A pandemic is a fast-moving situation, and as the H1N1 virus began to spread throughout the world in 2009, pharma companies leapt into action to start the process of developing vaccines. In late 2009, the first vaccines began to be authorised by the European Medicines Agency, the EU body whose job it is to give the green light to drug manufacturers to market new medicines. As with any new vaccine, clinical studies carried out by the pharma companies before the vaccines were approved had produced lots of data on the safety, tolerability and efficacy and vaccines. However, clinical studies don’t tell us everything we need to know about the effect of a vaccine because they’re limited, both in size and diversity. That’s why the authorities usually require the drug maker to carry out other studies ‘post marketing’ i.e. once the vaccine has been rolled out, so that they can continue to gather evidence about its safety and its effectiveness in a much wider swathe of the population.
Traditionally, efforts to monitor the coverage, benefits and risks of vaccines after approval have been fragmented. Once the vaccines are approved, certain data are inaccessible to the pharma companies because they are not within the companies’ control. This is true for data on effectiveness, though not for data on adverse events, since each company has its own database of post-marketing adverse event reports and many also have access to some real-world databases. While these are accessible, it is however sometimes not sufficient and additional data may be needed. The custodians of this data are disease surveillance bodies i.e. public health institutes and the pan-EU European Centres for Disease Control (ECDC), who are responsible for collecting information about diseases and vaccine effectiveness.
In order to maintain a reputation for independence, the ECDC and national public health bodies have traditionally been reluctant to build a relationship with pharma companies. This is understandable; the public’s willingness to take a vaccine can largely depend on the level of trust they have in the authorities, and the perception of independence is crucial in this regard. However, without access to these data, the pharma industry is unable to produce this post-marketing evidence. Beyond the problems this poses for the industry, the lack of solid, scientific evidence of the impact of a vaccine on a broad scale hampers public health bodies’ ability to detect adverse effects and other rare events in the population, in turn delaying their reaction to such events. This, too, is bad for public trust in vaccines.
Recognising that this way of doing things was unsustainable, ADVANCE set about conceiving a new system that would not only bring all these disparate groups around the table, but crucially, give them access to scientific, independent and transparent information, quickly and easily, so that they can feed their own decision-making and vaccine strategies. After two years of negotiation, ADVANCE were able to set up a consortium made up of the European Medicines Agency, the ECDC and other public health institutes, academic groups, and almost all vaccine manufacturers in Europe.
Having drawn up the best practice guidelines for collaboration between the different players, ADVANCE identified and made profiles of the different data sources that are capable of yielding rapid access to vaccine information – such as electronic health records, disease surveillance systems, and other healthcare databases. They also went about establishing exactly what kind of evidence different stakeholders would need access to, i.e. background rate of events (events that are temporally associated with but not caused by vaccination), vaccine coverage, whether the vaccine seems to work, and safety data. They then built new tools to link up this data and analyse it, taking into account the interoperability of the different systems, and ran their own test cases – proof of concept studies to make sure the tools worked.
The ADVANCE partners decided to set up an international non-profit called VAC4EU, analogous to the US body DataLink/Sentinel, that now stands ready to respond rapidly and reliably to questions from manufacturers, regulators and public health authorities about the impact of a vaccine on a given population, based on real-world data. VAC4EU does not pool all data from EU countries in one place; rather, the data is generated locally in each country or region, and local teams input their own data locally in a standardised, structured way. They then have the ability to run a programme that analyses the data and comes up with standardised results and to pool their evidence with other countries to get a more zoomed-out view.
There is a lot of heterogeneity in Europe’s health care systems, not to mention languages, and yet ADVANCE has definitively demonstrated that despite all these differences, a Europe-wide system can work; the VAC4EU platform can deliver robust data that not only deals with this heterogeneity, but can even exploit it. For example, European countries may be using different vaccines, having negotiated contracts independently with several manufacturers. Working in a standardised allows them to compare the different the effects of the different vaccines, giving them a chance to study the evidence for the benefits and adverse events of the different schemes on a much bigger scale. This not only has the effect of building collaboration between countries but also builds capacity within the countries themselves, helping spark new collaborative relationships between public health institutes and the national regulators.
Working on a European level also makes it possible to compare vaccine data between continents; for example, none of the vaccines that were deployed in the U.S. in the wake of the 2009 H1N1 pandemic were adjuvant vaccines (adjuvants are added to vaccines to or enhance immune responses). In Europe, on the other hand, a number of adjuvant vaccines were used. It would be very informative to be able to compare the evidence both continents on effectiveness and adverse effects.
The VAC4EU platform is designed to promote the best practices developed in the ADVANCE project related to collaboration between the different stakeholders, as well as study conduct, ethics, and privacy protection relating to the capture, sharing and trustworthy generation of real-world health data. It is intended to stimulate scientific discussions and keep up with new methods and other important developments. It can provide training, access to a unique vaccine expert community and study network that boosts links and consensus between the regulators, public health institutes, researchers, and vaccine manufacturers, as well as patient and citizen groups and healthcare providers.
With VAC4EU, all the necessary infrastructure is in place to carry out a pan-European monitoring of the effects of the COVID vaccines when they are rolled out in the population, helping to maintain public confidence in immunisation as an effective public health tool to control infectious disease. Limited funding has been made available from the EMA.
Achievements & News
In the run-up to World Immunisation Week 2019, the IMI Programme Office caught up with three projects working in this important area.###
- Vaccines are one of the most effective public health measures out, yet public distrust in immunisation programmes is limiting high vaccine uptake, resulting in outbreaks of vaccine-preventable infectious diseases that had almost disappeared. ADVANCE has paved the way for an open system for actively monitoring vaccine coverage, benefits and risks in Europe. Read more
- Zoonoses are infectious diseases that can be transmitted to humans from animals (and vice versa). IMI's ZAPI project is working to create new platforms and technologies that will facilitate a fast, coordinated, and practical response to new infectious diseases as soon as they emerge. Read more
- Every year, pharmaceutical companies develop vaccines designed specifically to combat the strains of influenza (flu) that are most likely to be in circulation the following winter. However, accurately predicting how much protection a new vaccine would actually offer against emerging virus types is far from easy. The FLUCOP project is developing tools to address this challenge. Read more
World Immunisation Week is organised by the World Health Organization at the end of April every year.
The ADVANCE project will hold a conference entitled ‘EU ecosystem for monitoring of post-licensure vaccine benefit and risk: From ADVANCE to VAC4EU’ in Brussels, Belgium on 6 March 2019. ###ADVANCE brings together all major stakeholder groups interested in the post-marketing monitoring of the health benefits and risks of vaccines, and the consortium has demonstrated that the wealth of existing real-world health care data in the EU can be used to generate actionable evidence on vaccine coverage, benefits, and risks. This event will showcase the projects’ outputs; debate whether and how rapid evidence may help in reducing vaccine hesitancy; and present VAC4EU, the association which will implement the ADVANCE blueprint in the post-project phase. VAC4EU will allow EU research organisations to join the community and study network and collaborate in generating high quality and timely evidence on vaccine coverage, benefits and risks.
IMI’s ADVANCE project has published a blueprint of a framework to rapidly provide scientific evidence of the benefits and risks of vaccines that are on the market. The document is the culmination of the project’s work and is designed to help health professionals, regulatory agencies, public health institutions, vaccine manufacturers and the general public make more informed decisions on the benefits and risks of vaccines. ###Vaccinations are a highly successful public health intervention. However, as they are used primarily in healthy people (often children), expectations on their safety and effectiveness are particularly high. ADVANCE was set up to pave the way for a framework to make it easier and faster for people to assess vaccine benefits and risks. The project’s blueprint has two parts. Firstly, there is a comprehensive manual for the future use of the framework. This sets out the steps needed to use the framework, the tools that can be used, and how to disseminate results. The second part of the blueprint addresses the future sustainability of the network through four different scenarios. The blueprint was written by ECDC (European Centre for Disease Prevention and Control) based on the outputs from almost all work packages of ADVANCE. It has undergone a comprehensive consultation process with representatives of the main stakeholders interested in the assessment of benefits and risks of vaccines, including the ECDC Advisory Forum. It has also gone through a public consultation on ECDC website.
The ADVANCE project has developed a web application with an interactive dashboard designed to make it easier to monitor the benefits and risks of vaccines in near real time. The tool is described in a paper in the journal Drug Safety. Once implemented, it would allow users to rapidly determine whether further regulatory or public health actions may be needed. ###The benefit-risk profile of vaccines that is determined initially in clinical studies may change during the vaccine’s life cycle, and needs to be further assessed once vaccines are on the market. In this study, the ADVANCE team assessed the feasibility and added value of using an interactive dashboard to monitor vaccine uptake, benefits and risks as well as composite benefit-risk measures. The dashboard was developed and demonstrated using simulated data mimicking the UK’s introduction of the rotavirus vaccine. Feedback from stakeholders (including public health institutes, regulatory authorities, and pharmaceutical companies) revealed broad support for the dashboard, with users appreciating the interactive interface and the ability to visualise individual components. The stakeholders were however less in favour of the composite benefit-risk measures offered. The ADVANCE team concludes that ‘the proposed methodology is promising’ and they are now testing the dashboard with real-world data.
Monitoring the benefits and risks of vaccines is a complex and critical activity which involves multiple participants. Decisions that have to be made at the planning stage of such studies are complex and numerous, which can prove challenging in situations where rapid action needs to be taken and a benefit/risk assessment is urgently needed.### To address that challenge, IMI’s ADVANCE project published a Code of Conduct: a document which contains a set of guiding principles for the multiple decisions that need to be taken at all stages of the planning, design, conduct and reporting of future studies. If adopted by all partners involved in a study, these recommendations will not only make it easier for the partners to collaborate, but will also give confidence to health professionals and the public about the quality of their results.
The ADVANCE Code of Conduct, now available in the journal Vaccine, was developed by members of a wide range of different organisations including regulatory and public health authorities, vaccine manufacturers and academic organisations. Its development was guided by three core and common values (best science, strengthening public health, transparency), and a review of existing guidance and relevant published articles. The document includes 45 recommendations in 10 topics: scientific integrity, scientific independence, transparency, conflicts of interest, study protocol, study report, publication, subject privacy, sharing of study data, and research contract. In the publication, the authors said they hope that ‘adoption of the ADVANCE Code of Conduct by all partners involved in a study will facilitate and speed-up its initiation, design, conduct and reporting'. The Code of Conduct is one of the four components of good practice guidance for vaccine studies, which will also include recommendations for good governance, quality management and communication on vaccine safety. This important deliverable of the ADVANCE project aims to pave the way for a European framework capable of rapidly delivering reliable data on the benefits and risks of marketed vaccines.
Vaccine project ADVANCE has launched a public consultation on its draft Code of Conduct, which was developed to support the planning, initiation, design, conduct and reporting of observational studies in the field of vaccines.###
The Code of Conduct will also support interactions between different parties involved in studies on vaccines and provide confidence to health professionals and the public about the quality of their results.
The development of this Code of Conduct is co-led by the European Medicines Agency (EMA) within the ADVANCE project.
The draft Code of Conduct and details of how to submit feedback can be found online.
The consultation closes on 15 November 2015.
ParticipantsShow participants on map
- Glaxosmithkline Biologicals SA, Rixensart, Belgium
- Janssen Vaccines & Prevention BV, Leiden, Netherlands
- Merck Sharp & Dohme Corp, Whitehouse Station, New Jersey, United States
- Novartis Pharma AG, Basel, Switzerland
- Pfizer Limited, Sandwich, Kent , United Kingdom
- Sanofi Pasteur SA, Lyon, France
- Takeda Pharmaceuticals International AG, Glattpark-Opfikon (Zurich), Switzerland
Universities, research organisations, public bodies, non-profit groups
- Aarhus Universitetshospital, Aarhus, Denmark
- Agencia Espanola De Medicamentos Y Productos Sanitarios, Madrid, Spain
- Agenzia Di Tutela Della Salute Della Val Padana, Mantova, Italy
- Erasmus Universitair Medisch Centrum Rotterdam, Rotterdam, Netherlands
- European Centre for Disease Prevention and Control, Stockholm, Sweden
- Fundacio Institut Universitari Pera La Recerca A L'Atencio Primaria De Salut Jordi Gol I Gurina, Barcelona, Spain
- Karolinska Institutet, Stockholm, Sweden
- London School Of Hygiene And Tropical Medicine Royal Charter, London, United Kingdom
- Rijksinstituut Voor Volksgezondheid En Milieu, Bilthoven, Netherlands
- Sciensano, Brussels, Belgium
- Statens Serum Institut, Copenhagen S, Denmark
- Tampereen Korkeakoulusaatio Sr, Tampere, Finland
- The European Medicines Agency, Canary Wharf, London, United Kingdom
- The Open University, Milton Keynes, United Kingdom
- The Royal College Of General Practitioners, London, United Kingdom
- Universitat Basel, Basel, Switzerland
- University Of Surrey, Guildford, United Kingdom
Small and medium-sized enterprises (SMEs)
- P95 CVBA, Leuven, Belgium
- Societa Servizi Telematici SRL, Padova, Italy
- Synapse Research Management Partners SL, Barcelona, Spain
- Aarhus Universitet, Aarhus C, Denmark
- Fundacion Estatal, Salud, Infanciay Bienestar Social, F.S.P., Madrid, Spain
- Universitats-Kinderspital Beider Basel, Basel, Switzerland
Non EFPIA companies
- Agenzia Regionale Di Sanita, Firenze, Italy
- Medicines and Healthcare products Regulatory Agency, London, United Kingdom
|Name||IHI funding in €|
|Aarhus Universitetshospital||120 947|
|Agencia Espanola De Medicamentos Y Productos Sanitarios||125 452|
|Agenzia Di Tutela Della Salute Della Val Padana||105 299|
|Agenzia Regionale Di Sanita||33 290|
|Erasmus Universitair Medisch Centrum Rotterdam||546 123|
|European Centre for Disease Prevention and Control||220 221|
|Fundacio Institut Universitari Pera La Recerca A L'Atencio Primaria De Salut Jordi Gol I Gurina||37 790|
|Karolinska Institutet||59 528|
|London School Of Hygiene And Tropical Medicine Royal Charter||89 533|
|Medicines and Healthcare products Regulatory Agency||36 654|
|P95 CVBA||544 004|
|Rijksinstituut Voor Volksgezondheid En Milieu||224 664|
|Societa Servizi Telematici SRL||109 683|
|Statens Serum Institut||241 230|
|Synapse Research Management Partners SL||757 235|
|Tampereen Korkeakoulusaatio Sr||161 195|
|The European Medicines Agency||219 246|
|The Open University||82 174|
|The Royal College Of General Practitioners||166 275|
|Universitat Basel||77 094|
|University Of Surrey||462 600|
|Name||Funding in €|
|Aarhus Universitet||34 817|
|Universitats-Kinderspital Beider Basel||303 980|
|Total Cost||4 999 811|