Adverse Events following Immunization

Causality assessment of Adverse Events following Immunization

Attribution of causality to AEFI, especially those considered severe, of public importance, and programmatically disruptive, are critical for ensuring vaccine safety. In 2005, WHO published an aide-mémoire to a systematic, standardized causality assessment process for serious AEFI (including clusters), providing a method for individual causality assessment to be used by staff of national immunization programmes, regulatory authorities and pharmacovigilance or surveillance departments.⁵ After 7 years, several limitations had been identified during its use in the field, including: the need for more detailed guidance on the elements required to perform the assessment of causality, confusion over the terms used to classify the likelihood of association of the event to the vaccine, and the incomplete use of parameters for establishing causal association.

Following the GACVS decision to review the causality assessment system in December 2010, a working group was established to review the aide-mémoire and develop a method that would be simple, objective, adaptable and evidence-based when used by countries with different resources and capabilities. After concluding a thorough review of the most innovative methods available for determining causation for drugs and biologicals, an algorithmic scheme that incorporates additional elements of causation was designed. The guide was harmonized after the Clinical Immunization Safety Assessment (CISA) network’s newly developed algorithm which is available in the USA⁶ and the new definition of AEFI proposed by the Council for International Organizations of Medical Sciences (CIOMS).⁷

The new WHO proposed method allows the National Committees for AEFI case review and causality assessment to screen serious cases reported by their surveillance system for completeness and quality of information, ensuring the objectiveness of the assessment. Cases deemed incomplete are directed towards additional case investigation and review. A checklist containing the elements of causality assessment was included to guide the Committee or the assessor to gather the evidence needed for case review, and when completed allows the application of an algorithm that helps determine if the AEFI could be consistent or inconsistent with an association with the immunization, or is deemed indeterminate due to lack of evidence. A repository of all AEFI cases sorted through this new document is considered critical and recommended to allow for future signal detection and determining the need for additional epidemiological studies.

GACVS recognizes the boundaries of the newly developed method, mainly the limitations in the ability to associate novel, previously unknown AEFIs potentially associated with immunizations, and restrictions due to insufficient information available for individual cases. However, the new AEFI causality assessment system will provide a standardized and transparent method that allows stakeholders to understand the nature of the decision-making process, and pave the way for future evaluation of the guide to refine its effectiveness. GACVS has recommended that this new WHO AEFI causality assessment approach should be made public as soon as it is finalized, and that complementary materials and simple software be developed for use in countries to enable immunization staff to field-test the algorithm. Of the next steps deemed most important is the development of a booklet to codify the algorithm and train countries in its use. The Committee encouraged the subgroup to further develop the product and endorsed the work process.

⁵Aide-mémoire: Adverse events following immunization (AEFI): causality assessment. Geneva, World Health Organization, 2005. Available from http://whqlibdoc.who.int/aide-memoire/a87773_eng.pdf; accessed July 2012.

⁶Halsey NA et al. Algorithm to assess causality after individual adverse events following immunizations. Vaccine, 2012. Available online at http://www.ncbi.nlm.nih.gov/pubmed/22507656, accessed July 2012.

⁷Definitions and application of terms for vaccine pharmacovigilance. Geneva, World Health Organization/ Council for International Organizations of Medical Sciences, 2012. Available at http://whqlibdoc.who.int/publications/2012/9789290360834_eng.pdf, accessed July 2012.

Full report of GACVS meeting of 6-7 June 2012, published in the WHO Weekly Epidemiological Record on 27 July 2012

Core variables for AEFI monitoring

Collection of harmonized data on AEFI allows for better comparison and pooled analysis with findings from vaccine safety surveillance systems. In collaboration with a network of countries and independent experts, a preliminary list of core variables had been proposed. This list was subsequently compared with the reporting forms from the WHO Programme for International Drug Monitoring (Uppsala Monitoring Centre) to verify which variables are captured by the current reporting forms. Through this exercise, it became apparent that vaccine safety monitoring needs tools which are more specific to the type of variables required for proper AEFI surveillance and that the current web-based interface developed for reporting of suspected drug reactions (VigiFlow) should be adapted for AEFI reporting. To address these issues, the GACVS in December 2011 suggested developing a simpler and vaccine-specific user interface to enter AEFI data. A subgroup of GACVS was tasked to address those issues and presented the status of ongoing activities at the June 2012 meeting.

Collection of basic and advanced AEFI information

It is recognized that for the purpose of signal detection, data collection tools should remain as simple as possible. However, when signals are detected, or in cases of serious AEFI, additional data are essential to allow inferences to be drawn on the association with vaccines and to assess the need for further investigation and action. The subcommittee presented GACVS with 22 core variables that should be collected for any AEFI (basic information) and an additional 33 variables of interest for a more detailed case review (advanced information). Basic information collected needs to be prioritized because the AEFI data collection, collation, transmission, analysis and feedback systems in different countries are heterogeneous. In addition, quantitative and qualitative aspects of data need to be considered. The suggested approach proposes a basic minimum of 22 variables with 10 identified as critical. This simple structure is expected to encourage countries that do not yet have an AEFI surveillance system in place to develop one. It is proposed that the reporting tool include the WHO-ART dictionary in order to standardize the terminology used to record signs, symptoms or a diagnosis, as well as a vaccine dictionary that will include details pertaining to all of the vaccines suspected. For the advanced information, details on the nature and frequency of reporting for events such as in campaigns or in routine immunization programmes, breast or bottle feeding, status of previous vaccination are proposed.

Vacciflow

“VacciFlow” will be developed as the adaptation of drug-specific VigiFlow 4.2 to facilitate the entry of vaccine-related AEFI data including immunization programme errors. Ideally “VacciFlow” will be used by both the national regulatory authority and the immunization programme staff. The possibility of incorporating this new interface with minimal computer capabilities and mobile phone technology was encouraged by GACVS. There will be 3 flexible levels created in “VacciFlow” enabling national and subnational level users to analyse and use the data available for action at each level. Automatic feedback to reporters on the status of the report will be built in. Adapting (modifying) existing AEFI reporting systems to adjust to the data proposed in this core set of variables will require an educational and dissemination effort in many countries. It is expected that the upcoming “VacciFlow” will be sufficiently simple and user-friendly to allow tailor-made adjustment for locally collected information.

Full report of GACVS meeting of 6-7 June 2012, published in the WHO Weekly Epidemiological Record on 27 July 2012

Global network for post-marketing surveillance and AEFI monitoring

GACVS was presented with an update on the progress of the global network for post-marketing surveillance (PMS Network) of adverse events following immunization (AEFI), a WHO-led pilot project aimed at enhancing the monitoring, reporting and sharing of vaccine safety data for countries introducing new prequalified vaccines.

Started in 2007, the aim of the project was to establish a network of at least 20 countries that have introduced newly prequalified vaccines, to stimulate the reporting of AEFI to a central database (VigiBase) located at the WHO Collaborating Centre for international drug monitoring (Uppsala Monitoring Centre; UMC), in Sweden. By 2011, 12 countries had been included in the network: Albania, Brazil, China, India, Islamic Republic of Iran, Kazakhstan, Mexico, Senegal, Sri Lanka, Tunisia, Uganda, and Viet Nam. Countries enrolled in the network have had a baseline evaluation of their national vaccine regulatory process and their AEFI surveillance system capability. In addition, countries were trained in the use of VigiFlow, a software platform to report and upload AEFI cases to UMC, and on the methods of causality assessment for vaccine AEFI classification.

The PMS Network has improved the reporting of AEFI for vaccines in most participating countries. Participating countries have recognized the need for and benefits of the network, but operational challenges exist. Due to lack of harmonization of current surveillance and reporting systems, including case report forms, software systems, and type of AEFI reported, the heterogeneous data accumulated at UMC is likely to provide only limited vaccine safety signals globally. Even though the network primarily focused on newly prequalified vaccines, data collected relates mainly to other, more traditional, vaccines prequalified or not. In addition, the network countries have identified the need for a simpler data processing tool that could be more specific for vaccines and that could be operated offline given the internet connectivity limitations in most countries. GACVS also recognized the limited value of spontaneous reports to generate comprehensive data that can later be used to determine vaccine safety/risk profiles via standard methods. Nevertheless, spontaneous reports of AEFI are important to generate signals for vaccine safety monitoring systems and can inform the design and conduct of careful epidemiological studies to assess potential risks.

GACVS also recognized the limited value of spontaneous reports to generate comprehensive data that can later be used to determine vaccine safety/risk profiles via standard methods. Nevertheless, spontaneous reports of AEFI are important to generate signals for vaccine safety monitoring systems and can inform the design and conduct of careful epidemiological studies to assess potential risks.

GACVS also acknowledges the importance of a global and centralized database for all drugs and vaccines. A more comprehensive and active database for vaccines could allow countries, regions, and investigators to detect global vaccine safety signals that could go unrecognized at a country level, as well as provide background data on common and uncommon adverse events. UMC has the capability and know-how to provide the data infrastructure needed for such an endeavour. UMC could develop a simple data entry tool, based on a minimal dataset, to serve the perceived needs of lower and middle income countries.

As part of the PMS Network activities, a dictionary for prequalified vaccines has been developed. This vaccine dictionary is considered an essential tool for the countries and AEFI systems to determine the components of vaccines that could be implicated in serious or relevant adverse events. It is therefore paramount to expand this dictionary to ensure the inclusion of other licensed vaccines in use, transparent participation from manufacturers, and free availability to countries that need it most.

GACVS also emphasized the need for strengthening AEFI surveillance systems at country and regional levels to improve the current reporting of safety signals following immunization. The development of regional networks could be the next step towards improving the reporting of AEFI and vaccine safety signals at the global level.

Full report of GACVS meeting of 7-8 December 2011, published in the WHO Weekly Epidemiological Record on 10 February 2012