We will establish 3 standard Brighton Collaboration Working Groups based on the ad hoc Task Forces established during the WHO-Brighton Collaboration process in preparation of the WHO/Brighton Collaboration consultancy in Geneva, July 2014. One group is dedicated to prioritized outcomes in the mother and will focus on mother’s health, obstetric events during pregnancy, and delivery outcomes. One group is dedicated to the neonate ( 28 days of life ) and will include outcomes in the fetus. A third group will focus on the development of the glossary of enabling terms. The first two groups will form working groups comprised of a total of about 100 -200 volunteer subject matter experts to develop and revise the large number of case definitions simultaneously. These working groups will include representatives of public and private stakeholders and seek wide geographic distribution including LMIC. They will review the evidence from the pre-existing WHO-Brighton Collaboration landscape analysis and develop a set of interim case definitions according to the Brighton Collaboration process and format (https://brightoncollaboration.org/public/what-we-do/setting-standards/case-definitions/process.html). These interim definitions will be submitted for peer review to the global Brighton Collaboration Reference Group consisting of 3000 volunteer professionals as well as the investigators of ongoing trials and key stakeholder organizations. Specific focus will be on applicability in LMIC. Comments of this consultation will be incorporated in the final version of the definitions to be published in the peer reviewed medical literature.
The work of this group will build on the enormous work done at the Enterprise Vocabulatory Services, National Cancer Institute also in collaboration with the National Children’s Study at NIH related to the establishment of ontologies, terminologies and disease concepts for the monitoring of drug and vaccine safety in pregnancy. It will utilize (and possibly improve) the UMLS system for terminology services and will draw on existing infrastructures for code mapping across disease code dictionaries. It will also leverage the extensive pharmacoepidemiological expertise specific to multinational observational studies and federated database research for the development of case identification algorithms at EMC. The groups will build on previous interaction between NIH, EMC and the Brighton Collaboration in the context of a European Commission funded project called Global Research in Pediatrics towards the finalization of WP 2 deliverables. The NIH has developed terminologies and ontologies for maternal, fetal, obstetric and neonatal outcomes in the frame of the national children’s study and a general terminology service. GAIA will build on this development and ensure compatibility with other terminologies by mapping and consensus formation. NIH will not be able to accept funding from the BCF and contribute in kind.
This work package will capitalize on an existing draft guideline for collection, analysis and presentation of data developed by the Brighton Collaboration for monitoring the safety of immunization in pregnancy. This will be tailored to the needs of this project and will be finalized based on feedback from investigators of ongoing studies and parallel projects. Based on the new case definitions and guidance document a data collection matrix will be developed outlining key variables to be collected in the different monitoring settings during the vaccine and program life cycle. The existing Automated Brighton Collaboration Case Classification tool (ABC tool) will be expanded to include the newly developed set of case definitions and guidelines for automated single case and batch classification by level of diagnostic certainty and to prompt the investigator on critical information to be collection (on follow-up) for a given case to meet a higher level of diagnostic certainty.
The work package will promote evaluation and implementation of the interim and finalized versions of the standards, guidelines and tools in parallel efforts. We will leverage the internationally recognized capacity of IABS to organizing scientific conferences and symposia on approaches to standardize assessment of biologicals by bringing together public and private stakeholders and working towards inclusion of these standards in regulatory frameworks. We provide advice and solicit feedback from investigators in ongoing studies and research consortia for potential improvement of case definitions. Finally, review and recommendation of the standards by key organizations will be sought by this working group.
Work plan control and update, schedule control, implementation of corrective actions.
Assurance of timely submission of deliverables with appropriate quality levels.
Risk Management and promotion of synergy and efficiency throughout.
Cost control and budget management.
Contract and legal management, entailing also the management of the subcontracts and formalizing updates of the work plan, roles and resources assignment as needed.
Definition of two Obstetric outcomes (Chorioamnionitis and Post-partum Endometritis) and two Neonatal outcomes (Neurodevelopmental delay and Neonatal seizures) will be developed, according to the feedback received through the BC consensus process from the priority list of the 2014 WHO consultation meeting and relevant to the vaccines that are under development and evaluation for pregnant women. The work will follow the standard Brighton Collaboration development process that was adapted to immunization in pregnancy in the PHASE I of GAIA.
Case based causality assessment of AECMI is not self evident and it is distinct from the causality assessment of AEFI of a single individual. Specific guidelines do not exist to address the considerations of causality assessment in the pregnant mother, the foetus, and the newborn when the pregnant woman is vaccinated. GAIA will develop a single document/tool to assess causality of AECMI. The WHO Causality Assessment of AEFI document will serve as the starting point and we will convene experts in the field for the development of this guideline.
Based on feedback from investigators, manufacturers, and public health organizations received at the GAPPS meeting, and substantiated by stakeholder interviews, GAIA will create structured variable lists with an exemplified CRF data collection format to facilitate study-specific CRF development and other forms of data collection, as well as implementation of GAIA outcome definitions.
GAIA will develop an Obstetric Risk Assessment Tool (ORAT) to evaluate the risk for obstetric complications in pregnant women who participate in clinical trials of maternal immunization. The ORAT will be applicable to all settings, and will be supported by a guidance document for investigators to assess the obstetric risk in women enrolling in clinical trials of vaccines given during pregnancy. The process will follow a review of existing literature, guidelines, and tools utilized in previous and on-going clinical trials of MI, and will convene experts in the field.
GAIA will use the Brighton Collaboration case definitions for creating Standard Medical Queries based on GAIA case definitions in collaboration with MedDRA key users (e.g., regulatory authorities, manufacturers, CIOMS) for submission to MSSO. This should facilitate the implementation of GAIA case definitions for adverse event monitoring of immunization in pregnancy.
Case Definition Map. The project will take all GAIA case definitions and map them to pertinent other definitions including ICD10, MedDRA, CDISC and other case definitions developed for pertinent disease monitoring. This is intended to make transparent the comparability of outcome data across perinatal health domains and settings.
In PHASE I, GAIA primarily focussed on the audience concerned with immunization and recognized the need for increased engagement of all medical specialties concerned with maternal health. Engagement of gynaecologists and obstetricians is an increased effort of GAIA, given the historically low exposure of OBGYN specialists to immunization questions. GAIA has also partnered with the CROWN (Core Outcomes in Women’s and Newborn Health) initiative, a consortium of all women and newborn health journals. Together with CROWN, GAIA proposes to efficiently disseminate GAIA outputs to this important audience. In addition, GAIA partners will maintain close interaction with key organizations including WHO, CIOMS, FDA, EMA, Public Health Canada, AVAREF, AMRH, manufacturers of vaccines for immunization in pregnancy, and professional societies. Furthermore, GAIA dissemination activities will be supported by the GAIA website, newsletters and social media.
GAIA will generate an inventory of planned and on-going clinical trials of vaccines and immunization in pregnancy. The utilization of GAIA case definitions in these trials will be assessed to understand the rationale for selecting the GAIA definitions, the applicability of the case definitions, and lessons learned from their utilization.
GAIA guidelines and outcome definitions are increasingly used by investigators from academia, manufacturers, and public health organizations. GAIA will launch a survey to all investigators having used GAIA guidelines or case definitions in the field to obtain feedback on applicability and usefulness as well as other performance parameters as applicable.
Impact assessment. Low birth weight, small for gestational age, the preterm birth and gestational Age (GA) assessment algorithm are defined terms that are key to the assessment of various neonatal outcomes. GAIA will investigate these parameters in order of priority in the context of an on-going RCT of maternal immunization with Pneumococcal vaccine (PCV13) in The Gambia MRC.
GAIA will generate an inventory of state-of-the-art methods for evaluation of outcome definition performance in immunization in pregnancy studies. This will require an appraisal of methods applied to similar case definitions and settings and their potential for translation to immunization in pregnancy.