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Introduction: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public private collaboration aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines, using existing electronic healthcare record (eHR) databases in Europe. Part of the data in such sources is missing due to incomplete follow-up hampering the accurate estimation of vaccination coverage. We compared different methods for coverage estimation from eHR databases; naïve period prevalence, complete case period prevalence, period prevalence adjusted for follow-up time, Kaplan-Meier (KM) analysis and (adjusted) inverse probability weighing (IPW). Methods: We created simulation scenarios with different proportions of completeness of follow-up. Both completeness independent and dependent from vaccination date and status were considered. The root mean squared error (RMSE) and relative difference between the estimated and true coverage were used to assess the performance of the different methods for each of the scenarios. We included data examples on the vaccination coverage of human papilloma virus and pertussis component containing vaccines from the Spanish BIFAP database. Results: Under completeness independent from vaccination date or status, several methods provided estimates with bias close to zero. However, when dependence between completeness of follow-up and vaccination date or status was present, all methods generated biased estimates. The IPW/CDF methods were generally the least biased. Preference for a specific method should be based on the type of censoring and type of dependence between completeness of follow-up and vaccination. Additional insights into these aspects, might be gained by applying several methods. [ABSTRACT FROM AUTHOR]

The 2009 influenza pandemic highlighted challenges for vaccine post-marketing monitoring in Europe, particularly the need to have appropriate infrastructures to strengthen public-private collaborations (PPCs) with suitable processes to improve stakeholder interactions and collection and analysis of safety and effectiveness data. The ADVANCE consortium comprises public and private stakeholders who have worked together to build and test new system components for vaccine post-marketing projects, one component being a governance framework for efficient, transparent and trustworthy PPCs. Based on the results of a landscape analysis and screening of formalised existing governance structures, we identified the elements of a governance framework and developed recommendations to support stakeholders willing and able to implement collaborative projects. These proposals and their implementation were discussed by 70 experts during a workshop to gain from their experience. We identified core governance principles and defined five fundamental functions (decision-making, scientific advice, quality control and audit, implementation and management, and financial administration) that can be attributed to individual partner organisations or to a committee with representatives from more than one partner organisation. We propose a generic governance model with options for its adaptation to specific contexts and projects. The advantages and disadvantages of PPCs were also examined. Stakeholders' concerns (e.g. scientific integrity and public trust) were addressed through recommendations about transparent decision-making rules and conflict of interest management. No one-size-fits-all solution for PPC governance exists but our recommendations could be used to set-up a tailored-made and fully transparent governance structure supporting collaborative projects in the European vaccine post-marketing environment. To allow the rapid establishment of robust projects, the next steps will involve this guidance being used by real-world collaborations to assess what works and what does not work and what added-value can be obtained from these collaborations. [ABSTRACT FROM AUTHOR]

• Europe needs a sustainable system for timely, high-quality evidence on vaccine benefits and risks. • European vaccine stakeholders have different perspectives but similar information needs. • The ADVANCE project (now VAC4EU) has developed and tested a system to generate the necessary evidence. The influenza A/H1N1 pandemic in 2009 taught us that the monitoring of vaccine benefits and risks in Europe had potential for improvement if different public and private stakeholders would collaborate better (public health institutes (PHIs), regulatory authorities, research institutes, vaccine manufacturers). The Innovative Medicines Initiative (IMI) subsequently issued a competitive call to establish a public-private partnership to build and test a novel system for monitoring vaccine benefits and risks in Europe. The ADVANCE project (Accelerated Development of Vaccine benefit-risk Collaboration in Europe) was created as a result. The objective of this paper is to describe the perspectives of key stakeholder groups of the ADVANCE consortium for vaccine benefit-risk monitoring and their views on how to build a European system addressing the needs and challenges of such monitoring. These perspectives and needs were assessed at the start of the ADVANCE project by the European Medicines Agency together with representatives of the main stakeholders in the field of vaccines within and outside the ADVANCE consortium (i.e. research institutes, public health institutes, medicines regulatory authorities, vaccine manufacturers, patient associations). Although all stakeholder representatives stated they conduct vaccine benefit-risk monitoring according to their own remit, needs and obligations, they are faced with similar challenges and needs for improved collaboration. A robust, rapid system yielding high-quality information on the benefits and risks of vaccines would therefore support their decision making. ADVANCE has developed such a system and has tested its performance in a series of proof of concept (POC) studies. The system, how it was used and the results from the POC studies are described in the papers in this supplementary issue. [ABSTRACT FROM AUTHOR]

Background: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private partnership aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines using European electronic health record (eHR) databases. This proof-of-concept study aimed to test the feasibility of near real-time (NRT) monitoring of vaccination coverage, benefits and risks based on multiple European eHR databases, using acellular pertussis vaccination in children aged <6 years as test case., Methods: A qualitative feasibility assessment on NRT monitoring was carried out using a survey and face-to-face discussion with ADVANCE data partners. Subsequently, a dynamic cohort study was conducted containing two distinct observation periods: a first period to establish a baseline (Jan 2014 to Mar 2018) and a subsequent 3-month period to test the actual feasibility of weekly NRT monitoring, based on which data latencies were calculated. An interactive web-application was additionally developed to facilitate the visual monitoring of vaccination coverage, the vaccine preventable disease incidence rates (benefits) and the incidence rates of adverse events (risks)., Results: Nine databases from four countries (Denmark, Italy, Spain and UK) participated in the qualitative feasibility assessment. Of them, five databases took part in the dynamic cohort study, with 5 databases providing baseline data and 3 databases participating to the NRT monitoring, providing data extractions on an almost weekly basis. The median data latency (time between event date and data release date) was between 1 and 2 weeks except for the benefit and risk events in one of the databases (latency 16 weeks)., Conclusion: Three European eHR databases successfully demonstrated the feasibility of providing data for weekly NRT monitoring, with short data latencies of 1-2 weeks for most events., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tom de Smedt, Chris McGee, Hanne-Dorthe Emborg, Marco Villa, Talita Duarte-Salles, declared no potential conflicts of interest. Kaatje Bollaerts and Maria Alexandridou received consultancy fees from GSK for work unrelated to the submitted work. Rosa Gini declared that her institution is participating in studies funded by Novartis, Eli Lilly, and Daiichi outside the scope of this project. Claudia Bartolini declared she has received grants from PHARMO Institute for work outside the submitted work. Simon de Lusignan declared he has received funding through his University to conduct enhanced surveillance of influenza vaccine (GSK), and is a member Seqirus and Sanofi Pasteur advisory boards for which he received personal payment within the limits defined by his university. Myint TinTin Htar declared that she is employed by Pfizer and holds company shares. Miriam Sturkenboom declared that she has received grants from Novartis, CDC and Bill & Melinda Gates Foundation, for work unrelated to the submitted work. Lina Titievsky declared that she is employed by Pfizer and holds company stocks/shares. Vincent Bauchau declared that he is employed by GSK and holds company shares., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines using electronic health record (eHR) databases in Europe. Proof-of-concept studies were designed to assess the proposed processes and system for generating the required evidence to perform B/R assessment and near-real time monitoring of vaccines. We aimed to test B/R methodologies for vaccines, using the comparison of the B/R profiles of whole-cell (wP) and acellular pertussis (aP) vaccine formulations in children as an example., Methods: We used multi-criteria decision analysis (MCDA) to structure the B/R assessment combined with individual-level state transition modelling to build the B/R effects table. In the state transition model, we simulated the number of events in two hypothetical cohorts of 1 million children followed from first pertussis dose till pre-school-entry booster (or six years of age, whichever occurred first), with one cohort receiving wP, and the other aP. The benefits were reductions in pertussis incidence and complications. The risks were increased incidences of febrile convulsions, fever, hypotonic-hyporesponsive episodes, injection-site reactions and persistent crying. Most model parameters were informed by estimates (coverage, background incidences, relative risks) from eHR databases from Denmark (SSI), Spain (BIFAP and SIDIAP), Italy (Pedianet) and the UK (RCGP-RSC and THIN). Preferences were elicited from clinical and epidemiological experts., Results: Using state transition modelling to build the B/R effects table facilitated the comparison of different vaccine effects (e.g. immediate vaccine risks vs long-term vaccine benefits). Estimates from eHR databases could be used to inform the simulation model. The model results could be easily combined with preference weights to obtain B/R scores., Conclusion: Existing B/R methodology, modelling and estimates from eHR databases can be successfully used for B/R assessment of vaccines., Competing Interests: Declaration of Competing Interest Tom de Smedt, Hanne-Dorthe Emborg, Giorgia Danieli, Talita Duarte-Salles, Consuelo Huerta, Elisa Martin-Merino, Gino Picelli and Lara Tramontan declared no potential conflicts of interest. Kaatje Bollaerts and Daniel Weibel received consultancy fees from GSK for work unrelated to the submitted work. Miriam Sturkenboom declared that she has received grants from Novartis, CDC and Bill & Melinda Gates Foundation, for work unrelated to the submitted work. Edouard Ledent and Vincent Bauchau declared that he is employed by GSK and holds company shares., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The Accelerated Development of Vaccine benefit-risk Collaboration in Europe (ADVANCE) public-private collaboration, aimed to develop and test a system for rapid benefit-risk monitoring of vaccines using healthcare databases in Europe. The objective of this proof-of-concept (POC) study was to test the feasibility of the ADVANCE system to generate incidence rates (IRs) per 1000 person-years and incidence rate ratios (IRRs) for risks associated with whole cell- (wP) and acellular- (aP) pertussis vaccines, occurring in event-specific risk windows in children prior to their pre-school-entry booster., Methods: The study population comprised almost 5.1 million children aged 1 month to <6 years vaccinated with wP or aP vaccines during the study period from 1 January 1990 to 31 December 2015. Data from two Danish hospital (H) databases (AUH and SSI) and five primary care (PC) databases from, UK (THIN and RCGP RSC), Spain (SIDIAP and BIFAP) and Italy (Pedianet) were analysed. Database-specific IRRs between risk vs. non-risk periods were estimated in a self-controlled case series study and pooled using random-effects meta-analyses., Results: The overall IRs were: fever, 58.2 (95% CI: 58.1; 58.3), 96.9 (96.7; 97.1) for PC DBs and 8.56 (8.5; 8.6) for H DBs; convulsions, 7.6 (95% CI: 7.6; 7.7), 3.55 (3.5; 3.6) for PC and 12.87 (12.8; 13) for H; persistent crying, 3.9 (95% CI: 3.8; 3.9) for PC, injection-site reactions, 2.2 (95% CI 2.1; 2.2) for PC, hypotonic hypo-responsive episode (HHE), 0.4 (95% CI: 0.4; 0.4), 0.6 (0.6; 0.6) for PC and 0.2 (0.2; 0.3) for H; and somnolence: 0.3 (95% CI: 0.3; 0.3) for PC. The pooled IRRs for persistent crying, fever, and ISR, adjusted for age and healthy vaccinee period were higher after wP vs. aP vaccination, and lower for convulsions, for all doses. The IRR for HHE was slightly lower for wP than aP, while wP was associated with somnolence only for dose 1 and dose 3 compared with aP., Conclusions: The estimated IRs and IRRs were comparable with published data, therefore demonstrating that the ADVANCE system was able to combine several European healthcare databases to assess vaccine safety data for wP and aP vaccination., Competing Interests: Declaration of Competing Interest Caitlin Dodd, Talita Duarte-Salles, Gino Picelli, Lara Tramontan, Giorgia Danieli, Ana Correa, Chris McGee, Elisa Martín-Merino, Consuelo Huerta, Hanne-Dorthe Emborg, Kaatje Bollaerts, Klara Berencsi declared no conflicts of interest. Daniel Weibel declared personal fees from GSK outside the submitted work. Olivia Mahaux, Francois Haguinet and Vincent Bauchau declared that they are employed by GSK and hold shares from GSK. Lina Titievsky declared that she is employed Pfizer and holds stocks from Pfizer. Miriam Sturkenboom declared that she has received grants from Novartis, CDC and the Bill & Melinda Gates Foundation outside the submitted work., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)