments
NA
Guidelines (2005)
revised in 2010 and
SOP developed in
2011.
Guideline (2005),
AEFI technical
guideline (2012); AEFI
MOH regulation
(2013)
National
guidelines
under
development
AEFI
guideline
dates and
update
Indonesia
Maldives
Nepal
Sri Lanka
Thailand
Chaired by
independent
senior
paediatrician
with
representatives
from Child
Health
Division,
Logistics &
Management
Division,
Department of
Drug
Administration,
WHO,
UNICEF and
pediatricians
Professors of
paediatrics and
microbiology
Faculty of
medicines;
virologists,
pathologists,
immunologists
Medical,
Research
Institutes, EPI
managers, NRA
representatives,
cardiologist
Children
Hospital,
Neurologist
and professors
of
pharmacology
and director of
Maternal &
Child Health
division
Epidemiologist,
paediatrician for
infectious
diseases,
paediatrician for
neurology,
neonatology,
representative
of the NCL,
associate
professor
forensic
medicine,
neuropathology,
epidemiologist
and
representative
of the NIP
2012: 3
2013: 1
2012: 4
2013:3
NA
Guidelines
2007 updated
in 2012
2003 and
updated in
2008
NA
Guidelines
2003 in
Nepalese
language in
2008
TimorLeste
NA
Viet Nam
2003 and
updated in
2013 and
2014
21
Causality assessment of adverse events following immunization
Bangladesh
Definition
to identify
serious
AEFI, i.e.
what is
reported as
serious AEFI
Death,
hospitalization,
cluster of reportable
AEFI,
parental/community
concerns
Bhutan
India
Includes death,
hospitalization,
cluster, persistent or
significant disability
/incapacity or lifethreatening condition
Indonesia
Maldives
Nepal
Severe local
Deaths and
reaction,
hospitalization
injection site
abscess
BCG
lymphadenitis
High fever
(more than 101
F) within 48
hrs
Rash
Seizures within
14 days
Encephalitis /
Meningitis
within 28 days
Encephalopathy
within 3 days
Loss of
consciousness /
shock within 48
hours
Anaphylaxis
Toxic shock
syndrome
VAPP
Hospitalization
Death
Public concerns
Sri Lanka
Thailand
Deaths,
hospitalization,
any event
believed to be
associated to
vaccine and/or
any people
concerns
Death,
hospitalization
and cases
suspected to be
associated to
vaccine, people
concerns
TimorLeste
NA
Viet Nam
Anaphylactic
shock,
intoxication
shock
syndrome,
suspected
programme
error a