D5.3 POC Research plan - advance-vaccines.eu · D5.3 POC research plan v1.3 7 This preliminary glossary of terms used in the review will be further developed in ADVANCE accumulating

© Copyright 2013 ADVANCE Consortium

www.advance-vaccines.eu

Accelerated Development of VAccine beNefit-risk Collaboration in Europe

Grant Agreement nº115557

D5.3 POC Research plan

WP5 – Proof-of-concept studies of a framework

to perform vaccine benefit-risk monitoring

V1.3 Final

Lead beneficiary: EMC

Date: 22-05-2016 Nature: Report

Dissemination level: PU

http://www.advance-vaccines.eu/


D5.3 POC research plan v1.3

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Contents

DOCUMENT INFORMATION ........................................................................................................... 4

DOCUMENT HISTORY .................................................................................................................... 5

DEFINITIONS ................................................................................................................................. 6

PARTICIPATING INSTITUTIONS IN WP 5 .......................................................................................... 8

EXECUTIVE SUMMARY ................................................................................................................... 9

1. BACKGROUND ......................................................................................................................... 10

2. PROOF OF CONCEPT STUDY: GENERAL CONCEPTS..................................................................... 13

2.1 AIM OF THE PROOF OF CONCEPT .................................................................................................. 13 2.2 PROOF OF CONCEPT STUDIES ....................................................................................................... 13 2.3 PROOF OF CONCEPT: TIMING AND PHASES ..................................................................................... 13 2.4 STRUCTURE OF POC STUDIES ....................................................................................................... 14 2.5 CHOICE OF POC PHASE1 STUDIES ................................................................................................. 15

2.5.1 Solicitation of proposals .............................................................................................. 15 2.5.2. Response to POC proposal solicitation ............................................................................... 15 2.5.3 Criteria to select POC Phase 1 ..................................................................................... 16 2.5.4 Selection criteria assessment results for POC Phase 1 ................................................ 18

3. IMPLEMENTATION OF THE POC STUDY ................................................................................ 18

3.1 FRAMING OF THE DRIVING B/R DECISION IN THE POC ............................................................................. 18 3.1.1 Framing the Vaccines Benefit-risk decision making ............................................................ 19 3.1.2 B/R decisions to be proposed for pertussis (1st POC) .................................................. 20

3.2 SELECTION OF THE B/R QUESTION ................................................................................................ 21 3.3. POC OUTLINE ........................................................................................................................... 21 3.4 ROLES FOR POC STUDY .............................................................................................................. 21

3.4.1 Requester..................................................................................................................... 22 3.4.2 Funder and sponsor ..................................................................................................... 22 3.4.3 Responsible party ........................................................................................................ 22 3.4.4 Principal investigator ................................................................................................... 23 3.4.5 Investigator ................................................................................................................. 23 3.4.6 Data controller ............................................................................................................ 23 3.4.7 Data custodian/provider ............................................................................................. 23 3.4.8. Data analyst ................................................................................................................ 23 3.4.9 Quality control committee .......................................................................................... 23 3.4.10 End user ....................................................................................................................... 24

3.5 POC GOVERNANCE .................................................................................................................... 24 3.5.1 Finance ........................................................................................................................ 24 3.5.2 Study Steering Committee ........................................................................................... 25 3.5.3 External Advisory Board .............................................................................................. 25

3.6 RESPONSIBILITIES IN ADVANCE POC ........................................................................................... 25 3.6.1 Responsibility of the POC Coordination team ............................................................. 25 3.6.2 Responsibility of the ADVANCE SC ............................................................................... 25 3.6.3 Responsibility of coordination team in the performance of the POC study ................ 25 3.6.4 Responsibility of POC Evaluation committee .............................................................. 26 3.6.4 Responsibilities for different roles ............................................................................... 26

3.7 RESEARCH CONTRACT ................................................................................................................. 27


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3.8 CONFLICTS OF INTEREST .............................................................................................................. 28 3.9 SCIENTIFIC INTEGRITY ................................................................................................................ 28 3.10 CONFIDENTIALITY ...................................................................................................................... 28 3.11 TRANSPARENCY ......................................................................................................................... 29 3.12 DATA ACCESS ............................................................................................................................ 29 3.13 OWNERSHIP OF RESULTS ............................................................................................................. 29 3.14 STUDY PROTOCOL ...................................................................................................................... 29 3.15 STUDY REPORT .......................................................................................................................... 29 3.16 PUBLICATIONS AND COMMUNICATIONS ......................................................................................... 30 3.17 FILING AND ARCHIVING .............................................................................................................. 30 3.18 QUALITY .................................................................................................................................. 30

3.19 REGULATORY STATUS ...................................................................................................... 33

4. PROPOSED EVALUATION PARAMETERS .................................................................................... 37

APPENDIX 1: DRAFT ADVANCE CODE OF CONDUCT .................................................................... 39

APPENDIX 2: POC TEMPLATE .................................................................................................... 77

APPENDIX 3: MONITORING B/R PROPOSAL (PROPOSAL 1) ........................................................ 78

APPENDIX 4 POC PROPOSAL INFLUENZA (PROPOSAL 2) ............................................................ 80

APPENDIX 5: PERTUSSIS (PROPOSAL 3) ..................................................................................... 84

APPENDIX 6 POC PROPOSAL ROTAVIRUS (PROPOSAL 4) ........................................................... 90

APPENDIX 7: ZOSTER PROPOSAL (PROPOSAL 5) ......................................................................... 94

APPENDIX 8: HPV PROPOSAL P95 (PROPOSAL 6) ........................................................................ 96

APPENDIX 9: VARICELLA POC PROPOSAL (PROPOSAL 7) ........................................................... 100

APPENDIX 10: POC PROPOSAL HPV-UTA (PROPOSAL 8) ............................................................. 104

APPENDIX 11: COMBINED HPV PROPOSAL ................................................................................ 106

APPENDIX 12: POC RANKING .................................................................................................... 110

APPENDIX: 13 FRAMING THE BENEFIT-RISK DECISION PROBLEM: PERTUSSIS VACCINATION, V1.3-111

APPENDIX 14: POC OUTLINE V1.5 .............................................................................................. 119


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DOCUMENT INFORMATION

Grant Agreement Number

115557 Acronym ADVANCE

Full title Accelerated Development of VAccine beNefit-risk Collaboration in Europe

Project URL http://www.advance-vaccines.eu

IMI Project officer Angela Wittelsberger ([email protected]@imi.europa.eu)

Deliverable Number 5.3 Title POC research plan

Work package Number 5 Title Proof-of-concept studies of a framework to perform vaccine benefit-risk monitoring

Delivery date Contractual Month 18 Actual Month

Status Final version / V1.3 Draft Final

Nature Report Prototype Other

Dissemination Level Public Confidential

Authors (Partner) EMC, GSK

Responsible Authors

Miriam Sturkenboom (EMC)

Germano Ferreira (GSK)

Vincent Bauchau

Email

[email protected]

[email protected]

Partner EMC, GSK Phone

Description of the deliverable

This

Key words Proof of concept, post-authorization studies, platform, distributed network. Collaboration, standard procedures


mailto:[email protected]





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DOCUMENT HISTORY

NAME DATE VERSION DESCRIPTION

Miriam Sturkenboom 26-1-2015 1.0 First draft

Germano Ferreira 14-2-2015 Editing

Kaatje Bollaerts/ Vincent Bauchau

Section 3.1 on B/R

Miriam Sturkenboom 27-2-2015 1.1 Completed draft for SC review

Vincent Bauchau, Patrick Mahy, Marianne van der Sande, Alena Khromava. Piotr Kramarz, Laurence Pagnon, Jan Bonhoeffer, Tin Tin Htar, Tyra Grove Krause

28-02-2015 1.1 Review

Xavier Kurz 12-03-2015 1.1 Section 5 (regulatory status)

Laurence Pagnon (WP1/WG3)

20-3-2015 1.1 Governance contribution

CoC group (WG4 WP11) 1-4-2015 1.1 CoC draft V3 (appendix 1)

POC outline group 1-4-2015 1.1 POC outline (appendix 14)

Germano Ferreira, Miriam Sturkenboom

6-4-2015 1.2 Incorporation of SC comments, adding sections, appendices and quality criteria

Miriam Sturkenboom, Vincent Bauchua, Alena Khromava, Laurence Pagnon

22-05-2016 1.3 Update regulatory section and preparing for submission which was not done last year


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DEFINITIONS Participants of the ADVANCE Consortium are referred to herein according to the following codes:

- EMC. Erasmus Universitair Medisch Centrum Rotterdam (Netherlands) - Coordinator - UNIBAS. Universitaet Basel (Switzerland) - Managing entity of the IMI JU funding - EMA. European Medicines Agency (United Kingdom) - EC. European Commission - ECDC. European Centre for Disease Prevention and Control (Sweden) - SURREY. The University of Surrey (United Kingdom) - P95. P95 (Belgium) - SYNAPSE. Synapse Research Management Partners, S.L. (Spain) - OU. The Open University (United Kingdom) - LSHTM. London School of Hygiene and Tropical Medicine (United Kingdom) - PEDIANET. Società Servizi Telematici SRL (Italy) - KI. Karolinska Institutet (Sweden) - ASLCR. Azienda Sanitaria Locale della Provincia di Cremona (Italy) - AEMPS. Agencia Española de Medicamentos y Productos Sanitarios (Spain) - AUH. Aarhus Universitetshospital (Denmark) - UTA. Tampereen Yliopisto (Finland) - WIV-ISP. Institut Scientifique de Santé Publique (Belgium) - MHRA. Medicines and Healthcare products Regulatory Agency (United Kingdom) - SSI. Statens Serum Institut (Denmark) - RCGP. Royal College of General Practitioners (United Kingdom) - RIVM. Rijksinstituut voor Volksgezondheid en Milieu * National Institute for Public

Health and the Environment (Netherlands) - GSK. GlaxoSmithKline Biologicals, S.A. (Belgium) – EFPIA Coordinator - SP. Sanofi Pasteur (France) - NOVARTIS. Novartis Pharma AG (Switzerland) - SP MSD. Sanofi Pasteur MSD (France) - CRX. Crucell Holland BV (Netherlands) - PFIZER. Pfizer Limited (United Kingdom) - TAKEDA. Takeda Pharmaceuticals International GmbH (Switzerland)


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This preliminary glossary of terms used in the review will be further developed in ADVANCE accumulating the contributions for the various deliverables and work packages.

- Aggregated Data: Summarized information - Anonymised Data: Data that cannot be traced back to the individual patient - Data “controller”: the “controller” shall mean the natural or legal person, public

authority, agency or any other body which alone or jointly with others determines the purposes and means of the processing of personal data

- Data “processor”: is anyone who processes personal data for a controller - Data custodian: An individual / organisation / or group responsible for providing the data

to the ADVANCE platform. These can be data controllers or processors - (Datasource) Fingerprinting: characterization of the actual data characteristics of a

database. - ETL: Extract, Transform, Load - Harmonised Data: The harmonised data follow a consensus and are formatted in the

same way - Identified or identifiable natural person: means anyone who “can be identified, directly

or indirectly, in particular by reference to an identification number or by one or more factors specific to his/her physical, physiological, mental, economic, cultural, or social identity.”

- Ontology: An ontology is defined as a hierarchy, or specification of clinical concepts and their relationships within agiven domain1

- Original Data: Data, as maintained by the Data Source or any organization which collects the data, before inclusion in the platform

- Personal Data: any information relating to an identified or identifiable natural person (data subject);

- Proof of concept (POC): is a demonstration, the purpose of which is to verify that certain concepts or theories have the potential for real-world application

- Proof-of-concept (POC) studies: studies that will be conducted during ADVANCE project to evaluate and provide evidence of whether proposed innovations in methods, guidances and methods of integration and collaboration work

- Third party: is anyone who processes data under “the direct authority” of a controller or processor (Note: the code of conduct may specify further).

- Study: de novo scientific information generation following a specific question and protocol

1 Gruber T. A translation approach to portable ontology specifications. Knowledge Acquisition 1993; 5 (2):199–220. doi:10.1006/knac.1993.1008


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Participating institutions in WP 5 Participant No. / Short name

Names

Part.1/ EMC

Miriam Sturkenboom, Peter Rijnbeek, Johan van der Lei, Daniel Weibel, Caitlin Dodd, Kartini Gadroen, Benedikt Becker

Part.21/ GSK Germano Ferreira, Vincent Bauchau

Part.2/ UNIBAS-UKBB Jan Bonhoeffer, Danitza Tomianovic, Jorgen Bauwens

Part.3/ EMA Peter Arlett, Xavier Kurz

Part.5/ SURREY Simon de Lusignan, Filipa Ferreira, Harshana Liyanage

Part.6/ P95 Thomas Verstraeten, Kaatje Bollaerts

Part.10/ PEDIANET Anna Cantarutti, Lara Tramontan, Luigi Comachio

Part.11/ KI Lisen Arnheim Dahlström

Part.12/ ASLCR Silvia Lucchi, Marco Villa, Salvatore Mannino

Part.13/ AEMPS-BIFAP Elisa Martín, Consuelo Huerta, Miguel Gil, Ana Llorente

Part.14/ AUH Klára Berencsi , Lars Pedersen

Part.15/ UTA Matti Lehtinen, Simopekka Vanska

Part.16/ WIV-ISP Patrick Mahy, Lieke van der Aa

Part.18/ SSI Kåre Mølbak

Part.19/ RCGP Douglas Fleming, Hayley Durnall

Part.20/ RIVM Marianne Van der Sande, Susan Hahne, Jacco Wallinga Nicoline van der Maas , Hester de Melker, Wim van der Hoek , Fiona van der Klis, Nynke Rots , Willem Luytjes

Part.22/ SP Christine Luxemburger, Adel Abou-Ali

Part.24/ SP MSD Hélène Bricout, Susanne Hartwig, Géraldine Dominiak, Sandrine Gilhet-Mailfait


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EXECUTIVE SUMMARY The POC Research plan is aimed to provide an overview of the procedures that guide the first round of proof of concept studies.


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1. BACKGROUND The ADVANCE project emerged from the need to build an integrated and sustainable framework for the continuous monitoring of the benefit/risk of vaccines in Europe. The ADVANCE vision is to deliver “Best evidence at the right time to support decision-making on vaccination in Europe”, and the mission is to establish a prototype of a sustainable and compelling system that rapidly provides best available scientific evidence on vaccination benefits and risks post-licensure for well informed decisions. This will be achieved by developing and testing a code of conduct, rules of governance, technical infrastructures, data sources, methods, and workflows in a European network of stakeholders. ADVANCE aims to build an integrated and collaborative framework. By integrated, we currently mean a coordinated and harmonised approach by all stakeholders across the European member states with a stake on benefit and safety of vaccines and vaccination programs. European member states will continue having their national level approaches. ADVANCE will complement, not replace, activities in place at national level to monitor the benefits and risks of vaccines. It is envisioned that the following areas are those where the ADVANCE collaborative framework will bring added value:

1) To increase statistical power and allow for stratifications to subpopulations 2) To exploit variability in exposure to different types of vaccines and schedules across member

states (e.g. adjuvanted versus non-adjuvanted) 3) To enlarge research capacity and expertise across the member states 4) To be able to estimate and understand different results between member states 5) To help in interpretation of results across member states and support harmonised decision-

making ADVANCE Work Package (WP) 5 captures all activities that require actual use of data from the electronic healthcare databases, surveillance data, cohort data etc. and the technical infrastructure in order to generate information on vaccines benefits and risks. Requests for the so-called Proof of Concept studies (POCs) will arrive from ADVANCE work packages 1, 3, and 4 and will be developed in close collaboration with these work packages, experts in the consortium and subsequently sent for consortium input. Specific tasks in WP5 are:

1) Implementation of an information technology infrastructure that allows for collaborative studies;

2) Fingerprinting of all databases in ADVANCE and those identified in WP 3 that may be willing to participate in POC studies later;

3) Creation of ontologies, mapping of vaccines to a standard dictionary and outcome mapping for the respective proof of concept studies;

4) Conduct of proof of concept studies proposed by the SC and WPs 1, 3, 4; 5) Stakeholder feedback evaluation on the use of data and processes based on the proof-of-

concept studies. In deliverable 5.1 we described task 1: the available infrastructure and the proposed way of collaboration and workflow for generating new evidence from secondary use of health care data. This workflow is the basis for the collaborative POC studies on vaccine benefit and risk which will start in project month 18.


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The concept of bringing data together within and across countries with the purpose of addressing vaccine benefit/risk questions in a collaborative and integrated approach can be addressed in several ways with respect to:

1) Standardization of protocols to conduct studies on multiple data sources 2) Local data extraction 3) Transformation of the data into analytical datasets 4) Pooled analyses of data

In ADVANCE steps 1, 3 and 4 will be harmonized and centrally coordinated for specific studies upon appropriate protocol approval (see figure 1).

Figure 1: Distributed collaborative information generation workflow, with common protocol, standardized transformation and shared analyses while data extraction and original data remain local. This is the accepted ADVANCE approach.

In the Deliverable 5.1 we also described that the generation of information through this workflow takes place in an environment that should allow for facilitation (see figure 2). de novo information generation about the burden of disease, vaccine utilisation, benefits and/or risks of vaccines may generally follow a generic study flow comprising study scoping and protocol writing, data extraction, data transformation, analysis and reporting/communication (fig 1). In order to deliver evidence on benefit/risk monitoring rapidly we need to shorten time of setting up investigation as well as the investigation time to obtain results. In order to shorten these time periods, we propose to enable and optimise the collaborative research network to be ready to be activated at any point in time. This will be done in collaboration with WP 1, through the development and testing of Good practices guidance including study code of conduct and principles of governance for multi stakeholders initiatives,) and WP 3 (privacy and ethics). In addition, to shorten further the time from research question to results, we need to build capacity and test the readiness of methods and infrastructures that are acceptable by all participating stakeholders.


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Figure 2: Information generation workflow and enabling environment for studies on vaccine benefits and risks, though public and private collaborations and partnerships and principles of governance.

This deliverable aims to describe the Proof of Concept research plan including the procedures that will be used, the information to be collected to validate or further improve the original concept design. It starts with the enabling circumstances and this will be followed by looking at the procedures for the generation of information, oversight and research governance, and overall lessons to be learned from the first phase of POC to be further improved and tested in the phase 2 of ADVANCE POC


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2. Proof of Concept study: general concepts

2.1 Aim of the proof of concept The aim of a proof of concept (POC) in ADVANCE, as in other Innovative Research and Development initiatives, is to test the overall concept design (Fig 3), based on ADVANCE WPs deliverables produced so far, including: processes, circumstances and workflows of a system that focusses on generating evidence on benefit/risk (B/R) of vaccines. This process to generate evidence operates by performing studies, namely epidemiology, pharmacoepidemiology and B/R analysis. Proof of concept … is a realization of a certain method or idea to demonstrate its feasibility. … to verify that some concept or theory has the potential of being used.

Figure 3: Illustrative sketch of phases in prototype development of a car

Each POC will therefore be driven by a concrete and relevant B/R decision “to be made”, in line with the ADVANCE vision and mission, and within each POC B/R decision “umbrella” can contain multiple studies and evidence generation efforts to inform such an overarching driving B/R decision (see Fig.5)

2.2 Proof of concept studies The proof of concept studies will therefore constitute the deliverables that will be used to test methods, the IT systems/solutions, measure process performance parameters as indicators to what may be improved, and the acceptance of circumstances (ethical, transparency, Public-private multi-stakeholders interactions). Both, the proof and the concept as well as the types of studies included in the POC evolution aim to serve the vision of ADVANCE: Best evidence at the right time to support decision-making on vaccination in Europe. To this effect, the studies performed as part of the proof of concept evaluation are not to solely focus on addressing and answering a specific scientific question relevant to the project stakeholders. Although, the scientific question will be an essential part of the research components, it will allow to test the Concept and generate knowledge when combined together with: the data requirements, accurate measurement of timeliness for results, barriers for approvals and code of conduct to be followed, in order to build an example type of a scenario that may appear and trigger the need for information on benefit/risk, mirroring as close as possible a real-world situation.

2.3 Proof of concept: Timing and Phases In ADVANCE the proof of concept will be performed in two rounds of POC studies:

1) Phase 1: using databases present in the consortium and following state of the current art improved processes, focusing on identifying issues and areas of improvement in the system [early Concept design]

a. March 2015 research plan for phase 1 POC studies ready b. January 2016: Results of Phase 1 POC studies ready (this was original timing)


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c. Due to delays in protocol review & regulatory issues results of first POC are now expected in September 2016

2) Phase 2: using databases in consortium and potentially others outside the ADVANCE consortium (testing the updated system [Prototype] improved based on the results from Phase 1 POC)

a. May 2016 research plan ready for phase 2 studies b. April 2017 results of POC studies ready

The workflow for optimization is the following:

Figure 4: Phases of the ADVANCE project

2.4 Structure of POC studies As stated above, each POC are organised to test a set of innovative approaches to collect information that can lead to a full vaccines B/R analysis, Scientific information that goes into the B/R assessment and decisions requires information components from different pillars: burden of disease, vaccine effectiveness, vaccine safety, vaccine coverage, and the B/R analyses combining the evidence of the four other streams. Each of these pillars generates the information using their own methods (obtained through WP 4 D4.1, 4.2 and 4.3), their own protocol and study team. The WP 5 leaders will ensure that information from the pillars will feed the B/R assessment properly, as described in the POC Outline document. Within each pillar we will assess the ADVANCE process parameters, which will help us learn, design and tune the system, such that it can actually fulfil the ADVANCE mission. Process evaluation will be done together with experts from the University of Surrey. The ADVANCE POC Phase 1 studies will be conducted based on several elements from an early, preliminary, working version of draft ADVANCE Code of Conduct (CoC) (Appendix 1) such that this CoC can be assessed for acceptance and suitability for purpose as well. Pieces of this draft document are included in this deliverable in order to have a complete reference standard.


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Figure 5: Structure of the ADVANCE B/R proof of concept study: multiple pillars conducted as separate studies that collectively should provide the information for the proof of concept B/R analysis. At the same time all process parameters will be measured.

2.5 Choice of POC phase1 studies The identification and selection of POC and POC studies for ADVANCE was performed in close consultation with all partners and proactively seeking input from networks beyond the ADVANCE consortium (e.g. ECDC Advisory Forum). The overall selection was initiated by solicitation of proposals, review of proposals suggested during the WPs meetings and workgroups, agreement on the selection criteria for the first POC and ranking of proposals for relevance across all partners, followed by decision in SC advised by SAB input. The steps and results are described in the following sections.

2.5.1 Solicitation of proposals

POC proposals for the first phase were solicited from the entire consortium with the following rationale: The ADVANCE mission is to establish a prototype of a sustainable and compelling system that rapidly provides best available scientific evidence on vaccination benefits and risks post-licensure for well informed decisions. This will be achieved by developing and testing a code of conduct, principles of governance, technical infrastructures, data sources, methods, and workflows in a European network of stakeholders. We need to test the system that we built according to different scenarios that would routinely demand or trigger the benefit/risk evaluation of vaccines in real life, such as for example the approval of a new vaccine by a regulatory agency, the introduction of a new vaccination program by a public health authority, the fulfilment of a benefit-risk management activity by a vaccine manufacturer. A template was provided with 2 sections: one was the general ADVANCE objective and the second the scientific information (appendix 2).

2.5.2. Response to POC proposal solicitation

A total of 8 responses were received for POC proposals. They are listed in table 1. The full proposals are attached in the appendices 3-11. Proposals were presented during the general assembly meeting in Annecy


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Table 1: Key features of the submitted Proof of concept study proposals Proposal Objective Authoring

institution Vaccine Scenario

1 Establish the feasibility of continuously updating the information on the B/R from the first day after a vaccine is launched

Vincent Bauchau (GSK (WP4)

independent New vaccine on the market and subsequent unexpected new safety concern (signal) in the post-marketing era.

2 What is the benefit-risk of influenza vaccination in the targeted population? In different years seasons (i.e. …….) compared to non-vaccination?

Miriam (WP5) (Erasmus MC)

Influenza Seasonal vaccine with annual changes in composition, different matches against circulating viruses

3. What is the B/R of pertussis vaccination in various populations, and impact of formulation change (aP/wP) in B/R assessment?

Germano (WP5) (GSK)

Pertussis-containing vaccines

Old vaccine with varying formulations (whole-cell a-cellular formulation), varying vaccination schedules and boosting recommendations.

4 What is the benefit-risk of Rotavirus vaccination in children in Europe?

Thomas (P95) Rotavirus New vaccine, old safety issue

5 To compare validity, reliability and timeliness of using different methods and data sources to collect data.

University Surrey

Zoster New vaccine, methods of privacy

6 Assess IMI ADVANCE platform for data availability on cervical cancer screening uptake, human papillomavirus (HPV) vaccination coverage and HPV-related burden of disease covering different European countries.

Kaat (P95) HPV New vaccine, new safety issues

7 To assess the association between varicella vaccine and the occurrence of febrile convulsions

Anna (PEDIANET)

Varicella New vaccines, old safety issue

8 Establish the feasibility of continuously updating the information on the B/R from the first day after prophylactic HPV vaccines were launched.

Lise and Matti (UTA)

HPV New HPV vaccines on the market/programs and subsequent unexpected new safety concern (signals) in the post-marketing era.

9 Evaluate the B/R of the quadrivalent (6/11/16/18) and bivalent (16/18) HPV vaccines at licensure and annually thereafter

Vincent, Lise, Matti, Anna, Kaat (Combined from proposals above)

HPV New HPV vaccines on the market/programs and subsequently unexpected safety issues may arise in the post-marketing era which could trigger B/R evaluation.

Telephone calls were conducted with the proposers with the request to merge or edit according to the template. Table 1 summarizes the main features of the proposals, the HPV proposals (6 and 8), and the key methods from proposal 1 (monitoring), 5 (ethics privacy), and 7 (data linkage) were combined in proposal 9.

2.5.3 Criteria to select POC Phase 1

Criteria to select POC studies were obtained by querying the SC, the following list was obtained and was further combined in the criteria in Table 2. Criteria for POC study ranking

Population diversity (age groups)

• Is the vaccine in proposed POC part of recommended programs (relevance for PH)

• Is the vaccine in the proposed POC recommended for special risk groups

• Is the proposal aligned with ADVANCE values /mission

• Is this POC likely to deliver key learning for developing ADVANCE further


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Do we have appropriate benchmarking data (on the vaccine) to be able to understand

failures?

• Is this POC acceptable by the different stakeholders (no deal-breaker sensitivities)

• Not overburdening resources in consortium

• Feasibility in terms of complexity /data requirements

• More than one brand available

• Representativeness of different circumstances that ADVANCE needs to be able to address

(see table below)

Will this POC be able, if successful, to convince you (or our organisation) of the added value

of doing this sort of thing in this (novel) way?

Does the POC cover more than a single European country?

Can be conducted using fairly recent data

Does the POC allow us to test and/or demonstrate one or more innovations from what is

possible today?

Vaccine coverage

Rare events

Determination of speed of assessment (i.e. how close to real-time)

Ability to go back to the cohort/population for further follow-up data collection if needed

Has the topic been identified as a public concern from a screening of social media

monitoring?

During the SC meeting in Amsterdam (November 2014), these criteria were aggregated into the following way, which was used to rank the proposals (Table 2). Table 2: Criteria for ranking the POC proposals Criteria summary Criteria details

Population diversity Population diversity (vaccine for different or only one age group?

Is the vaccine in the proposed POC recommended for special risk groups?

Wide use / vaccination program Is the vaccine in proposed POC part of recommended vaccination programs?

How widely used the vaccine under study is?

ADVANCE Vision alignment / innovation

Will the proposal answer important topics for the ADVANCE mission and vision?

Is this POC likely to deliver key learnings for developing ADVANCE further?

Does the POC allow us to test and/or demonstrate one or more innovations from what is possible today?

Existing benchmarking data Do we have appropriate benchmarking data (on the vaccine) to be able to understand failures of the POC (e.g. when we have strange results)

How long has it been in use?

Can POC be conducted using fairly recent data

Will POC test the ability to go back to the cohort/population for further follow-up data collection if needed

Stakeholder acceptance Is this POC acceptable by the different stakeholders (no deal-breaker sensitivities)

Will this POC be able, if successful, to convince you (or our organisation) of the added value of doing this sort of thing in this (novel) way?

What would be the added benefit of studying a vaccine in ADVANCE over a single-centre or single-country study (in terms of speed of analysis and sample size

Feasibility / workload Is this POC very labour intense and thereby overburdening resources in consortium?


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Is this POC potentially feasible? in terms of complexity /data requirements?

Multiple Countries How many databases / data sources could be tested for the vaccine under study?

Does the POC cover more than a single European country?

Multiple Vaccine Brands Is for this POC more than one brand of vaccine available?

Social Media Has the topic been identified as a public concern from a screening of social media monitoring?

2.5.4 Selection criteria assessment results for POC Phase 1

From a total of nine proposals received (see appendix 3-11), screening by the SC to find synergies resulted in five updated proposals being put forward to be ranked during the SC meeting in Amsterdam; results are attached in Appendix 12. The Pertussis proposal ranked highest although immediately followed by the HPV (combined) and influenza proposals. The pertussis proposal was perceived to be of high public health relevance and therefore chosen to go forward after a vote in the SC.

3. Implementation of the POC study Upon selection and ranking of the overarching POC proposals and B/R assessment scenario, a POC B/R assessment linked with a B/R decision will be framed, and further POC studies will be developed to address the pillars required in the B/R analyses and assessment. The following stepwise approach is taken Step A: Frame the main B/R questions related to pertussis vaccination. These problems are formulated independently of data availability and choice of methodology. This will define the driving B/R decision “to be made” and select the B/R questions which are most relevant for our (1st) POC Step B: Design a feasible, acceptable POC outline based on the selected B/R question: the benefit-risk model will be further developed for implementation in the pillar-studies of the POC: i.e. trimming down the outcome tree, collecting value judgements, developing the protocol and statistical analysis plan written to collect and analyse the evidence needed to populate the benefit-risk model. For each study a specific study team will be constituted that will be liaising with a Working Group responsible to keep the alignment of all studies within the same POC towards the overall Benefit/Risk driving decision “to be made” (the POC B/R alignment working group). This working group will be an operational group constituted by the leads of the study teams and the oversight of the WP5 leads. The roles and responsibilities of each level of POC governance are described below.

3.1 Framing of the driving B/R decision in the POC Following SC discussion about the POC research plan in Rotterdam (December 2014) a small working group coordinated by Kaat Bollaerts (P95), Susan Hahné (RIVM) and Nicoline van der Maas (RIVM) was created to define a generic frame the B/R study question/decision model for any POC and then apply this framework to pertussis (step A) to help define the research questions. A document was created for framing the benefit-risk problem (appendix 13). The subsequent steps are:

1. Collecting evidence (and optionally, grading evidence): identifying adequate data requirements and available data sources and extracting evidence related to the formulated benefit-risk decision problem;

2. Benefit-risk synthesis: integrating (and weighting) the various benefits and risks, potentially including preference elicitation from relevant stakeholders;


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3. Sensitivity- and scenario analysis (optional): sensitivity analysis propagates and investigates data uncertainty (uncertainty objective in nature) whereas scenario analysis investigates the effect of subjective choices (e.g. choice of data source, value function);

4. Communication

The general concepts of framing the B/R for vaccines as described in appendix 13 are listed below.

3.1.1 Framing the Vaccines Benefit-risk decision making

The decision problem: First, the decision problem requiring the benefit-risk analysis needs to be clearly defined. Vaccine-related decision problems might relate to different points in the life cycle of a vaccine or the roll out of a vaccination programme and might be triggered by certain events. Examples of vaccine-related benefit-risk decision problems, excluding pre-marketing decisions and economic evaluations (which are both out of scope for ADVANCE), are:

1. Whether a request for marketing authorization should be submitted to the regulatory authorities;

2. Whether a new safety risk emerging in the post-marketing period shifted the benefit-risk balance and whether the vaccine should be relabelled, restricted or withdrawn from the market;

3. Whether there are new indications for vaccination; 4. Whether the recommended age of vaccination is optimal; 5. Whether the current vaccination schedule can be optimized with respect to the benefit-risk

balance; 6. Which vaccination coverage should be targeted; 7. Whether vaccination should be (strongly) recommended for specific populations.

Clearly formulating the decision problem will help selecting the appropriate target population, comparators, benefits and risks. This will consequently narrow down and precisely define the evidence required for the benefit-risk analysis. Who is the decision-maker: This might be the vaccine manufacturer (e.g. request marketing authorization; updating the risk management plan, revising the vaccine labelling, respond to a request of a regulatory authority), a regulatory body (e.g. approving a new indication, restricting the use, withdrawing a product from the market), a public health authority (e.g. recommending a vaccination program, extending the vaccination to additional populations at risk), but might also be the health care provider (e.g. advising vaccination to an individual) or the potential vaccine recipient (deciding whether they – or their children – will be vaccinated or not). Such decisions are often no done in isolation and different stakeholder may hold joint initiatives and partnership frameworks to improve the outcome of better informed decisions. Relevant stakeholders/audience: The stakeholders are the (groups of) people that are potentially affected by the decisions made or to be made. Immunization and schedule: This entails clearly defining the vaccine (specific brand or not) and its usage (recommended number of doses, recommended age at vaccination, co-administration, combination vaccine) Target population: The target population is the group intended to receive the vaccination. The target population can vary in age, sex, indication, region, specific subpopulations etc. Examples of target populations are


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neonates, infants, children, adolescents, elderly, males, females, pregnant women, high-risk groups. A special target population are the close contacts of highly susceptible and vulnerable individuals (e.g. cocoon strategy). Comparators A benefit-risk decision always implies a (explicit or implicit) comparison. Meaningful comparators in the context of vaccine-related benefit-risk are: no preventive measure, alternative preventive measure (e.g. HPV screening), alternative vaccine brand/vaccination schedule. An often chosen comparator is the standard of care. Perspective This might be an individual perspective (only taking into account the health outcomes that directly apply to the individual eligible for vaccination) or a societal perspective (broader perspective, taking into account all criteria relevant (partially) immunized population including transmission rates and herd immunity). Time frame and analytic horizon The time frame (the period over which vaccination is applied) and the analytic horizon (the period over which health outcomes occur as a result of vaccination are considered) should be sufficiently long to capture all benefits and risks vaccine-related health outcomes. Health outcomes (criteria) This includes the identification of all favourable and unfavourable effects that occur as a result of vaccination. These health outcomes might encompass direct and indirect effects. In addition to identifying all relevant health outcomes, the adequate time windows for observation for the different health outcomes need to be defined as well (e.g. adverse events within 30 days after vaccination, protective effect 10 years after vaccination). The criteria to the decision can be visually and hierarchically summarized in an outcome tree or value tree. Which measures will be used will be defined in the POC outline. A generic example of an outcome tree for vaccines is given in Figure 1. It is generally advised to start building the value tree including all criteria and then subsequently trimming down the tree by excluding criteria that not meet certain predefined conditions (e.g. no difference between comparators, no established effect)3.

3.1.2 B/R decisions to be proposed for pertussis (1st POC)

Guided by a general concept on how to frame B/R decision based on the lessons learnt in the PROTECT project and in collaboration with the coordination team, 4 B/R study questions i.e. decision problems were framed, which were submitted to the SC for further specifying the POC study (see appendix 12) The following four decision scenarios were proposed:

1. Is the benefit-risk balance of current paediatric acellular pertussis (aP) combination better than the benefit-risk balance of infant combination vaccines containing whole pertussis (wP) to justify switching from wP to aP?

2. Should maternal pertussis vaccination be recommended by public health authorities? 3. Should pertussis booster vaccines be given to adolescents (10 years and above) and adults? 4. Comparing the B/R balance of different paediatric vaccine schedules of acellular pertussis

combination vaccines including co-administration with other routine paediatric vaccines


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3.2 Selection of the B/R question SC was advised in their choice to consider the principles for success of the first ADVANCE POC:

1) To do what is actually already known in terms of a scientific question so that we have a benchmark somewhere to test the system against;

2) To do something simple (to be able to have results quickly which, according to IAB, in VSD experience was a key to success).

Based on an official vote in the SC the first proposal was selected.

3.3. POC outline Based on the B/R decision framing an outline document was created between B/R methods experts, WP 5 leads, vaccine safety and disease experts in EFPIA, academia and public health institutions. This document serves as a guidance to formation of the study teams and protocol development. The POC outline comprises the following information:

1) How this POC fits with ADVANCE mission/vision, the innovation to be tested and the lessons we expect to learn?

2) POC Scenario; 3) Benefit/risk decision frame; 4) State of the art knowledge (benchmark data)

a. Description of state of the art knowledge about disease and epidemiology; b. Description of state of the art knowledge about vaccine (benefits and risks and B/R

models); c. Description of state of the art knowledge about vaccine schedules in EU.

5) Components of the value tree (risks and benefits, time window and target population for each of the benefits/risks);

6) Description of decision model and the required input parameters (relative measures, absolute measures) for the B/R analysis (i.e the measures that the pillars should produce)

a. Coverage b. Benefits c. Risks d. Benefit-risk e. Utilities/preferences (weights for the benefits and risks)

7) Description of the data sources from which the required data could be obtained; 8) Overarching structure of the “n” pillar studies: how will they be articulated to deliver

information that can be combined in the B/R analysis? 9) Specification of output parameters including dummy table shells of minimal information that

needs to be provided by the pillars; 10) Input from each WP: what do they want to test

The POC outline was created by multi-stakeholder group of experts and is attached as appendix 14

3.4 Roles for POC study Each of the various inputs necessary for the B/R analyses will be evidence generated by individual studies coordinated and aligned. In this section we present the study-level governance framework to be tested in the ADVANCE POC phase 1 studies. WP 1 is developing a code of conduct for ADVANCE which has been drafted and reviewed by wider consortium (appendix 1). The initial drafts were used below to define roles and responsibilities in the


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POC. Please note that further versions/updates of the CoC may differ from the CoC sections which were the basis of this document early 2015. Roles and responsibilities in a study were defined in section 6 of this draft document and are listed here. Under each section we have described in italic how we envision these roles in the POC study, the responsibilities are described in section 3.6. The pros and cons of these will be evaluated along the POC study by the POC Evaluation committee and reported to WP 1. These choices were discussed with the WP 5 members during a face to face meeting in Rotterdam in January 2015 and subsequently approved by the SC (comments and discussion points are included). The ADVANCE code of conduct (CoC) states that the functions defined below are considered key functions that should be present in all studies. Additional ones may be needed for some studies. These functions may be executed by many different persons or a small number of them. However, it is considered a principle of good practice that each function is clearly allocated to a person or organisation in the planning phase of the study. The term “organisation” is used in this chapter to designate any regulatory agency, public health institute, academic institution, company or any other body involved in the study. We list here all roles as outlined in the CoC (version January 2015) and provide how we implement and agreed these for the first POC study. Governance structure is defined in section 3.5. For clarity and readability purposes, short definitions (arriving from current version of CoC) are included, for the extended versions and clarifications we refer to appendix 1.

3.4.1 Requester

An entity (person or organization) that requests a study to be performed. For example, the requester may be a regulatory authority asking a company to provide post-marketing data in the context of the risk management plan or a public health institute contracting a study to academic institutions. In some cases, the requester can also be the sponsor but this is not always the case, such as when a regulatory authority request a study to a vaccine manufacturer.

o For the pertussis POC we assume the requester to be a regulatory agency/public health agency to mimic real life situation.

3.4.2 Funder and sponsor

An entity (person or organization) who provides some or all of the financing for a study. A study may have more than one funder and/or sponsor.

o For the Pertussis POC B/R study the funder is IMI, in a post-ADVANCE era this will be different

3.4.3 Responsible party

An entity (person or organisation) taking responsibility for the conduct of the study, including its design, initiation, implementation, coordination, analysis, documentation and communication. The responsible party may allocate the activities associated to its functions to members of the organisation based on their experience and training. It may also subcontract or delegate some of its activities to other entities. Depending on the study organisation, there may be more than one responsible party for a study, for example a responsible party for each study site.

o For the POC study we have different responsible parties Overall B/R POC (coordination & process evaluation): responsible parties are Erasmus University and GSK as WP5 co-leads


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For the 5 study groups (Pillars): responsible party is the institution of the POC study group principal investigator, which will be chosen by open solicitation

3.4.4 Principal investigator

A person within the responsible party who has overall responsibility for the conduct of study across all study sites.

o For the POC pillars: we have different principal investigators in the 5 different pillars: benefits, risks, coverage, preference solicitation and B/R analysis. These PIs will be called for and can apply with CV and letter of motivation. Overall POC study: WP 5 leaders

3.4.5 Investigator

A person who has responsibility for the conduct of a study at a study site. If several investigators are involved in a same site, a lead investigator has overall responsibility for the study at that site.

o For the POC study each person participating in the specific study group/pillar will be an investigator. Investigators will be from multiple sites and stakeholders.

3.4.6 Data controller

An entity (person or organisation), which alone or jointly with others, determines the purposes and means of the processing of personal data in compliance with the ethical, professional, regulatory and legislative provisions applicable to these data.

o For the POC study each site that will provide data to the POC study will have/be a data controller. The sites will have to name the data controller entity/person

3.4.7 Data custodian/provider

In the context of a study with secondary use of data, an entity (person or organization) which possesses legal power of control over the data and has responsibility to maintain, store and give access to the data. Generally, the data owner/provider is also the primary user of the data.

o For the POC study, each local database (site) that will provide data to the POC study will have a data provider who has the control of the data and the responsibility to maintain /store and give access to these. Often it is not one person who is data owner but an institution. The local sites will have to name the person delegated from the organization who will be the data provider/owner for the ADVANCE studies.

3.4.8. Data analyst

A person who analyses the study data in collaboration with the data controller to produce the study results.

o For the POC study, each site that will provide data to the POC study will need a data analyst to extract the data from the data source and to run the standardized scripts.

3.4.9 Quality control committee

A study quality control committee as part of the evaluation committee will be responsible to ensure all documentation and enforce compliance during the study (see section quality criteria from WP 1 WG2), the WG2 leads may be part of this committee. In addition, a process and ethics evaluation will be done (see governance figure)

o For the POC study, members from regulatory and EFPIA partners will be invited to be part of this team. The WG2 leads may be part of this committee. In addition, a process and ethics evaluation will be done, WP 3 should be involved in this


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3.4.10 End user

An entity (person or organization) which uses the study results directly or indirectly. For example, an end user may be a regulatory authority that requested the study or a health care professional that uses published results for her/her decision to vaccinate.

o For the POC study, the ADVANCE all partners and the requester, plus IMI will be end users

3.5 POC Governance A POC governance document was created by WP1 Working Group 3, chaired by Laurence Pagnon. Although the implementation of all recommendations was late in the process for this first POC and not yet discussed with SC or consortium, we would like to use as many recommendations as possible including the diagram that was prepared, so that this POC may inform the WG3. It was slightly modified to fit with WP 5 discussions/SC decisions.

Figure 6: POC Governance structure diagram as proposed by WP1-WG3 (slightly modified)

3.5.1 Finance

For the POC study (As this is part of ADVANCE funding) no finance needs to be established, resource use will be distributed according to the RAM.

ADVANCE Steering Committee Decision making

ADVANCE Scientific Advisory Board

Technical/scientific advisory function

POC Coordination team

Implementation/Management

POC Evaluation Committee Quality control-Ethics §

Process observer

SYNAPSE Finance

Study group Preference

Implementation

Study group Coverage

Implementation

Study group Safety

Implementation

Study group Effectiveness

Implementation

Study group B/R synthesis

Implementation


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3.5.2 Study Steering Committee

Executive committee that includes representatives of the main entities involved in a study, having a central role in the governance structure and the management of the study and having ultimate responsibility to take all necessary decisions regarding scientific, operational and financial aspects of the study. The role of the scientific committee should be established before the study starts.

o For the POC study, the ADVANCE SC will be the POC steering committee

3.5.3 External Advisory Board

Committee of independent experts external to the project appointed by the SC to provide scientific expertise and knowledge necessary to assist the Steering Committee. Members of an EAB should declare potential conflicts of interest and sign a non-disclosure agreement of confidential data.

o For the POC study, the ADVANCE SAB will be the external advisory board

3.6 Responsibilities in ADVANCE POC

3.6.1 Responsibility of the POC Coordination team

An overarching POC coordination team will be created which is constituted by the principal investigators of the pillars and the WP 5 leads. This working group will meet weekly and will be responsible to take decisions on alignment of the studies towards the B/R analyses and assessment of process parameters. Representatives of other ADVANCE WPs will be nominated as optional invitees of the discussion upon the interest and importance of the topics.

3.6.2 Responsibility of the ADVANCE SC

As described in the ADVANCE DoW governance section: The SC will be an operative body in charge of overall coordination and steering of the project work, following up progress in each of the critical areas as reported by the WPLs and the ADVANCE CT, approving all project deliverables and ensuring that objectives and milestones are fulfilled with an appropriate quality level. The SC will be responsible for decision making on most issues related with the project execution, with prerogatives regarding technical development decisions (e.g. choice between different technological options), minor work plan updates (task description modifications, add/delete tasks, creation of task forces, implementation of mitigation and contingency plans), and effort/budget re-assignment in pursue of optimal efficiency. In the POC study, the ADVACNE SC will play the role of study steering committee. In more operational terms the responsibilities of the SC will be:

1) To select the POC proposal 2) To select the POC decision problem 3) To provide input and approve the POC Research plan 4) To provide input and approve the POC outline 5) To select the pillar PIs 6) To approve the study teams and their responsibilities 7) To provide input and approve the protocols 8) To approve process evaluation plan 9) To monitor at high level the progress of the study and deviations 10) To review and approve the reports/publications

3.6.3 Responsibility of coordination team in the performance of the POC study

The POC study will be coordinated by a multi stakeholder team comprising of the WP 5 leads, and the principal investigators of the study groups. In more operational terms the responsibilities of the coordination team are:

1) To coordinate solicitation and review of POC proposals


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2) To coordinate POC decision problem selection 3) To write the POC Research plan 4) To coordinate POC outline writing 5) To call for study teams 6) To coordinate the POC and ensure that the output leads into a coherent overarching B/R

analysis 7) To provide templates for all required documents 8) To provide information to the quality/ethics control committee 9) To coordinate writing and reviewing of the study protocols 10) To monitor at detailed level the progress of the study in its content and timing 11) To support the study PI in the selection the databases that can be used 12) To make a working plan for the data providers/investigator that is aligned across the

different study groups 13) To support the harmonization of all outcome variables 14) To coordinate alignment of statistical analyses plans 15) To coordinate and leverage script writing across the pillars 16) To make and maintain Master file for archiving 17) To report to SC on progress and timelines 18) To ensure appropriate writing/review and approval the reports/publications by the study

team Some tasks may be delegated to technical persons.

3.6.4 Responsibility of POC Evaluation committee

The recommendation of the WP1 Wg3 is that this committee will be in charge of the overall evaluation of the POC studies which more specifically correspond to the following roles and responsibilities:

- Ensure the compliance of the POC studies to the appropriate guidelines, national and international standards and referenced guiding principles detailed in the GPG (draft version); it includes more specifically the control of the legal and ethical aspects of the POC studies and the monitoring of the data processing (data access, protection, security);

- Ensure the transparency of the funding flow when applicable; - Check the potential conflict of interests which may occur in the POC governance

committee and in the POC study teams, and make sure proper declarations are made;

- Is responsible to write the POC evaluation protocol in close collaboration with the POC CT to define the process parameters to evaluate and the corresponding key performance indicators

- Is responsible to observe, evaluate independently the conduct of the POC studies and write the corresponding process evaluation report with the lessons to be learnt.

The POC EC will be created and implemented at the beginning of the POC studies. This committee will be composed by members which should be independent from the POC CT and the study teams with the appropriate expertise and experience in the quality control, project controlling and auditing. It is recommended to have one person dedicated to the quality control /ethics of the POC studies and 2 different persons dedicated to the POC evaluation. In the spirit of ADVANCE, these roles may be endorsed by a representative from any partner whatever s/he is coming from, either public or private stakeholders.

3.6.4 Responsibilities for different roles

As per CoC it should be ensured that:


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all entities (persons or organisations) involved in a study have the qualification and expertise to perform their tasks and are listed in the study protocol;

o For the POC study: will be done by SC based on the curriculum vitaes that were requested

the appropriate ethics /scientific committee(s) are consulted and provided with the full documentation about the study;

o For the POC study: ethics approvals from databases & stakeholders will be monitored and collected by the PIs of the different studies

all persons involved in the study are aware of the rules of confidentiality and privacy legislations and ethical conduct and have received and read the study protocol;

o For the POC study: all investigators need to sign off that they understand the protocol. Responsibility to collect this is for PI of the study.

sufficient resources in terms of time and personnel have been allocated for the study, including for data security and for the preparation, analysis, presentation and dissemination of the results;

o For the POC study, this is implicit by the DoW

where relevant, study subjects receive adequate information about the study's objectives and protocol, thus allowing them to refuse to participate;

o For the POC: data controllers have this responsibility.

Where relevant, information about the study progress in terms of recruitment, data collection, any modification of the protocol (amendments) and the reasons for it are communicated to the study funder/and requester (without communicating results other than final or scheduled interim results);

o For the POC: study progress needs to be collected by POC CT

information about potential serious public health issue arising from the study are communicated to the study funder/requester and to relevant regulatory and public health authorities;

o For the POC: by the investigators

results are communicated by all appropriate means with scientific rigor and in respect of a scientific independence.

o For the POC: scientific communication follow the process defined in the ADVANCE project handbook

Data custodians/providers Data custodians/providers should provide sufficient resources in terms of time and personnel for the provision of high quality data in accordance with the agreed protocol

o For the POC: all data owners will be asked to participate, once commitment has been provided it should be carried to the end

Data controller The data controller from the participating databases should monitor compliance of data processing with applicable national and international standards of data security and data protection. The data controller must have appropriate qualifications for these duties.

o For the POC: data controllers in each site will review the protocol and the data sharing arrangements and will be responsible for verification by the evaluation committee

3.7 Research contract Since we will have no funding that will be supplied for the POC study beyond the funding provided by IMI which is agreed in the grant agreement, we don’t need a research contract for the POC study.


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3.8 Conflicts of interest We will follow the draft code in collecting declaration of interest (DoI) forms stating all interests that may lead to potential conflicts. It was decided in the WP 5 and SC that we will not restrict roles based on DoI for this POC, but will be transparent about what is done by whom.

3.9 Scientific integrity As per CoC (see appendix 1): All researchers involved in the study team should be qualified and experienced scientists, acting in accordance with the values of science, including: - Honesty (conveying information truthfully and honoring commitments) - Accuracy (reporting findings precisely and preventing errors) - Efficiency (using resources wisely and avoiding waste) - Objectivity (letting the facts speak for themselves and avoiding improper bias) - Transparency. This will be requested from the applicants to the POC study teams Scientific integrity is facilitated through the following recommendations in the CoC - Clear and transparent roles and responsibilities - Study design geared towards desired outcome - Protocol posting on ENCePP before data collection and analysis - Study outcome shall not affect disclosure, publication, remuneration - Predefined agreement on publication - Decisions on study report and publications by authors only, selected on criteria of the International Committee of Medical Journals Editors (ICMJE) - Declaration of Interest for all study team members/authors - Disclosure of all funding sources, all affiliations and all roles in the study - Sources affecting data quality should be identified and disclosed to users - Research contract established whenever more than one organisation is involved - Clarify on role of data provider in data interpretation - Adherence to Good epidemiological practices and Good pharmacoepidemiological practices, without restriction - Demonstrable expertise and autonomy of individuals responsible for pharmacoepidemiological research within their organisations. In the POC study we will have

1) Declaration of interest 2) High transparency and defined roles and responsibilities 3) Draft code of conduct /governance 4) SC review

3.10 Confidentiality For the POC study: adhering to data privacy principles and legislation is a responsibility of the local data controller, only [pseudo-] anonymized data will be shared. Data controllers will provide the POC CT & evaluation committee group with approval documents. The data controllers will sign a data sharing agreement


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3.11 Transparency The current draft CoC defines transparency as: Transparency is the degree of disclosure to which study information is open to all for verification. For the POC study: we will attain to the highest level of transparency:

1) Study protocols will be registered in the EU-PAS register 2) All declarations of interest will be available as well as CVs of all study team members 3) Statistical analysis plan will be made available & analysis scripts 4) Study report will be registered (EU-PAS) 5) Data analysts locally will archive and provide access if requested to data extraction programs

and original data 6) Access to local & central sites will be allowed for audit purposes 7) All studies will be published

3.12 Data access For the POC study:

1) Local databases will provide access to original data and extraction scripts if requested and will adhere to archiving and quality principle (see below). Guidelines for archiving will be provided.

2) Access will be provided to all analytical datasets and scripts at the Remote Research Environment.

3.13 Ownership of results For the POC study: ownership of results is arranged in the grant agreement

3.14 Study protocol In the POC study, we will adhere to the current CoC principles:

1) Scientific validity a. ENCePP methods guidance will be followed b. ENCePP checklist will be followed c. Protocol will be written based on POC outline by study team that will comprise

clinician, epidemiologist, statistician, vaccinologist and the local study sites d. A SAP (including data management plan) will be written e. Protocol will be reviewed by SC

2) Ethical/privacy aspects a. Ethical /privacy section will be included

3) Contractual aspects a. Roles and responsibilities of study team members will be described b. DoIs of all study team members will be included c. Regulatory status will be described in protocol

4) Registration a. The protocol will be registered in the EU-PAS register

5) Amendments a. Amendments to the protocol will be listed and time stamped

6) Content and format a. EMA PASS template will be followed as much as possible

3.15 Study report In the POC study we will:

1) Create a plan for the report writing with responsibilities and timelines In the report we will:


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1) Describe and interpret all the results; 2) List deviations from the protocol; 2) List changes to analysis plan after analysis has begun; 3) Describe how missing data are handled.

The report will be written (tasks may be delegated) by the POC CT. All comments will be recorded and made available. For the content and format the STROBE guidance will be used and the EMA PASS template for reporting. The report will be reviewed independently by the SC and the SAB, comments will be recorded and made available.

3.16 Publications and communications In the POC study we will implement these principles:

1) Publication policy will follow ADVANCE publication & ICMJE guidelines 2) Protocol and reports will be registered in EU PAS 3) Study results will be described, reports and publications will be reviewed by SC and SAB.

Comments will be listed and made available 4) Study results that require regulatory action (even if this is not the intention of the POC study)

may be used by companies and regulators to fulfil their requirements 5) Data will only be made available in aggregate form

Further ADVANCE guidance on communication of study results will be developed by WP 1 WG 4. Recommendations will be incorporated in the POC study. Since the POC studies are testing a system rather than focusing on the scientific question, the following disclaimer shall be added in a very visible manner to all study documents, such as (but not limited to): outlines protocol, reports, presentations, publications…

"The studies described in this protocol [report / manuscript/presentation/article] are/were conducted as part of the IMI ADVANCE project (Grant Agreement nº115557; http://www.advance-vaccines.eu/) with the aim to test methodological aspects of the design, conduct and reporting of studies for vaccine benefit-risk monitoring activities. The protocol [report/manuscript/presentation/article] presented herein related solely to the testing of these methodologies and were not intended to inform regulatory or clinical decisions on the benefits and risks of the exposures under investigation. Therefore, any use of information from these studies should carry over this warning and be used accordingly with caution."

3.17 Filing and Archiving For the POC study we will adhere to the COC filing and archiving principles as much as possible. Since most data controllers/analysts may have different practices for archiving and filing a plan will be developed by the POC CT (to be evaluated by the POC EC), which details the way of archiving some of which needs to be done locally and some archiving that will be central. A Master file will be created.

3.18 Quality WG2 in WP 1 has conducted a survey on the quality parameters. In the survey a list of criteria was generated. Please see this list of criteria below and see how these will be implemented in the initial POC

Item Criteria POC Implementation



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Study protocol development and protocol deviations

Documented expert review of protocol

All protocols need approval by POC CT and SC

Recommended or standard template for protocol

EMA template

Reporting and communication of study results

Documented expert review of study report

By POC CT and SC

Recommended or standard template for study report

EMA template

Qualification of external vendors/service providers/data providers/analysts (if applicable)

Documented process of vendor qualification

Per ADVANCE DoW

Defined criteria for assessment of vendors

Not necessary, but databases assessed by fingerprinting

Ensure independent research in case of unconditional grant

Written documentation of scientific independence

DoI

Protection of data on premises, servers and individual work stations

Use of security logs To be defined

Designated and controlled areas for data storage

Data controller responsibility local sites, and central

Access to data only for authorized personnel

Centrally organized on RRE, locally data controller

Log on with multi-character passwords

RRE organized (token)

Data storage after study end for minimum of five years

Local and central storage

Data storage index present for audit and inspection purposes

Storage and archiving rules will be sent

Protection of identifiable and confidential data

Replacing of overt personal identifiers by clear identifiers, keeping the mapping key separate from the pseudo-anonymized data

Locally according to national rules and EC directive. Centrally only anonimized data

All researchers must sign a confidentiality agreement

Is part of RRE practice

Back-up At least one (but preferably multiple) back-up(s) in different location(s)

Will be advised, to be instructed

Process of electronic data transfer

Only sent data from one place to another by secure methods (encrypted)

From local to RRE through ftp line and anonimized

Data processing (and statistical programming if applicable)

System-generated audit trails in place

Local and central trails necessary: will be described

Application/execution of standard consistency and accuracy checks

Fingerprinting


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Availability of Statistical Analysis Plan (SAP) prior to data analysis

Part of POC

Use of validated statistical software

SAS & R

Annotated study programming (programming giving explanatory notes for each step)

Will be part of process

Standard process for statistical programming control (i.e. review or double-programming)

Double programming

Archival of SAP and statistical programs

Part of SOP

Organization and responsibilities for data privacy

Formally documented that data is legally obtained

Ethics/Scientific committee review documentation

Presence of (an) allocated person(s) responsible for data privacy

Evaluation Committee

Ethical review board Process for obtaining Ethics Committee approval on an appropriate level

Local processes have been identified

Informed consent Obtain ethics approval of informed consent or waiver of informed consent

Local processes identified by WP 3, monitoring by POC EC

Ensure sufficient qualification of study personnel

Ensure a principal investigator is qualified and appointed

PI should be PhD, epidemiologist and have proven experience to guide multisite studies

Have written organisational charts and personnel tasks in place

See roles and responsibilities above

Training system

Initial and continued training of personnel

Capacity building within ADVANCE

Continuous documentation of training status and certification

CV of investigators are collected

Commitment Allocation of resources and qualified personnel prior to study start

Public call for people

Existence of quality cycle

Continuous cycle of planning, adherence, control & assurance, improvements of all processes in place

POC EC

Written policies and procedures for main processes/activities and systems

Quality plans on procedures Drafts available, further development by WP1/WG2

Quality manuals for procedures POC Research plan….

Periodic review and update of procedures

Part of ADVANCE life time

Record management policy To be developed

Urgency processes/escalation policies

Not available


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Document control and document management

Review and approval process of documents

As per ADVANCE project handbook and communication guidance

Tracability of records (version control processes / timestamps)

To be developed

Controlled document management system

To be developed

Audit and inspection preparedness

Inspection plan available To be developed

Periodic internal audit POC EC?

Documentation of audit reports and results

Periodic check of study facilities and equipment

POC EC

Deviation management; corrective and preventive actions and follow-up

POC EC

Ensure adherence to procedures/compliance management

Written compliance management process

Not available

3.19 Regulatory status The European legislation describes obligations to be fulfilled by marketing authorisation holders (MAHs) and national competent authorities for medicinal products (including vaccines) authorised in the European Union (EU). The European legislation does not apply to post-authorisation studies conducted by organisations such as academia, medical research charities or research organisations in the public sector. These organisations should follow local requirements defined in the national legislation applicable in the countries where research is conducted. In the context of the ADVANCE consortium, proof-of-concept studies (POCs) will collect and analyse data on vaccines authorised in the EU. Vaccine MAHs are partners of the ADVANCE consortium and participate in the design, conduct and funding (through in-kind contribution) of the POCs concerning vaccines (at the product or substance level) for which they hold an authorisation. They should therefore be considered as having a control on the design of POCs, in which case requirements of the Good Pharmacovigilance practices (GVP) applies.2 . POCs should therefore follow legal requirements applicable to post-authorisation studies (PAS) as well as additional requirements applicable to post-authorisation safety studies (PASS) in case they fulfil the definition of a PASS. It is assumed that POCs will be non-interventional. Registration of the study in the EU PAS register; Guidance on the format and content of the study protocol and study report; Recommendations for the communication of study protocol, interim reports and final reports to national competent authorities; Recommendations regarding the quality systems, audit and inspections. Implementation in the POC studies

2 Good Pharmacovigilance practices (GVP). Module VI - Management and reporting of adverse reactions to

medicinal products. VI.C.1.2. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/09/WC500172402.pdf


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Given the experimental and unusual nature of the POC studies, the EFPIA partners initiated a discussion in 2014, including during the face-to-face SC meeting in November 2014. From the EFPIA side, there were two points to consider: - how to make sure that the POC studies will not be perceived as real studies, as they were designed for system-testing and not for delivering any robust data - how to be able to combine the regulations with the need to experiment more freely on study design and data sources During the year 2015 there has been further debate about the regulatory status of the POC studies. EMA had initially advised to consider the POC RISK study a PASS category IV. This has raised much concern in the EFPIA stakeholder group since they would never design nor support studies like these if they needed to be PASS (ie, delivering robust data on vaccine safety). Several meetings were held amongst EFPIA and between EFPIA and EMA (September 2015, March 2016) to find solutions. EMA was explicit that they could provide advise but that final decision was with MAHs. In house clearance reviews and comments that were received in February 2016 clearly indicated that the EFPIA companies did not consider the Risk study as PASS, since it is about system testing rather than providing estimates. EMA re-reviewed the updated objectives in March 2016 and released the following advice on April 18, 2016:

EMA Legal service’s informal opinion on the RISK POC of ADVANCE This opinion is based on the following objectives of the RISK POC protocol:

OBJECTIVE of the RISK Proof-of-concept study for ADVANCE

This proof-of-concept study aims to test components of the ADVANCE system for the benefit-risk monitoring of vaccines in Europe, more specifically:

To evaluate participating databases on quality criteria for inclusion in the study

To test integration of incidence rates of specific safety events into the benefit-risk analysis.

This objective will be addressed by answering the following question: “Has the initial benefit-risk profile in children prior to school-entry booster been maintained after the switch from whole-cell pertussis vaccines to acellular pertussis vaccines”?

Specific events that will be addressed include injection site reactions, fever, somnolence, persistent crying, irritability, febrile or afebrile seizure/convulsion, hypotonic-hyporesponsive episode, extensive limb swelling.

Incidence rates will be calculated:

a) within specific risk windows after each dose of whole-cell pertussis or acellular pertussis vaccines in pre-school children

b) in the time period outside the risk windows before and after each dose of whole-cell pertussis or acellular pertussis vaccines in pre-school children

c) Over calendar time, to allow for analysis that will focus on sequential monitoring of B/R

“It is believed that the definition of PASS under Article 1(15) of Directive 2001/83/EC (“any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures”) and the definition currently included in GVP Module VIII for a PASS of category 4 (“some studies that may provide safety information of less significance”) are quite broad to encompass any study that may provide information on the safety of the authorised medicinal product.


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In light of the current wording of the legislation and of the GVP, it is not sure whether the proposed ADVANCE proof of concept study on risks of pertussis vaccines could fall outside the PASS category (and be considered as a PAS). However, based on Article 107m(8) of Directive 2001/83/EC, Articles 107n to 107q shall apply exclusively to studies referred to in paragraph 1 which are conducted pursuant to an obligation imposed in accordance with Articles 21a or 22a. Therefore, the obligations under Articles 107n to 107q do not apply to non-interventional post-authorisation safety studies which are initiated, managed or financed by the MAH voluntarily.”

POC Protocols were updated to better highlight the system testing goal and the feasibility assessment was more extended, the SAB confirmed in the General Assembly Meeting in April that the focus should be on system testing. After further reflection and review of the protocols, several EFPIA partners (Pertussis vaccines MAHs) have confirmed that, according to their internal decision processes, the POC studies were not considered as PASS. They have further provided the WP5 leads with recommended sections for the protocols early Amy 2016. These sections (see text box below) have been incorporated in the protocols.


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5. Proposed process parameters

POC RISK PROTOCOL

PROTECTION OF HUMAN SUBJECTS

Regulatory and Ethical Compliance

The European legislation describes obligations to be fulfilled by marketing authorisation holders (MAHs) and national competent authorities for medicinal products (including vaccines) authorised in the European Union (EU). The European legislation does not apply to post-authorisation studies conducted by organisations such as academia, medical research charities or research organisations in the public sector. These organisations should follow local requirements defined in the national legislation applicable in the countries where research is conducted. In the context of the ADVANCE consortium, proof-of-concept studies (POCs) will be conducted to test new approaches (data sources, methods) by using a test cases; within this framework the POC studies will collect and use data on vaccines authorised in the EU. Vaccine MAHs are partners of the ADVANCE consortium and participate in the design, conduct and funding (through in-kind contribution) of the POCs concerning vaccines (at the product or substance level) for which they hold an authorisation. They should therefore be considered as having a control on the design of POCs, in which case requirements of the GVP applies. (21) The GVP requirements' will be addressed in the following ways:

1) The study protocol and study report will be posted on the EU PAS register.

2) The POC studies will be monitored by MAHs as PAS.

3) This proof-of-concept study aims to test components of the ADVANCE system for the benefit-risk monitoring of vaccines in Europe, more specifically:

- To evaluate participating databases on quality criteria for inclusion in the study

- To test integration of incidence rates of specific safety events into the benefit-risk analysis.

The objectives of this study are on methodological aspects and not intended to provide any information on the safety of the concerned Pertussis containing vaccines. Therefore, this study is not considered as a PASS.

4) Management and reporting of adverse events/adverse reactions:

This study is observational, based on secondary use of data in large healthcare databases and will provide only incidence rates of events by vaccines type (aP/wP). Thus the reporting of suspected adverse reactions in the form of

individual case safety reports (ICSRs) is not required and no individual adverse events/reactions will be summarised in the final study report. POC BENEFITS/COVERAGE/B/R PROTOCOL

PROTECTION OF HUMAN SUBJECTS

Regulatory and Ethical Compliance

The European legislation describes obligations to be fulfilled by marketing authorisation holders (MAHs) and national competent authorities for medicinal products (including vaccines) authorised in the European Union (EU). The European legislation does not apply to post-authorisation studies conducted by organisations such as academia, medical research charities or research organisations in the public sector. These organisations should follow local requirements defined in the national legislation applicable in the countries where research is conducted. In the context of the ADVANCE consortium, proof-of-concept studies (POCs) will be conducted to test new approaches (data sources, methods) by using a test cases; within this framework the POC studies will collect and use data on vaccines authorised in the EU. Vaccine MAHs are partners of the ADVANCE consortium and participate in the design, conduct and funding (through in-kind contribution) of the POCs concerning vaccines (at the product or substance level) for which they hold an authorisation. They should therefore be considered as having a control on the design of POCs, in which case requirements of the GVP applies. (21) The GVP requirements' will be addressed in the following ways:

1) The study protocol and study report will be posted on the EU PAS register.

2) The POC studies will be monitored by MAHs as PAS.

3) This proof-of-concept study aims to test components of the ADVANCE system for the benefit-risk monitoring of vaccines in Europe, more specifically:

- To evaluate suitability of participating databases on quality criteria for inclusion in the study

- To test integration of incidence rates of pertussis /coverage or B/R by age in infants and children up to school-entry or age 6 years into the benefit-risk analysis.

The objectives of this study are on methodological aspects and not intended to provide any information on the benefits of the concerned Pertussis containing vaccines. Therefore, this study is not considered as a PAES/PASS.

4) Management and reporting of adverse events/adverse reactions:

This study is observational, based on secondary use of data in large healthcare databases and will provide only incidence rates of events by vaccines type (aP/wP). Thus the reporting of suspected adverse reactions in the form of individual case safety reports (ICSRs) is not required and no individual adverse events/reactions will be summarised in the final study report.


37

4. Proposed evaluation parameters The aim of the POC study is to test the ADVANCE system. Therefore, the POC EC will assess various process parameters and create an evaluation protocol Initially we plan to evaluate the following parameters but these may be modified/updated and further specified by the POC EC

a) Time: – Process time of all steps in workflow locally and centrally (list to be created) a. Preparatory/negotiation/run-in time b. Protocol development c. Protocol review-SC d. Protocol submission-approval: databases e. Protocol submission-approval: stakeholders f. Protocol submission-approval PRAC: rapporteurs g. Cycle time between full approval of protocol and starting protocol implementation h. Cycle time between starting protocol and report

b) Cost: resources (person time, machine time) needed to run the POC study through the different workflow steps

a. Hours spent per task and person in study team b. Hours spent per task and person in working group c. Hours spent for data extraction by database d. Time to run Jerboa by database e. Payment for getting approvals f. Travel/meeting cost

c) Acceptability of study proposal, workflow and report by stakeholders (stakeholder feedback survey).

a. Before and after survey i. Needs fulfilled? (from WP 1)

d) Compliance: with legislation, standards, approvals to run the study a. Review of approval feedback b. Legal and regulatory feedback c. SAB review for best practices

e) Quality of process, data management, data integrity, privacy and security, validation of the writing, validation of the programming, number of amendments to the protocols, number of errors than need correction.

a. Protocol deviations/amendments b. Findings in QC in double programming c. Findings of data security issues d. Review of documents e. Audit of study (EFPIA audit group payment) e.g PHARSAFER

f) Transparency: what information can be made public (protocol, authors), how much time

after it was done, is the information understandable, the decision-making processes (minutes, agendas), whose interests are involved / who benefits.

a. Ask WP 1 how to measure transparency in the process b. Look at WHO document

(http://apps.who.int/medicinedocs/documents/s16732e/s16732e.pdf_ c. Feedback from WP 7 d. Feedback from patient organization e. Ethics review (Gerd Leonhard: TEdX talk)

g) Flexibility / adaptability

http://apps.who.int/medicinedocs/documents/s16732e/s16732e.pdf_


38

h) Accesibility of data (study results and resources) to different stakeholders a. Data access approval b. Refusals and why c. Interaction between different stakeholders


39

Appendix 1: Draft ADVANCE Code of Conduct

Draft Good Practice Guidance

Module 1: Draft Code of Conduct

Version 3.0

27 March 2015

Deliverable 1.6. Guidance on best practices - draft

ADVANCE Work Package 1/working group 1


40

Table of Contents

1. EXECUTIVE SUMMARY ............................................................................................................. 42

1.1. INTRODUCTION ................................................................................................................................ 42 1.2. GUIDING PRINCIPLES FOR THE CODE OF CONDUCT ................................................................................. 42 1.3. COMPONENTS OF THE CODE OF CONDUCT - SUMMARY.......................................................................... 43 1.4. CONCLUSIONS ................................................................................................................................. 47

2. BACKGROUND ....................................................................... ¡ERROR! MARCADOR NO DEFINIDO.

3. OBJECTIVES OF THE GOOD PRACTICE GUIDANCE ...................................................................... 48

4. STRUCTURE OF THE GOOD PRACTICE GUIDANCE ...................................................................... 48

5. MODULE 1. CODE OF CONDUCT ............................................................................................... 49

5.1. INTRODUCTION ................................................................................................................................ 49 5.2. GUIDING PRINCIPLES ........................................................................................................................ 49

5.2.1. The need for guiding principles ........................................................................................... 49 5.2.2. Definitions ........................................................................................................................... 50 5.2.3. Methods .............................................................................................................................. 52

5.2.3.1. Mapping of guiding principles .............................................................................................52

5.2.3.2. Ranking the principles, a survey of ADVANCE researchers .................................................52

5.2.4. Selected principles for guiding the ADVANCE Code of conduct .......................................... 53 5.3. COMPONENTS OF THE ADVANCE CODE OF CONDUCT .......................................................................... 55

5.3.1. Methods .............................................................................................................................. 55 5.3.1.1. Review of existing guidelines ..............................................................................................55

5.3.1.2. Literature search .................................................................................................................57

5.3.2. Recommendations of the Code of conduct ......................................................................... 57 5.3.2.1. Scientific integrity ................................................................................................................57

5.3.2.1.1. Definition ......................................................................................................................57

5.3.2.1.2. Recommendations .......................................................................................................57

5.3.2.1.3. Additional reading ........................................................................................................58

5.3.2.2. Transparency .......................................................................................................................58

5.3.2.2.1. Definition ......................................................................................................................58



5.3.2.3. Conflicts of interest .............................................................................................................60

5.3.2.3.1. Definition ......................................................................................................................60



5.3.2.4. Study protocol .....................................................................................................................61

5.3.2.4.1. Definition ......................................................................................................................61



5.3.2.5. Study report.........................................................................................................................63

5.3.2.5.1. Definition ......................................................................................................................63


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5.3.2.6. Publications and scientific communications .......................................................................64



5.3.2.7. Subject privacy ....................................................................................................................65

5.3.2.7.1. Definition ......................................................................................................................65



5.3.2.8. Sharing of study data ...........................................................................................................67

5.3.2.8.1. Definition ......................................................................................................................67



5.3.2.9. Research contract ................................................................................................................68

5.3.2.9.1. Definition ......................................................................................................................68



6. CONCLUSIONS ......................................................................................................................... 70

7. ANNEXES ................................................................................................................................. 71

ANNEX 1. .................................................................................................................................... 71

ANNEX 2 ..................................................................................................................................... 74

ANNEX 2. .................................................................................................................................... 76


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1. Executive Summary

1.1. Introduction

Effective collaboration between stakeholders and governance for the conduct of studies are among

the main objectives of ADVANCE. In this context, Work Package 1 will develop a good practice

guidance including core values to be integrated in this framework, models for interactions, principles

of governance between public private stakeholders and minimum quality criteria as components of a

sustainable, transparent and high quality organisation of vaccine studies and trust into vaccination

programmes. A communication strategy will be informed by structured information on the

population’s perceptions on vaccines and immunisation programs.

The good practice guidance (GPG) is divided into four modules covering different aspects:

Module 1: Code of Conduct

Module 2: Governance models

Module 3: Minimum quality requirements

Module 4: Communication recommendations.

This Deliverable 1.6 “Guidance on best practices-draft” includes Module 1. Module 2 is submitted in

parallel as Deliverable 1.5 “Initial conceptual model for public private interactions” Modules 3 and 4

are in development.

It is acknowledged that a Code of Conduct should be a short document providing clear

recommendations. This text will be developed at a later stage as a basis for a public consultation.

Being a Deliverable to be produced as a report of WP1-WG1 activities, this document provides

additional information on the methods used and the thinking behind the development of the

components of the Code of Conduct, the results of a literature review as well as a long version of the

recommendations to facilitate comments from ADVANCE partners.

1.2. Guiding principles for the Code of Conduct

The overarching objective of this Good Practice Guidance is to improve public health through a

scientific and transparent framework for rapid monitoring the B/R of marketed vaccines. To achieve

this, the GPG will be guided by the values and principles of science, improvement of public health

and transparency. Accordingly, the recommendations in the different GPG modules will all follow

these three lines:

1. Science. Benefit-risk monitoring should rapidly deliver the best evidence possible on the research

question, applying the appropriate scientific methods with integrity.

2. Public Health. All decisions on the prioritisation, conduct and communication to be taken in the

framework of benefit-risk monitoring should be guided by the extent to which they serve improving

the health of individuals and populations.

3. Transparency. Benefit-risk monitoring should be conducted in a transparent manner (disclosing

key decisions and their rationales taken for the selection and design of the study, during study

conduct as well as their interpretations and conclusions, funding sources, roles of each stakeholder,

including declaration of conflict of interest).


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1.3. Components of the Code of Conduct - Summary

Minimum requirements that should be uniformly applied are usually identifiable by the modal verb

“must”. Recommendations that should be considered for implementation are identifiable by the

modal verb “should”.

Scientific integrity

All researchers involved in the study team should be qualified and experienced scientists, acting in

accordance with the values of science, including honesty, accuracy, efficiency, objectivity,

transparency. The study team must perform its work objectively, without predetermined outcomes

and using the most appropriate techniques. The recommendations of the ADVANCE Code of Conduct

are intended to safeguard the scientific integrity of the studies and how it is perceived.

Transparency

1. Every vaccine benefit-risk study must be registered in a publicly accessible database before the

start of data collection. The EU PAS Register should be used for this purpose. Registration should

include the study protocol or outline of the protocol providing enough information to understand

and evaluate the methods used in the study.

2. Sources of research funding must be made public at the time of study registration, in the study

protocol and in the presentations of results. A list of all recipients of financial and non-financial

public and private support for the study should be published or made available on request.

3. Declaration of Interests (DoIs) must be disclosed at an early stage of the study and made

available on request, without a need for justification by the requester. Potential interests must

be declared in the study report and in publications.

4. In case of primary data collection, the main study results must be provided to the subjects who

participated in the study or to their representatives.

5. The final study report should be uploaded into the publicly accessible database where the study

is registered.

6. Other unpublished study information should be made available to researchers from outside the

study team in an open and collaborative approach (for access to data, see “Sharing of study

data”).

7. Recommendations from the external advisory board must be made available to all participants in

the study, including the study requester and study funder.

Conflicts of interest

1. Actual or potential conflicts of interest must be identified and addressed at the planning phase

of the study in order to limit any possible undue influence on its design and support the

credibility of the study team and results.

2. All Declarations of Interests (DoIs) must be disclosed to a committee (or equivalent) at the time

of joining the study team and must be regularly updated.

3. DoIs must be evaluated in relation to specific activities of the study and the action taken must

be proportionate to the gravity of the potential conflict of interest as determined by the risk

that a researcher’s contribution will be (or perceived to be) influenced by his/her interests and

the damage this may cause to the study validity and credibility of the study team and results.


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4. Actions taken should balance the need to prevent any damage while preserving the timely

availability of the best scientific expertise for a specific activity.

Study protocol

1. A protocol must be drafted as one of the first steps in any research project. Its objectives include

to justify the need for the study, to demonstrate the appropriateness of the proposed methods

for testing the stated hypothesis, to demonstrate the feasibility of doing the study as proposed,

to demonstrate that the investigator(s) have the ability and skills to conduct the proposed study

and to demonstrate that appropriate provisions, meeting legal requirements, have been made to

protect participants' personal data.

2. The study protocol must be developed by a team of persons covering relevant expertise. The

process for reaching an agreement on design options should be agreed beforehand.

3. A detailed draft protocol should undergo independent scientific review by experts that did not

participate to its writing and are not anticipated to be directly involved in the study as

investigators.

4. The protocol must include a section with the ethical considerations involved and information

regarding funding, institutional affiliations, potential conflicts of interest, data protection and any

incentives for subjects.

5. The protocol must include a description of the contribution of each party to the study design,

writing of protocol and the study work programme with information on timelines, data

ownership, data access, publications and authorship.

6. For studies on authorised medicinal products with involvement of the marketing authorisation

holder, regulatory obligations and recommendations applicable to the study must be addressed

in the protocol.

7. The protocol may be amended and updated as needed throughout the course of the study.

Amendments or updates to the protocol after the study start must be documented in a traceable

and auditable way.

8. The protocol must be sufficiently detailed to serve as the study's basic document. It should be

made available to all study participants before the study starts.

9. The study protocol must follow an internationally-agreed format in order to ensure that all

important aspects of the study design are covered and to facilitate its development, assessment

and review.

Study report

1. Responsibilities as regards the study report must be clearly established, including on the primary

responsibility for writing interim and final reports and the possibility for persons from outside the

study team to provide comments. This plan should be incorporated into the study protocol and

research contracts.

2. A number of principles must be followed for reporting results:

Any deviations from the analysis plan must be clearly documented in the report.

Outcomes resulting from changes to the analysis plan after data analysis has begun must

not be used for the purpose of verifying or rejecting the prior hypotheses of causal

association stated in the protocol but can be used to generate further hypotheses.


45

Interpretation of statistical measures, including confidence intervals, should be

tempered with appropriate judgment and acknowledgments of potential sources of error

and limitations of the analysis. Sensitivity analyses should be conducted.

Investigators should present how missing and non-interpretable data were handled.

3. Interpretation of the research results of a secondary data analysis is the responsibility of the

secondary user of data. The data provider may be invited to provide comments.

4. The intermediate results of the study may be presented or published only subject to a procedure

approved in advance. Intermediate results must always be explicitly presented as such.

5. The STROBE statement should be considered when analysing and reporting data.

6. It is recommended to follow the template on format and content of post-authorisation safety

studies published by the European Medicines Agency, and adapt it where necessary to outcomes

other than safety.

7. Sources of funding, affiliations and any potential conflicts of interest must be declared in the final

report.

Publications and scientific communications

1. Attempts should therefore be made to rapidly publish results in a peer-reviewed scientific

journal and the publication should not be delayed without due justification. Presentations at

meetings are not substitutes for publications in peer reviewed literature.

2. The publication policy must be agreed in advance and included in the protocol and the research

contract. The principal investigator must be able to independently prepare publications based on

the study results irrespective of the source funding or data ownership. The requester/funder

should be entitled to view the results and interpretations included in the manuscript and provide

comments prior to submission of the manuscript for publication.

3. All relevant study results must be made publicly available, irrespective of the results.

Information published must be accurate and complete. In no circumstances should the results

be changed. The results of a study should undergo independent peer review before they are

made public or the media are informed.

4. In cases where the study is discontinued for any reason, the presentation or publication of any

preliminary or partial results or conclusions may be presented or published but the results from

a discontinued study must be identified as such.

5. Procedures must be put in place to rapidly inform regulatory and public health authorities of the

results of the study, irrespective of the submission of a manuscript for publication.

6. Authorship of publications must follow the rules of scientific publication published by the

International Committee of Medical Journal Editors (ICMJE).

Subject privacy

1. Every precaution must be taken to protect the privacy of research subjects and the

confidentiality of their personal information. In a study with primary data collection where

personal/identifiable data are needed, the study protocol must include a justification for the

need for such data and document that informed consent from the study subjects has been

obtained and that agreement from the relevant ethical committee has been granted.

2. In case where personal data are collected or used in a study:


46

informed consent must be obtained;

investigators working with personal data must be identified throughout the study period;

investigators must take care to use data that offers the best possible protection of the

personal privacy of data subjects;

investigators must ensure that personal identifiers will be removed from any study files that

are accessible to non-study personnel in accordance with applicable laws and regulations.

Sharing of study data

1. An open and collaborative approach to study data sharing with persons from outside the study

team should be followed. Data sharing will normally concern the anonymised analytical dataset.

Data sharing will normally concern only the anonymised analytical dataset. Raw data with

personal identifiers should normally not be shared unless it can be shown that the data

protection legislation, contractual agreements with primary data providers and any other

conditions imposed by national legislations or ethics committee are not infringed.

2. Data should normally be shared only after the study report is finalised.

3. Sharing of study data should be based on a written request specifying the ground of the request,

the nature of the data requested and a protocol on the analyses to be conducted. The written

request should normally be preceded by informal discussions on the reasons for the request and

it acceptability and feasibility. It is the responsibility of the study team to verify the compliance of

the request with the data protection legislation and to seek approval or ask advice from

concerned persons or committees, including, if relevant, the steering committee, the data

controller, the data provider and the ethics committee.

4. Requests to data sharing must be made on specific grounds with a justification based on the

interest for public health.

5. The decision to share study data lies at the appropriate level of the study governance (study

team or steering committee). The public health objective of the request and the scientific quality

of the protocol must be important elements to be considered.

6. Depending on the nature of the request, data may be provided by electronic transmission of data

or remote access via a protected website. Alternative options may be explored with the data

requester, e.g. re-analysis of the data by the original investigator or by an independent

researcher.

7. Analyses performed with shared data must follow the provisions of the ADVANCE Code of

Conduct, including the possibility to ask a Declaration of Interests (DoIs) to the data requester.

8. Study data sharing may be subject to a contractual agreement specifying that the data will not be

used for other purposes than those defined in the protocol and referring to the ADVANCE Code

of Conduct. The data requester may be asked to compensate for costs incurred for dataset

preparation, providing access and/or analysis of data.

Research contract

1. A research contract must never lead investigators or other entities, directly or indirectly, to

violate the principles of the Helsinki Declaration for medical research, or act against applicable

legal or regulatory obligations.

2. A research contract must specify that the study will be conducted according to the ADVANCE

Code of Conduct.


47

3. Key elements of any research contract are clarity and transparency: all relevant aspects must be

covered in a way that is understandable by all the parties concerned.

4. In cases where several research contracts are established for a same study, the terms of

agreement should be communicated to the management entity of the study to ensure

transparency and clarity about different roles and responsibilities.

5. Research contracts must include a number of core elements or indicate they will follow the

recommendations of the ADVANCE Code of Conduct.

1.4. Conclusions

A structured approach has been followed to develop draft guiding principles and code of conduct.

Attempt has been made to differentiate between requirements that have to be followed to ensure

validity and credibility of the study results and recommendations that should be considered for

implementation. A consensus on the use of “must” and “should” for different aspects of the Code of

Conduct will be an important next step for the development of the ADVANCE Code of Conduct. For

this reason, it is intended to perform a broad public consultation.

The recent pandemic influenza vaccines experience highlighted many issues in the way the current

post-marketing monitoring system for vaccines is functioning in Europe and what could be improved.

Several factors limited the capacity to collect European data on vaccine exposure, safety and

effectiveness, including:

the lack of data sources, expertise or willingness;

the difficulty to establish efficient interactions between multiple stakeholders (regulators, public

health agencies, vaccine manufacturers);

the lack of confidence between private and public sectors;

concerns about possible (perception of) conflicts of interest;

disharmonised communications;

lack of mechanisms allowing the funding of studies.

Although these observations were made in the context of the pandemic influenza vaccines, they are

also relevant for other marketed vaccines including MMR, DTaP, Rotavirus, Pneumococcal, HPV

vaccines.

On the other hand, a few successful projects demonstrated the potential for effective collaborations

in Europe:

the Vaccine European New Integrated Collaboration Effort (VENICE) project collected coverage

information through web-based surveys across all the EU/EEA Member States for ECDC to

support monitoring at national and EU level (ref);

the Influenza - Monitoring Vaccine Effectiveness (I-MOVE) consortium utilised various methods

including cohort studies and case-control studies based on sentinel and other surveillance with

laboratory confirmation, publishes harmonised protocols that are regularly updated, facilitates

standard approaches and allows for meta-analysis and replication of I-MOVE data (ref);

the VAESCO consortium demonstrated the usefulness of a collaborative federated database-

driven approach in the EU for assessment of burden of disease and vaccine safety. This effort

translated the experience of the US Vaccine Safety Datalink.


48

To address limitations in the current capacity for conducting rapid vaccine benefit-risk monitoring

activities, the ADVANCE project was initiated with the vision to deliver best evidence at the right time

to support decision-making in Europe. Its mission is to establish a validated and tested best practice

framework to rapidly provide robust data on vaccine benefits and risks to support accelerated

decision making throughout the life cycle of vaccines. For this purpose, it needs to fulfil the needs of

different target groups and stakeholders (e.g. national authorities, insurance companies, regulatory

agencies, public health agencies, vaccine manufacturers, health care providers, consumers, etc).

Effective collaboration between stakeholders and governance for the conduct of studies are among

the main objectives of ADVANCE. In this context, Work Package 1 will develop a good practice

guidance including core values to be integrated in this framework, models for interactions, and

principles of governance between public private stakeholders that might be utilised to build a

sustainable, transparent and high quality organisation of vaccine studies and trust into vaccination

programmes. A communication strategy will be informed by structured information on the

population’s perceptions on vaccines and immunisation programs.

2. Objectives of the good practice guidance

An objective of ADVANCE is to propose a good practice guidance for vaccine benefit-risk monitoring

activities that can be used as a reference for the planning, initiation, design, conduct and reporting of

rapid post-marketing vaccine benefit-risk monitoring activities. This deliverable presents a draft of

the guidance that will be open for consultation. Ultimately, the guidance will be adopted by the main

stakeholders concerned by such activities following a broad consultation.

To achieve its objectives, this guidance aims to:

1. be practical and address key aspects that represented stumble blocks in the past, including

funding aspects, content of research contracts, ethical issues, interactions between involved

stakeholders;

2. be agreed by all stakeholders;

3. be sustainable, namely propose solutions that could be applied after the ADVANCE project

and be accepted by organisations beyond those involved in ADVANCE;

4. be tested in real-life situations through Proof-of-Concept studies;

5. take into account different situations and different needs and requirements of involved

stakeholders for a given study.

3. Structure of the good practice guidance

The good practice guidance is divided in four modules covering different aspects:

Module 1: Code of Conduct

Module 2: Governance models

Module 3: Minimum quality requirements

Module 4: Communication recommendations.

Module 1 Is included in this Deliverable 1.6 “Guidance on best practices-draft”.

Module 2 is presented as parallel as Deliverable 1.5 “Initial conceptual model for public-private

interactions” and will be further submitted as Deliverable 1.10 “Final conceptual model for

public-private interaction”.


49

Module 3 is developed separately and will be added in Deliverable 1.9 “Guidance on best

practice – final”.

Module 4 is developed separately and its components will be developed as Deliverables 1.4

“Analysis of public concerns and perceptions related to benefits and risks of vaccine”, 1.7

“Analysis of key issues and gaps about perception and knowledge on benefits and risks of

vaccines”, and 1.12 “Strategy for public communication in the context of vaccine benefit risk-

communication”.

4. Module 1. Code of Conduct

4.1. Introduction

Many guidelines with recommendations on the planning and conduct of epidemiological studies

already exist. Most of them were developed by learned societies and professional associations at

national and international levels based on a large amount of experience and expertise. In addition,

the new pharmacovigilance legislation that came into force in Europe in 2012 provided a regulatory

framework for the post-authorisation monitoring of medicinal products, including vaccines, which

was translated into a series of Modules of Good pharmacovigilance practices (GVP).

Although these various guidelines could be used as a starting point, it was considered that none of

them fulfilled all the needs of the rapid post-authorisation benefit-risk monitoring of vaccines or

could be used as a stand-alone reference to ADVANCE. In addition, most of them have not been

developed specifically for vaccines. This field has a number of key characteristics including focus on

preventive health care, use biological materials, a limited number of vaccine manufacturers, a broad

range of concerned stakeholders in most countries (including public health authorities, regulatory

authorities, vaccine manufacturers, academic institutions, health care professionals, vaccinated

individuals and the public), existence of national vaccination programmes and potentially large

exposed populations in all age groups. Moreover, specificities of the benefit-risk monitoring of

vaccines required more attention to aspects such as actual or perceived potential conflicts of

interest, research contracts or transparency.

4.2. Guiding principles

4.2.1. The need for guiding principles

Monitoring the benefit/risk balance of vaccines is both a complex and critical activity that involves

multiple participants and multiple stakeholders. Decisions to be made include prioritisation of

vaccine and issues selected for closer monitoring, collaboration in a partnership, allocation of

resources, composition of teams, roles and responsibilities, study designs, conclusion from specific

analyses and an agreed position on the benefit/risk balance. This can be particularly challenging

where very rapid action needs to be taken and a (updated) benefit/risk assessment is needed with

great urgency. Guiding principles may provide a solid foundation to guide these multiple decisions

and the many stakeholders. These principles will form the backbone for the governance models of

the partnerships and the code of conduct for the studies.

The so-called principle-based approach has been advocated by many authors and stakeholders, in

multiple fields. As a first example in the pharmaceutical-regulatory field, the first module of the new

European Guideline on good pharmacovigilance practices (GVP) provides a list of Principles for good

pharmacovigilance practices, which "should guide the design of all structures and processes as well as

the conduct of all tasks and responsibilities". The European Medicines Agency (EMA) also list their


50

"guiding principles" in their Annual Report (2013, p 2; see Annex 1).3 As another example, the

Platform on Ethics & Transparency of the European Commission issued a "List of Guiding Principles

Promoting Good Governance in the Pharmaceutical Sector".4

Several initiatives similar to ADVANCE have selected a principle-based approach. This approach was

illustrated in the US by the expert review for the design and the implementation of the Vaccine

Safety Datalink (VSD) Data Sharing Program (IOM, 2001).5 In Europe, a very extensive and systematic

work on the principle-based approach was undertaken in Scotland in the framework of the Scottish

Health Informatics Programme (SHIP) initiative. This approach has been described in a series of

publications by two main researchers, Graeme Laurie and Nayha Sethi from the School of Law,

University of Edinburgh (e.g. Laurie & Sethi 2012, 2013).6,7 This approach was adopted by the

Scotland government, as described for example in the "Joined-up data for better decisions: Guiding

Principles for Data Linkage" document8 and the SHIP Blueprint 9

The principle-based approach has the following characteristics and advantages:

Explicit statement of the core values and standards Improves transparency and trust Provides decision-makers with a common frame of reference and values to take decisions Broad application to a diverse range of circumstances (even where no rule or guidance yet

exists) Ensures that proportionate levels of governance are applied based on the real risks involved

(Adapted from Laurie & Sethi, 2013. Model of principled proportionate governance developed by the authors in the context of the Scottish Health Informatics Programme, SHIP)

4.2.2. Definitions

While we use the concept of "guiding principle", it should also be acknowledged that similar and

related concepts are often used, such as values, code of conduct, best practices, standards, ways of

working. Clear definitions and demarcation of these concepts are sometimes elusive and, in any case,

many organisations have not necessarily been very explicit about the exact concept they are

referring to.

As a working definition, a guiding principle is:

3 EMA, mission statement http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000106.jsp,

accessed 27 Jan 2015 4 European Commission, Platform on Ethics & Transparency 2012. List of Guiding Principles Promoting Good

Governance in the Pharmaceutical Sector http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/outcomes_et_en.pdf, accessed 27 Jan 2015. 5 IOM (Institute of Medicine) 2001 Vaccine Safety Research, Data Access, and Public

Trust - Committee on the Review of the National Immunization Program's Research Procedures and Data Sharing Program. - The National Academies Press, http://www.nap.edu/catalog/11234/vaccine-safety-research-data-access-

and-public-trust, accessed 27 Jan 2015. 6 Laurie & Sethi 2012. Information governance of use of health-related data in medical research in Scotland:

towards a good governance framework - University of Edinburgh, School of Law, Research Paper 2012/13. 7 Laurie & Sethi 2013. Model of principled proportionate governance developed by the authors in the context of the Scottish Health Informatics Programme, SHIP. 8 Scotland.government: "Joined-up data for better decisions: Guiding Principles for Data Linkage"

http://www.scotland.gov.uk/Publications/2012/11/9015, accessed 27 Jan 2015 9 SHIP 2012 A Blueprint for Health Records Research in Scotland.

http://www.scot-ship.ac.uk/sites/default/files/Reports/SHIP_BLUEPRINT_DOCUMENT_final_100712.pdf

Accessed 6 Jan 2015.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000106.jsp

http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/outcomes_et_en.pdf

http://www.nap.edu/catalog/11234/vaccine-safety-research-data-access-and-public-trust

http://www.nap.edu/catalog/11234/vaccine-safety-research-data-access-and-public-trust

http://www.scotland.gov.uk/Publications/2012/11/9015

http://www.scot-ship.ac.uk/sites/default/files/Reports/SHIP_BLUEPRINT_DOCUMENT_final_100712.pdf


51

- a guide to making decisions;

- criteria by which our decisions are likely to be judged by others.

Similarly, Laurie & Sethi stated that "Principles should be seen as fundamental starting points to

guide deliberation and action."

There is a relationship between values, principles and code or best practice, as expressed by Gilman

(2005)10: "The critical elements in a code are the clear articulation of principles that are derived from

values. This distinction has its clearest conceptualization in the 18th century writings of Jeremy

Bentham. For him a principle was “a general law or rule that guides behaviour or decisions,” whereas

values articulate “an aspiration of an ideal moral state.”

Again, the clearest description of the relationship between values, principles and best practices

relevant to the cause of ADVANCE comes from the SHIP in their "Guiding Principles and Best

Practices" document from the SHIP Information Governance Working Group (SHIP 2010)11:

‘Principles’ are fundamental starting-points to guide deliberation and action. They reflect the values

that underpin the (SHIP) project and its commitment both to promote the public interest and to

protect individual interests. Principles are not rules. Principles sometimes conflict. This is why they are

starting points for deliberation or action. Because of their fundamental importance, however, it is

expected that they are followed where they are relevant to a given data use, storage, sharing or

linkage practice. Any departure must be fully and appropriately justified.

‘Best Practices’ are examples of principles in action. These are instances of optimal governance and in

that sense they are aspirational. As with principles, where instances of best practice are not or cannot

be followed, clear justification should be offered.

A further useful description of the relationship between values and principles comes from the ethical

field as follows:

"An ethical principle is a statement concerning the conduct or state of being that is required for the

fulfilment of a value; it explicitly links a value with a general mode of action. For example, justice may

be considered a significant value, but the term itself does not tell us what rule for conduct or state of

society would follow if we include justice in our value system. We would need a principle of justice to

show us what pattern of action would reflect justice as a value. A common form of the justice

principle is “Treat equals equally and unequals unequally.” We might interpret this principle as

meaning that if all adult citizens are politically equal they should all have the same political rights and

obligations. If one has the vote, all must have it."12

10 Gilman 2005. ETHICS CODES AND CODES OF CONDUCT AS TOOLS FOR PROMOTING AN ETHICAL AND PROFESSIONAL PUBLIC SERVICE Successes and Lessons - WORLD BANK. 11 SHIP 2010. Guiding Principles and Best Practices - A document of the SHIP Information Governance Working

Group.http://www.scot-ship.ac.uk/sites/default/files/Reports/Guiding_Principles_and_Best_Practices_221010.pdf

Accessed 6 Jan 2015.

12 Terry L. Cooper, The Responsible Administrator: An Approach to Ethics in the Administrative Role, 4th edition

(San Francisco, Jossey-Bass Publishers, 1998), p. 12, quoted by Gilman (2005)

http://www.scot-ship.ac.uk/sites/default/files/Reports/Guiding_Principles_and_Best_Practices_221010.pdf


52

4.2.3. Methods

4.2.3.1. Mapping of guiding principles

There is a large number of principles (and values) which are listed explicitly by organisations and

typical stakeholders involved in ADVANCE or similar activities (see Annex 1 for typical examples from

a convenience sample). The most frequent of these principles and values may be (in no particular

order): Transparency, Privacy, Integrity, Scientific Independence, Ethics, Trust, Partnership, Public

health, Open dialogue, Respect, Accountability, Commitment, and many more. While such an

inventory may become very large, it may contain several terms which are just different ways of

expressing very similar concepts, and some others of very restricted use. Even a cursory glance at a

few stakeholders (see Annex 1) suggests that there may be a small core set of guiding principles

common to many stakeholders (Table 1). This was further evaluated with the support of a survey.

4.2.3.2. Ranking the principles, a survey of ADVANCE researchers

An attempt was made to rank the various principles (see previous section) to see their relative

importance for the stakeholders involved in ADVANCE and to identify if any consistent core set

would be present. To this end, a survey was performed during the General Assembly of the ADVANCE

consortium which took place in Annecy, September 2014.

The survey was anonymous and was presented as exploratory, preparatory and non-binding work.

After a short introduction, the attendees received a paper questionnaire with the following

instructions:

1- Please select the top 3 principles and give a rank, 1 to 3 (1=most preferred)

2- Indicate if you feel that some very important principles are missing from the total list and from

your top 3

3- Indicate whether you believe that you could provide a clear operational definition for each

principle

4- Indicate in which type of organisation you are working (PHI, Regulatory, Academia, Industry).

The questionnaire can be found in Annex 2.

Answers were collected from 47 attendees distributed among all stakeholders: 15 from Public Health

Institutes, 10 from Academia, 6 from Regulatory Agencies, 11 from Vaccine Manufacturers, and 5

others (such as ADVANCE project managers). There were very few missing or invalid answers, which

were not used in the analyses; therefore, some of the total of the counts below are be slightly lower

than 47.

The answers to each question are described below:

In Question 1, the attendees were asked to select their top 3 principles from a short list derived from

a mapping of stakeholders’ statements (see questionnaire can be found in Annex 2 for the full list).

We collected 46 questionnaires with answers suitable for analysis. Based on the mean ranks, the top

3 principles were the following, per stakeholder group and overall:


53

There was a clear trend for a few principles to emerge on the top: Science, Improving Public Health

and Transparency. Consistency was very high, since this overall top 3 was also the top 3 in two major

groups, Public Health Institutes and Academia. Each other stakeholder group always shared two of

this top 3. Independence appeared only in the top 3 in the Regulatory Agency group, and Ethics

appeared only in the Vaccine Manufacturers group.

Question 2 was asking whether respondents felt that some very important principles were missing

from the short list presented in Question 1. Only 9 (19%) respondents provided entries with

additional principles. The additions did not show any systematic trends nor clusters. Examples of the

suggestions were: Quality, Robustness, Pragmatism, Sustainability, Honesty, Passion, Fun ... Overall

the answers to this question suggest that the shortlist of principles used in question 1 contains most

of the candidate principles needed for the ranking and identifying a core set.

Question 3 was asking the attendees whether they believed that they could provide a clear

operational definition for each principle, if/when asked. The proportions of positive answers are

shown in the Table below.

PRINCIPLE N %

Transparency 26 55%

Science 24 51%

Improving public health 21 45%

Partnership 21 45%

Ethics 19 40%

Accountability 14 30%

Trust 13 28%

Independence 11 23%

Open dialogue 11 23%

Integrity 10 21%

Respect 10 21%

Commitment 9 19%

Excellence 9 19%

Reliability 9 19%

Only two principles (Transparency, Science) reached a proportion above 50%, and the proportion

was 40% and above only for 5 principles. Overall these proportions were correlated with the ranking

score observed in Question 1; both questions share the same top 3.

4.2.4. Selected principles for guiding the ADVANCE Code of conduct

Within ADVANCE, there was a clear trend for a small and consistent set of principles to emerge:

Science, Improving Public Health and Transparency.


54

These three principles are clearly among the ethical considerations for the post-marketing

monitoring and regulation of vaccines identified by Thompson et al. (2014).13 In this review, the

similar considerations were expressed as "Protection of the public from harm", "Highest quality of

evidence possible", and "Transparency".

The selected principles have been developed independently in some extensive guidelines or similar

documents, a few of which are mentioned below, while others are more extensively cited and used

in the rest of this draft GPG.

For Science, here is a selection of general guidances:

- On Being a Scientist, from the National Academy of Sciences (USA), 1989

- The Netherlands Code of Conduct for Scientific Practice, by the VSNU (Association of Universities in

the Netherlands), 2012.14

- IARC Code of Good Scientific Practice, 2008

- The European Charter for Researchers (European Commission, 2005)

Public health is defined by WHO as "all organized measures (whether public or private) to prevent disease, promote health, and prolong life among the population as a whole. Its activities aim to provide conditions in which people can be healthy and focus on entire populations, not on individual patients or diseases."

(http://www.who.int/trade/glossary/story076/en/, accessed 26 March 2015)

Improvement of Public Health are directly related to ethics principles, as expressed in foundational

texts such as the Declaration of Helsinki.

The importance and need for "targeting transparency" is reviewed by Weil, Graham & Fung 2013.15

Guiding principles can, and should be used explicitly for deriving best practices. Such a complete

approach is developed in details by Laurie & Sethi (2012) for the SHIP initiative, where each of the

selected guiding principle is described and then followed by the related best practice. Other detailed

examples of derivation can be seen in the Netherlands Code of Conduct for Scientific Practice.

We suggest to guide the ADVANCE Code of Conduct by using the three main principles in as follows:

1. Benefit-risk monitoring should rapidly deliver the best evidence possible on the research question,

applying the appropriate scientific methods with integrity.

2. All decisions on the prioritisation, conduct and communication to be taken in the framework of

benefit-risk monitoring should be guided by the extent to which they serve improving the health of

individuals and populations.

3. Benefit-risk monitoring should be conducted in a transparent manner (disclosing key decisions and

their rationales taken for the selection and design of the study, during study conduct as well as their

interpretations and conclusions, funding sources, roles of each stakeholder, including declaration of

conflict of interest).

13 Thompson et al. (2014) Ethical considerations in post-market-approval monitoring and regulation of vaccines.

Vaccines 32:7171-4. 14 VSNU (Association of Universities in the Netherlands) 2012 The Netherlands Code of Conduct for Scientific Practice. http://www.vsnu.nl/files/documenten/Domeinen/Onderzoek/The_Netherlands_Code_of_Conduct_for_Scientific_Practice_2012.pdf 15 Weil, Graham, Fung 2013 Targeting transparency. - Science 340:1410-1.

http://www.who.int/trade/glossary/story076/en/

http://www.vsnu.nl/files/documenten/Domeinen/Onderzoek/The_Netherlands_Code_of_Conduct_for_Scientific_Practice_2012.pdf


55

This may be summarised by stating that the aim of the ADVANCE Good Practice Guidance is to

"Improve public health through a scientific and transparent framework for rapid monitoring the B/R

of marketed vaccines".

4.3. Components of the ADVANCE Code of Conduct

4.3.1. Methods

Two sources of information were used in order to develop recommendations for the code of

conduct: a review of already existing guidelines and a literature search.

Many of the recommendations included in this draft code of conduct are based on recommendations

already expressed, sometimes with many more details, in already existing guidelines. However, it has

been decided not to specifically refer to existing guidelines for expressing ADVANCE

recommendations, but to provide links to selected guidelines for additional reading. There are

several reasons for it:

The review aimed to incorporate recommendations from a wide spectrum of stakeholders, and

existing texts were amended, revised and expanded as needed, to meet the needs of ADVANCE

and apply recommendations to the specific fields of vaccines and vaccination programmes.

Providing references to existing guidelines would have been misleading as original texts have

been changed.

None of the original guidelines was considered as presenting comprehensive recommendations

fulfilling the objectives of ADVANCE; recommendations included in the draft ADVANCE CoC were

extracted from different existing guidelines.

For each element of the code of conduct, the following structure has been followed: a proposal for

a definition when possible, a list of recommendations and a list of selected references for

additional readings. These references provide links to existing guidelines or publications that have

been used as a main source for the recommendations or which support them.

Minimum requirements that should be uniformly applied are usually identifiable by the modal verb

“must”. Recommendations that should be considered for implementation are identifiable by the

modal verb “should”.

4.3.1.1. Review of existing guidelines

The review of existing guidelines was performed in several steps:

1) Identification of relevant guidelines listed in the electronic ENCePP Guide on methodological

standards in pharmacoepidemiology

(http://www.encepp.eu/standards_and_guidances/methodologicalGuide.shtml);

2) Request for additional guidelines to members of ADVANCE WP1 WG1;

3) Extraction of information on 14 topics identified in these guidelines using a standard format;

4) For each topic, the information available in the guidelines was compiled;

5) Review of the information for each topic by one member of the ADVANCE WP1 WG1 to

select and summarise relevant information for the Code of conduct;

6) Discussion of each topic in WG1 (first stage) and WP1 (second stage) in order to keep

relevant recommendations, identify missing recommendations and agree on a text for the

http://www.encepp.eu/standards_and_guidances/methodologicalGuide.shtml


56

missing recommendations, and complement this information with information identified in

the literature search;

7) A broad consultation on a draft code of conduct used in proof-of-concept studies (starting

April 2015);

8) Revision based on the results of the consultation and the evaluation of the proof-of-concept

studies.

The original guidelines used as sources of recommendations in a first step of the development of

the code of conduct are listed below:

ADELF (Association of French-speaking Epidemiologists), Recommendations for

professional standards and good epidemiological practices (Version 2007),

http://adelf.isped.u-bordeaux2.fr/Documentation.aspx

AGENS, DGSPM and DGEpi (German associations), GPS – Good Practice in Secondary Data

Analysis, http://dgepi.de/fileadmin/pdf/leitlinien/gps-version2-final_ENG.pdf

EMA, European Medicines Agency policy on the handling of conflicts of interests of

scientific committee members and expert,

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/10/WC50009790

5.pdf

EMA, Guideline of good pharmacovigilance practices (GVP) Module VIII - Post-

authorisation safety studies,

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/

WC500129137.pdf

EMA, Guideline on good pharmacovigilance practices (GVP)-Product- or Population-

Specific Considerations I: Vaccines for prophylaxis against infectious diseases,


WC500157839.pdf

ENCePP, The ENCePP Code of Conduct,

http://www.encepp.eu/code_of_conduct/index.shtml

FDA, Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies

Using Electronic Health Care Data Sets,

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida

nces/UCM243537.pd

Federation of the medical scientific associations, Code of conduct for health research,

http://www.federa.org/sites/default/files/bijlagen/coreon/code_of_conduct_for_medical

_research_1.pdf

ICJME, Uniform Requirements for Manuscripts Submitted to Biomedical Journals,

http://www.icmje.org/urm_main.html

IEA, Good Epidemiological Practice (GEP), http://ieaweb.org/good-epidemiological-

practice-gep/

ISPE,Good Pharmacoepidemiology Practices (GPP),

http://www.pharmacoepi.org/resources/guidelines_08027.cfm

Nefarma (Dutch association of innovative industry), Code of conduct on Transparency of

Financial Relations, http://www.nefarma.nl/cms/streambin.aspx?requestid=F21F264A-

A1BF-4D0E-ADB3-46569B1DC2FA

Several Dutch medical associations, Code for the prevention of improper influence due to

conflicts of interest, http://knmg.artsennet.nl/web/file?uuid=2fa2e8fd-2a57-4859-be5c-

cb50c66faee9&owner=a8a9ce0e-f42b-47a5-960e-be08025b7b04&contentid=116006


http://dgepi.de/fileadmin/pdf/leitlinien/gps-version2-final_ENG.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/10/WC500097905.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/10/WC500097905.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129137.pdf





http://www.federa.org/sites/default/files/bijlagen/coreon/code_of_conduct_for_medical_research_1.pdf



http://ieaweb.org/good-epidemiological-practice-gep/



http://www.nefarma.nl/cms/streambin.aspx?requestid=F21F264A-A1BF-4D0E-ADB3-46569B1DC2FA


http://knmg.artsennet.nl/web/file?uuid=2fa2e8fd-2a57-4859-be5c-cb50c66faee9&owner=a8a9ce0e-f42b-47a5-960e-be08025b7b04&contentid=116006



57

STROBE Initiative,Strengthening the Reporting of Observational studies in Epidemiology

(STROBE) Statement Guidelines for reporting observational

studies,http://download.journals.elsevierhealth.com/pdfs/journals/0895-

4356/PIIS0895435607004362.pdf

The CONSORT Group, CONSORT: Consolidated Standards of Reporting Trials,

http://www.consort-statement.org/

WMA, Declaration of Helsinki - Ethical Principles for Medical Research Involving Human

Subjects, http://www.wma.net/en/30publications/10policies/b3/index.html

4.3.1.2. Literature search

A literature search was performed to identify any relevant guidance that had not been included.

The search was performed in several steps:

1) An algorithm for literature search was developed and tested; its application to different

databases gave the results presented in Annex 3.

2) The abstracts of the 112 identified articles were reviewed and 15 articles were kept.

3) The full articles related to the 15 articles were extracted and sent to the ADVANCE WP1

WG1.

4) Each member of WP1 WG1 who reviewed a topic of the code of conduct screened the full

article for additional relevant recommendation on their topic;

5) Any relevant information is submitted for inclusion in the draft code of conduct and

discussed with WG1 and WP1 before a broader consultation.

4.3.2. Recommendations of the Code of conduct

4.3.2.1. Scientific integrity

4.3.2.1.1. Definition

Scientific integrity is acting in accordance with the values of science, such as truthfulness, honesty

and open reporting, even when no one is looking over the researcher's shoulder.16

4.3.2.1.2. Recommendations

1. All researchers involved in the study team should be qualified and experienced scientists, acting

in accordance with the values of science, including:

- Honesty (conveying information truthfully and honoring commitments)

- Accuracy (reporting findings precisely and preventing errors)

- Efficiency (using resources wisely and avoiding waste)

- Objectivity (letting the facts speak for themselves and avoiding improper bias)

- Transparency.

2. The study team is responsible and accountable for the integrity and validity of its work. It must

ensure that its work is of the highest integrity - this means that its work is to be performed

objectively, without predetermined outcomes using the most appropriate techniques. The

16 KNAW (Royal Netherlands Acadamy of Arts and Sciences) 2013 Responsible research data management and

the prevention of scientific misconduct, p73. https://www.knaw.nl/nl/actueel/publicaties/responsible-research-data-management-and-the-prevention-of-scientific-misconduct?set_language=en


http://www.wma.net/en/30publications/10policies/b3/index.html

https://www.knaw.nl/nl/actueel/publicaties/responsible-research-data-management-and-the-prevention-of-scientific-misconduct?set_language=en

https://www.knaw.nl/nl/actueel/publicaties/responsible-research-data-management-and-the-prevention-of-scientific-misconduct?set_language=en


58

research must be factual, transparent, and designed objectively. According to accepted principles

of scientific inquiry, the research design must generate an appropriately phrased hypothesis and

the research must answer the appropriate questions rather than favour a particular outcome.

3. The following recommendations are intended to safeguard the scientific integrity of the studies

and how it is perceived:

- Clear and transparent roles and responsibilities

- Study design not geared towards desired outcome

- Protocol posting before data collection and analysis

- Study outcome shall not affect disclosure, publication, remuneration

- Predefined agreement on publication

- Decisions on study report and publications by authors only, selected on criteria of the

International Committee of Medical Journals Editors (ICMJE)

- Declaration of Interest for all study team members/authors

- Disclosure of all funding sources, all affiliations and all roles in the study

- Sources affecting data quality should be identified and disclosed to users

- Research contract established whenever more than one organisation is involved

- Clarify on role of data provider in data interpretation

- Adherence to Good epidemiological practices and Good pharmacoepidemiological practices,

without restriction

- Demonstrable expertise and autonomy of individuals responsible for pharmacoepidemiological

research within their organisations.

4.3.2.1.3. Additional reading

IEA, Good Epidemiological Practice (GEP), http://ieaweb.org/good-epidemiological-practice-gep/



Federation of the medical scientific associations, Code of conduct for health research,

http://www.federa.org/sites/default/files/bijlagen/coreon/code_of_conduct_for_medical_resear

ch_1.pdf.



4.3.2.2. Transparency


Transparency is having study information accessible to all.


1. Every vaccine benefit-risk study must be registered in a publicly accessible database before the

start of data collection. For this purpose, the EU electronic register of post-authorisation studies







59

(EU PAS Register) maintained by the European Medicines Agency and accessible through the

European medicines web-portal is a publicly available database allowing registration of study

characteristics and documents, such as study protocol and reports. Study registration should

include the study protocol or outline of the protocol providing enough information to understand

and evaluate the methods used in the study.

2. Sources of research funding must be made public at the time of study registration, in the study

protocol and in the presentations of results, whether they are presented orally or in writing. A

statement providing a list of all recipients of financial and non-financial public and private

support for the study, including investigators, patient associations and professional associations,

should be made available on request, uploaded or attached as an annex to the registered

protocol.

3. Declaration of Interests (DoIs) must be disclosed at an early stage of the study and made

available on request, without a need for justification by the requester. Potential interests must

be declared in the study report and in publications. DoIs of the members of the external advisory

board must be made available on request.

4. In case of primary data collection, the main study results must be provided to the subjects who

participated in the study or to their representatives. They should be able to receive the complete

results or conclusions by a simple request.

5. The final study report should be uploaded into the publicly accessible database where the stsudy

is registered (e.g. EU PAS register).

6. Other unpublished study information should be made available to researchers from outside the

study team in an open and collaborative approach. Such information may include the detailed

study protocol (e.g. codes used for exposure and disease identification), the statistical analytical

plan, programming codes and detailed interim and final results generated in the study. Provision

of this information should be based on a written request stating the purpose of the request. For

access to study data, see “Sharing of study data”.

7. Recommendations from the external advisory board must be made available to all participants in

the study, including the study requester and study funder.


ADELF (Association of French-speaking Epidemiologists), Recommendations for professional

standards and good epidemiological practices (Version 2007), http://adelf.isped.u-

bordeaux2.fr/Documentation.aspx

ENCePP, The ENCePP Code of Conduct, http://www.encepp.eu/code_of_conduct/index.shtml



Nefarma (Dutch association of innovative industry), Code of conduct on Transparency of Financial

Relations, http://www.nefarma.nl/cms/streambin.aspx?requestid=F21F264A-A1BF-4D0E-ADB3-

46569B1DC2FA








60

4.3.2.3. Conflicts of interest


A conflict of interest is a situation in which a person involved in a research project has a professional

or personal interest sufficient to influence the objective exercise of his/her judgment towards any

activity of the project.

Financial relationships are the most easily identifiable conflicts of interest, but conflicts can occur for

other reasons, such as professional position, personal relationships or rivalries, academic

competition or beliefs.


1. Actual or potential conflicts of interest must be identified and addressed at the planning phase of

the study in order to limit any possible undue influence on its design and support the credibility

of the study team and results. Perceptions of conflicts of interest are as important to be

addressed as actual or potential ones. The research contract must have a clear description of the

management of conflicts of interest.

2. All interests that may lead to potential conflicts must be declared on a standardised form. All

Declarations of Interests (DoIs) must be disclosed to a committee (or equivalent) at the time of

joining the study team and they must be regularly updated.

3. The committee should review and evaluate DoIs in relation to specific activities of the study, e.g.

design of protocol, data collection, data analysis, data interpretation or writing of study report,

and take appropriate action(s) in the event of an actual or potential conflict of interest. Any

action taken must be proportionate to the gravity of the potential conflict of interest, as

determined by two factors:

i. the risk that a researcher’s contribution will be (or perceived to be) influenced by his/her

interests,

ii. the damage this may cause to the study validity and credibility of the study team and results.

4. Actions taken should balance the need to prevent any damage while preserving the timely

availability of the best scientific expertise, and may vary according to the nature of the research

and the gravity of the conflict of interest for a specific activity. They may include for a concerned

person not taking part to some activities or discussions or providing only consultative advice.

Other actions may include setting-up a peer-review process or a multi-stakeholder decision-

making process.


IEA, Good Epidemiological Practice (GEP), http://ieaweb.org/good-epidemiological-practice-

gep/

Several Dutch medical associations, Code for the prevention of improper influence due to

conflicts of interest, http://knmg.artsennet.nl/web/file?uuid=2fa2e8fd-2a57-4859-be5c-

cb50c66faee9&owner=a8a9ce0e-f42b-47a5-960e-be08025b7b04&contentid=116006









61

4.3.2.4. Study protocol


Document containing all the technical details of the design, implementation, analysis, documentation

and publication of the results of an epidemiological study, including timelines. The study protocol

includes all the procedures developed or used during the study and any changes made to the initial

protocol.


1. A protocol must be drafted as one of the first steps in any research project. Its main objectives

are:

to justify the need for the study – that is, why the study should be conducted, given the

current state of knowledge;

to demonstrate the appropriateness of the proposed methods for testing the stated

hypothesis, and justify the methodological choices and why some of the possible options

may have not been relevant or feasible;

to demonstrate the feasibility of doing the study as proposed - that is, that the study can be

completed successfully in the specified time and with the available resources;

to demonstrate that the investigator(s) have the ability and skills to conduct the proposed

study and are aware of all limitations in the design;

to demonstrate that appropriate provisions, meeting legal requirements, have been made to

protect participants' personal data.

2. The study protocol must be developed by a team of persons covering relevant expertise (i.e.

clinical, epidemiological and statistical expertise and expertise on specific clinical or

methodological aspects of the study). The process for reaching an agreement on design options

should be agreed beforehand between the different persons involved. Internationally-agreed

guidelines such as those developed by learned societies or ENCePP 17 and standard checklists,

such as the ENCePP Checklist for study protocols,18 should be consulted to ensure that all

important aspects of the protocol have been covered.

3. A detailed draft protocol should undergo independent scientific review by experts that did not

participate to its writing and are not anticipated to be directly involved in the study as

investigators. While such peer review process might extend the delay by which a final protocol

will be available, this peer review process should not be sacrificed to gain time and should be

documented.

4. The protocol must include a section with the ethical considerations involved and information

regarding funding, institutional affiliations, potential conflicts of interest, data protection and any

incentives for subjects. The protocol must be submitted for consideration, comment, guidance

and approval to the concerned research ethics committee before the study begins.

5. The protocol must include a description of the contribution of each party to the study design,

writing of protocol and the study work programme with information on timelines, data

17 ENCePP Guide on methodological standards in pharmacovigilance and pharmacoepidemiology.

(http://www.encepp.eu/standards_and_guidances/methodologicalGuide.shtml). 18 ENCePP Checklist for Study Protocols. http://www.encepp.eu/standards_and_guidances/checkListProtocols.shtml

http://www.encepp.eu/standards_and_guidances/methodologicalGuide.shtml


62

ownership, data access, publications and authorship. The protocol should be used as the

reference document to be used as the basis for contractual agreements between parties.

6. For studies on authorised medicinal products with involvement of the marketing authorisation

holder, regulatory obligations and recommendations applicable to the study must be addressed

in the protocol.

7. The study protocol should be registered in the EU Post-Authorisation Study Register before the

start of data collection (see EMA, Guideline of good pharmacovigilance practices (GVP) Module

VIII - Post-authorisation safety studies).

8. The protocol may be amended and updated as needed throughout the course of the study.

However, amendments or updates to the protocol after the study start must be documented in a

traceable and auditable way including the dates of the changes. Changes to the protocol that

may affect the interpretation of the study must be identifiable and reported as such in

publications and in the publicly available register where the study is included, and should be

considered when interpreting the findings. This includes additions or amendments to the

objectives or endpoints after the study start. An explanation for the change(s) to the protocol

should be recorded with the protocol amendments or provided upon request once the study

results have been published.

9. The protocol must be sufficiently detailed to serve as the study's basic document. It should be

made available to all study participants before the study starts.

10. The study protocol must follow an internationally-agreed format in order to ensure that all

important aspects of the study design are covered and to facilitate its development, assessment

and review. It is recommended to use the Guidance for the format and content of the protocol

for non-interventional post-authorisation safety studies published by the European Medicines

Agency as a basis for the format of the study protocol, with adaptations as needed.


EMA. Guideline of good pharmacovigilance practices (GVP) Module VIII - Post-

authorisation safety studies)


WC500129137.pdf

EMA. Guidance for the format and content of the protocol of non-interventional post-

authorisation safety studies

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2012/10/WC50013317

4.pdf

ENCePP Checklist for study protocols

(http://www.encepp.eu/standards_and_guidances/checkListProtocols.shtml)










63

4.3.2.5. Study report


Document presenting the rationale, objectives, methods and results of the study, the interpretation

and discussion of the results, including their limitations, and providing conclusions and

recommendations arising from the study.


1. There must be a plan for responsibilities as regards the study report, including on the primary

responsibility for writing interim and final reports and the possibility for persons from outside the

study team to provide comments. This plan should be incorporated into the study protocol and

research contracts.

2. A number of principles must be followed for reporting results:

Any deviations from the analysis plan must be clearly documented in the report and a

reasonable scientific explanation should be provided in line with the provisions for changes

to the study protocol.

Outcomes resulting from changes to the analysis plan after data analysis has begun, e.g.

formation of new sub-groups based on knowledge of (initial) study results, must not be used

for the purpose of verifying or rejecting the prior hypotheses of causal association stated in

the protocol but can be used to generate further hypotheses. Important safety concerns,

even if based purely on subgroup analyses, must be documented and evaluated

appropriately.

Interpretation of statistical measures, including confidence intervals, should be tempered

with appropriate judgment and acknowledgments of potential sources of error and

limitations of the analysis. Sensitivity analyses should be conducted to examine the effect of

varying the study population inclusion/exclusion criteria, the assumptions regarding

exposure, potential effects of misclassification, unmeasured confounders, and the

definitions of potential confounders and outcomes on the association between the a priori

exposure of interest and the outcome(s).

Investigators should develop a plan to assess and handle missing and non-interpretable data.

It is important to provide the percentage of missing data for key variables of interest.

Guidance on how to manage missing data is included in the ENCePP Guide on

methodological standards in pharmacovigilance and pharmacoepidemiology.

3. Interpretation of the research results of a secondary data analysis is the responsibility of the

secondary user of data. The data provider may be invited to provide comments based on his

knowledge and experience with the data.

4. The intermediate results of the study, i.e. the preliminary or partial findings, analyses and

conclusions formulated by the members of the team responsible for the study prior to its

completion, may be presented or published only subject to an advance approval procedure.

Intermediate results must always be explicitly presented as such. In any case, the intermediate

results as well as the data, either raw or already treated, or the data, results, analyses and

conclusions that can be derived from these intermediate results cannot be transmitted to a third

party or used in other studies unless this transmission or use is expressly foreseen in the protocol

and is expressly approved by the principal investigator.


64

5. The STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement

should be taken into consideration when analysing and reporting data.

6. It is recommended to follow the template on format and content of post-authorisation safety

studies published by the European Medicines Agency, and adapt it where necessary to outcomes

other than safety.

7. Sources of funding, affiliations and any potential conflicts of interest must be declared in the final

report.





authorisation safety studies)


WC500129137.pdf

STROBE Initiative, Strengthening the Reporting of Observational studies in Epidemiology

(STROBE) Statement Guidelines for reporting observational

studies,http://download.journals.elsevierhealth.com/pdfs/journals/0895-

4356/PIIS0895435607004362.pdf

The CONSORT Group, CONSORT: Consolidated Standards of Reporting Trials,


EMA. Guidance for the format and content of the final study report of non-interventional

post-authorisation safety studies.

http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_g

uideline/2013/01/WC500137939.pdf.

4.3.2.6. Publications and scientific communications


1. Publication of the results of studies, whether positive or negative, is for the benefit of the

scientific and public health community. Attempts should therefore be made to rapidly publish

results in a peer-reviewed scientific journal and the publication should not be delayed without

due justification. Presentations at meetings are not substitutes for publications in peer reviewed

literature. A summary of the main results of the study should be made available to the public (eg.

through registration in the EU PAS Register).

2. The publication policy has to be agreed in advance and included in the protocol and the research

contract. The research contract should include a publication policy allowing the principal

investigator to independently prepare publications based on the study results irrespective of the

source funding or data ownership. The requester/funder should be entitled to view the results

and interpretations included in the manuscript and provide comments prior to submission of the

manuscript for publication.

3. All relevant study results must be made publicly available, irrespective of the results. Information

published must be accurate and complete. In no circumstances should the results be changed.

Withholding information or refusing to divulge results can be justified only by exceptional

circumstances for example if the methodological problems encountered during the study deprive






65

the results of all meaning. The results of a study should undergo independent peer review before

they are made public or the media are informed.

4. In cases where the study is discontinued for any reason, the presentation or publication of any

preliminary or partial results or conclusions may be presented or published but the results from a

discontinued study must be identified as such.

5. Procedures must be put in place to rapidly inform regulatory and public health authorities of the

results of the study, irrespective of the submission of a manuscript for publication

6. Authorship of publications must follow the rules of scientific publication published by the

International Committee of Medical Journal Editors (ICMJE). Publications must be signed only by

those who made a substantial contribution as described in this guidance.


EMA, Guideline of good pharmacovigilance practices (GVP) Module VIII - Post-authorisation

safety studies,

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC50

0129137.pdf

EMA, Guideline on good pharmacovigilance practices (GVP)-Product- or Population-Specific

Considerations I: Vaccines for prophylaxis against infectious diseases,

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/12/WC50

0157839.pdf



WMA, Declaration of Helsinki - Ethical Principles for Medical Research Involving Human

Subjects, http://www.wma.net/en/30publications/10policies/b3/index.html

4.3.2.7. Subject privacy


Privacy is the ability of an individual to be left alone, out of public view, and in control of information

about oneself.19

Personal data are any information relating to an identified or identifiable natural person. An

identifiable person is one who can be identified, directly or indirectly, in particular by reference to an

identification number or to one or more factors specific to his physical, physiological, mental,

economic, cultural or social identity.20


1. Privacy of study subjects in relation to personal data is a core principle of any medical research

and divulgation of confidential personal data may have serious implications. In the European

Union, the right to privacy is a fundamental right enshrined in Article 8 of the European

19 European Data Protection Supervisor.Glossary. https://secure.edps.europa.eu/EDPSWEB/edps/EDPS/Dataprotection/Glossary 20 Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:31995L0046:en:HTML







https://secure.edps.europa.eu/EDPSWEB/edps/EDPS/Dataprotection/Glossary


66

Convention of Human Rights and Article 7 of the Charter of Fundamental Rights of the EU. The

protection of personal data is guaranteed by the EU legislation, in particular by Regulation (EC)

No 45/2001 and by Directive 95/46/EC. Every precaution must therefore be taken to protect the

privacy of research subjects and the confidentiality of their personal information. In a study with

primary data collection where personal/identifiable data are needed, the study protocol must

include a justification for the need for such data and document that informed consent from the

study subjects has been obtained and that agreement from the relevant ethical committee has

been granted. In a study where personal/identifiable data are not needed or are not available

(such as in a study with secondary data analysis), this should be stated in the protocol.

2. In case where personal data are collected or used in a study, the following principles must be

followed:

• Informed consent must be obtained a fundamental principle for the self-determination of

patients and for the respect of their right to privacy.

• Investigators working with personal data must be identified throughout the study period.

• Investigators must take care to use data that offers the best possible protection of the

personal privacy of data subjects. Anonymised data must be used preferentially and

researchers must avoid working with data that have overt personal identifiers, or can

reasonably directly or indirectly identify a person. Where personal data is required (e.g during

data collection or as part of the data cleaning process), the principle investigators are

responsible for the security and processing of any personal data in accordance with the

applicable data protection legislation.

• Investigators must ensure that personal identifiers will be removed from any study files that

are accessible to non-study personnel in accordance with applicable laws and regulations.

Whenever feasible, study files must be coded and stripped of personal identifiers, and code

keys stored separate from study files. Data and links must be kept in a secured place. Back-up

copies must be subject to the same degree of data security. On completion of the study, data

must be kept in a secured place for the time period required by law to document published

results.


Directive 95/46/EC of the European Parliament and of the Council on the protection of

individual data and on the free movement of such data.

http://ec.europa.eu/justice/policies/privacy/docs/95-46-ce/dir1995-46_part1_en.pdf

Regulation (EC) No 45/2001 of the European Parliament and of the Council of 18 December

2000 on the protection of individuals with regard to the processing of personal data by the

Community institutions and bodies and on the free movement of such data. http://eur-

lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2001:008:0001:0022:EN:PDF

Good Epidemiological Practice (GEP). IEA Guidelines for proper conduct in epidemiological

research (http://ieaweb.org/good-epidemiological-practice-gep/)

Code of Conduct for Medical Research

(http://www.federa.org/sites/default/files/bijlagen/coreon/code_of_conduct_for_medical_r

esearch_1.pdf).

Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. http://www.wma.net/en/30publications/10policies/b3/index.html

http://ec.europa.eu/justice/policies/privacy/docs/95-46-ce/dir1995-46_part1_en.pdf






67

4.3.2.8. Sharing of study data


Analytical data set: the minimum set of data required to perform the statistical analyses leading to

the results for the primary objective(s) of the study.21


1. An open and collaborative approach to study data sharing with persons from outside the study

team should be followed. Data sharing will normally concern only the anonymised analytical

dataset. Raw data with personal identifiers should normally not be shared unless it can be shown

that the data protection legislation, contractual agreements with primary data providers and any

other conditions imposed by national legislations or ethics committee are not infringed.

2. Data should be shared only after the study report has been finalised.

3. Sharing of study data should be based on a written request specifying the ground of the request,

the nature of the data requested and a protocol on the analyses to be conducted. The written

request should normally be preceded by informal discussions on the reasons for the request and

it acceptability and feasibility. It is the responsibility of the principle investigator (or another

person within the study team) to verify the compliance of the request with the data protection

legislation and to seek approval or ask advice from concerned persons or committees, including, if

relevant, the data controller, the data provider and the ethics committee.

4. Requests to data sharing must be made on specific grounds with a justification based on the

interest for public health, including:

to corroborate the study results if there is evidence of conflicting results with different

studies addressing the same research question, or in case of suspected methodological issues

which might impact on the study outcome (such as the statistical analysis performed);

to perform additional research based on the data, such as a patient-based meta-analysis,

sub-group analyses, accounting for confounding factors, use of alternative statistical

methods, or testing of new hypotheses with public health impact;

in the context of an audit by a competent authority;

It is at the discretion of the principle investigator or study team to share the data for other

reasons.

5. The decision to share study data lies at the appropriate level of the study governance (e.g. study

team or steering committee). The public health objective of the request and the scientific quality

of the protocol must be important elements to be considered for the decision.

6. Depending on the nature of the request, data may be provided by electronic transmission of data

or remote access via a protected website. Alternative options may also be explored with the data

requester, e.g. re-analysis of the data by the original investigator or by an independent

researcher.

7. Analyses performed with shared data must follow the provisions of the ADVANCE Code of

Conduct. A Declaration of Interests (DoIs) may be asked to the data requester. DoIs should be

21 Guideline on good pharmacovigilance practices (GVP) Module VIII – Post-authorisation safety studies (Rev 1). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129137.pdf


68

reviewed following the same procedure as for the original study. Depending on the nature of the

analysis to be performed, the data requester may have to follow regulatory requirements if it is a

marketing authorisation holder or someone acting on its behalf.

8. Study data sharing may be subject to a contractual agreement specifying that the data will not be

used for other purposes than those defined in the protocol, referring to the ADVANCE Code of

Conduct and describing the publication policy and authorship if applicable. The data requester

may be asked to compensate for costs incurred for dataset preparation, providing access and/or

analysis of data.




ENCePP Code of Conduct – Implementation Guidance for Sharing of ENCePP Study Data.

http://www.encepp.eu/code_of_conduct/documents/Annex4_SharingData.pdf

4.3.2.9. Research contract


A research contract is a written agreement between two or more parties involved in a research

project, intended to be enforceable by law.

The research contract may have different objectives. It may set out the conditions under which, for

example:

• funding is provided for a research project;

• part of the research project is sub-contracted by one party to another one;

• different parties agree to enter into a collaboration, or partnership for a same project;

• the provider of primary data will give access to the data and allow their secondary use for a

research project.


1. A research contract must never lead investigators or other entities, directly or indirectly, to violate

the principles of the Helsinki Declaration for medical research,22 or act against applicable legal or

regulatory obligations.

2. A research contract must specify that the study will be conducted according to the ADVANCE

Code of Conduct.

3. Key elements of any research contract are clarity and transparency: all relevant aspects must be

covered in a way that is understandable by all the parties concerned.

22 WMA, Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects,





69

4. In cases where several research contracts are established for a same study, the terms of

agreement should be communicated to the management entity of the study to ensure

transparency and clarity about different roles and responsibilities.

5. Research contracts must describe the following elements or indicate they will follow the

recommendations of the ADVANCE Code of Conduct:

• scientific rationale, main objectives and brief description of the research to be carried out;

• the work to be undertaken and the tasks covered by the contract (with deliverables and

timelines as appropriate and contingency plans if timelines cannot be met), as well as the

roles and responsibilities of the different parties for their implementation;

• rights and obligations of each of the concerned entities

• procedure for achieving agreement on the study protocol;

• procedure for achieving agreement on the interim and final study reports;

• communication plan for the scheduled progress and final reports;

• publication policy and authorship;

• intellectual property rights on the protocol and results;

• process for disclosure, update and management of potential conflicts of interests;

• transparency measures: which information will be made public, and how; provision regarding

registration of the study and publication of the protocol;

• archiving of data, rights of data ownerships and access to data;

• storage and availability of analytical dataset and statistical programmes for regulatory audit

and inspection;

• if relevant, provisions for meeting pharmacovigilance obligations, including the reporting of

adverse reactions and other safety data by investigators, where applicable;

• the financial contributions/payment terms of the contract;

• any liability and indemnities due for violating the terms of the contract.


AGENS, DGSPM and DGEpi (German associations), GPS – Good Practice in Secondary Data

Analysis, http://dgepi.de/fileadmin/pdf/leitlinien/gps-version2-final_ENG.pdf


authorisation safety studies,


WC500129137.pdf



IEA, Good Epidemiological Practice (GEP), http://ieaweb.org/good-epidemiological-

practice-gep/



http://dgepi.de/fileadmin/pdf/leitlinien/gps-version2-final_ENG.pdf








70

5. Conclusions

A structured approach has been followed to develop draft guiding principles and code of conduct.

In the Code of Conduct, attempt has been made to differentiate between requirements that have to

be followed to ensure validity and credibility of the study results and recommendations that should

be considered for implementation. A consensus on the use of “must” and “should” for different

aspects of the Code of Conduct will be an important next step for the development of the ADVANCE

Code of Conduct. For this reason, it is intended to perform a broad public consultation.


71

6. Annexes

Annex 1.

Examples of values and principles from a convenience sample of stakeholders.

EMA

1) Values

Excellence: We foster regulatory, scientific and professional capability, competence and knowledge

to provide state-of-the-art advice and independent expertise.

Commitment: We are passionate about our work and our mission to improve public and animal

health in a proactive and innovative way.

Reliability: We deliver what we promise.

Respect: We treat our staff, network, partners and stakeholders fairly and with respect, by

encouraging open dialogue and responding to their needs.

Accountability: Our decisions, activities and outcomes are transparent through open ways of

working and mutual trust.

Source: EMA Flyer, May 2014

2) Guiding principles

1. We are strongly committed to public and animal health.

2. We make independent recommendations based on scientific evidence, using state-of-the-art

knowledge and expertise in our field.

3. We support research and innovation to stimulate the development of better medicines.

4. We value the contribution of our partners and stakeholders to our work.

5. We assure continual improvement of our processes and procedures, in accordance with

recognised quality standards.

6. We adhere to high standards of professional and personal integrity.

7. We communicate in an open, transparent manner with all of our partners, stakeholders and

colleagues.

8. We promote the well-being, motivation and ongoing professional development of every

member of the Agency.

Source: http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000106.jsp, accessed 18 Aug 2014


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SHIP (Scotland)

"Our four values are: collaboration, transparency, innovation, and excellence." (…)

"…two key principles at stake: (1) promotion of the general public interest and (2) protection of the

privacy and other interests of individual citizens, …

Source: SHIP 2012 Blueprint

ECDC

"That excellence, independence and transparency are engendered as core values of ECDC is clear

from the Founding Regulation, “the confidence of the Community institutions, the general public and

interested parties in ECDC is essential. For this reason, it is vital to ensure its independence, high

scientific quality, transparency and efficiency"

Source: ECDC Management Board 2012, Independence policy; MB26/11 http://www.ecdc.europa.eu/en/aboutus/transparency/documents/independence-policy-draft-jan-2013.pdf. Accessed 18 Aug 2014

See also the Founding Regulation (EU law). http://eur-lex.europa.eu/legal-content/EN/ALL/;jsessionid=XQV9Tz2p2T8Tzr1Ff1pwrsHKLnfhsh9gMJ6nH2SZTNFFrLb9cR9W!-1136552967?uri=CELEX:32004R0851

Institute of Medicine, Vaccine Data Link (U.S.)

In the course of its deliberations, the committee found that several overarching principles emerged.

The principles can be described as common themes inherent in the committee’s recommendations

and thus principles that should be considered in any modifications of the VSD data sharing program

or any determinations about whether, when, and how to release VSD preliminary findings. The four

overarching principles that emerged from the committee’s recommendations are these:

• Independence. Ensure that potential biases and potential conflicts of interest are minimized,

balanced, or otherwise managed in the design and implementation of all processes,

practices, and policies related to the VSD.

• Transparency. Ensure that all processes, practices, and policies related to the VSD are

developed in the spirit of openness, clearly articulated, and easily available to interested

persons or entities, and that any deviations from them are documented and justified.

• Fairness. Ensure that all processes, practices, and policies related to the VSD are designed

and implemented in a fair manner.

• Protection of confidentiality. Ensure that the design and implementation of the VSD protect

the confidentiality of individually identifiable information.

Source: Institute of Medicine (U.S.) Committee on the Review of the National Immunization Program’s Research Procedures and Data Sharing Program (2005) Vaccine safety research, data access, and public trust - National Academy Press, http://www.nap.edu/catalog/11234/vaccine-safety-research-data-access-and-public-trust Accessed 13 Jan 2015

Vaccine manufacturer: GSK values

- (Operate with) Transparency

- (Demonstrate) Respect for the people

- (Act with) Integrity

http://www.ecdc.europa.eu/en/aboutus/transparency/documents/independence-policy-draft-jan-2013.pdf

http://www.ecdc.europa.eu/en/aboutus/transparency/documents/independence-policy-draft-jan-2013.pdf

http://eur-lex.europa.eu/legal-content/EN/ALL/;jsessionid=XQV9Tz2p2T8Tzr1Ff1pwrsHKLnfhsh9gMJ6nH2SZTNFFrLb9cR9W!-1136552967?uri=CELEX:32004R0851




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- (Be) Patient focus

Source: http://uk.gsk.com/en-gb/careers/working-at-gsk/our-culture-and-values/, accessed 26

March 2015

http://uk.gsk.com/en-gb/careers/working-at-gsk/our-culture-and-values/


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Annex 2

Questionnaire used for the survey of ADVANCE participants WP1 WORKSHOP, ADVANCE General Assembly, Annecy, 18 September 2014

1. Review the list of principles in the table below and select your top 3 principles. Write a number 1 to 3 (1=most preferred) in the last column

Principle Related concepts My TOP 3

Science Scientific method, quality

Ethics "Patient first", compassion, empathy

Improving public health

Excellence Efficiency, Contiguous improvement

Integrity Discipline, Diligence

Transparency

Open dialogue

Independence Scientific independence

Partnership Collaboration, cooperation

Trust

Reliability

Respect

Accountability

Commitment

2. If you feel that some very important principles are missing from the table, you can list them in this box (free text - please keep it simple)


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3. Indicate whether you believe that you could provide a clear operational definition for each principle

Principle Tick if you believe that you could provide a clear, operational definition

Science

Ethics

Improving public health

Excellence

Integrity

Transparency

Open dialogue

Independence

Partnership

Trust

Reliability

Respect

Accountability

Commitment

4. Indicate (tick) in which type of organisation you are working:

Public Health Institute

Regulatory Agency

Academia

Vaccine Manufacturer

Other

THANK YOU


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Annex 2.

Results of the literature search for additional guidance relevant to the Code of conduct


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Appendix 2: POC template

POC STUDY TEMPLATE

1. ADVANCE Evaluation protocol IMI ADVANCE Objective: [Alignment of these POC proposal with ADVANCE mission] POC Scenario: IMI ADVANCE Innovation components:

Description of the state of art

Innovation beyond the current state of the art

- Validity

[Are the POC results consistent with the current knowledge?]

- Timeliness

[Is the POC approach in ADVANCE able to deliver the results faster than what is expected by current practices? - time to data availability, time to results]

Process parameter evaluation:

[Check list of the parameter matrix checklist]

POC Successes or areas for further development:

2. Scientific Research protocol

[Aligned with ENCEPP checklist for study protocols Appendix 1]

Scientific question:

Scientific research objectives: Design: Populations: Exposure: Outcome: BoD: Effectiveness/Impact: Coverage: Safety: Data sources: Methods: Vaccine choice [Why Pertussis?]: PROS CONS Support Background Literature:


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Appendix 3: Monitoring B/R proposal (proposal 1) Authors: Vincent Bauchau (WP 4) This is an outline for an ambitious, innovative (if not disruptive) POC (MOK?) study, focusing on methods and data sources (and currently agnostic towards codes of conduct). This can be seen as stretching our desired system to its limit, trying to reach directly our vision of immediate and useful information. This proposal is described intentionally at a very conceptual level and very succinctly. Further development and specifications are of course needed but will come only after further discussion and agreement (if any). This proposal is not yet in the new, specific template but will updated to comply with that format later on. Objective: Establish the feasibility of continuously updating the information on the B/R from the first day after a vaccine is launched Design Sequential monitoring of deviations from the B/R expectation (derived initially from clinical development data) based on post-marketing events observed in existing observational databases and/or disease surveillance networks, starting at vaccine launch Scenario: New vaccine on the market and subsequent unexpected new safety concern (signal) in the post-marketing era. Data sources: Clinical development (approval) data for deriving the expectations around the B/R. Available, existing HER databases for all needed information on real-world (post-marketing) use; Disease surveillance network data as an alternative source of infection events. Vaccination records from same or linkable database (registries). Method: Sequential monitoring (such as maxSPRT; possibly event based) of the B/R difference expectations; Expectation will be based on a B/R model integrating the following information: - Expected effectiveness (and/or impact) extrapolated from clinical efficacy measurement (possibly only immunogenicity) - Burden of the preventable disease (assumed to be known at time of launch) - Risks (safety profile), as known from clinical development - Common metric or weighting scheme for benefits and risks The expectation should be expressed as a minimal B/R difference needed for vaccine use; this minimum will be used as the threshold in the monitoring; the model should derive the impact of each new vaccine failure recorded post-launch, as well as any event for a known or new (serious) safety concern. If disease event in the vaccinated are counted in observational databases where specificity is <100% then the model should incorporate conversion factors to estimate the expected proportion of true vaccine failures.


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The B/R model may be based on either the individual/direct effect perspective and/or the population/indirect perspective. Study design: Mock-up roll-back of existing (database) information from time of vaccine launch. The study should start with one country and then move on to as many countries as possible, taking up lessons from failures and improving (if possible) in an incremental way. Which vaccine: The vaccine for this MOCK/POC should be selected on the following criteria: - Relatively wide usage - Relatively high probability of exposure to infectious agent in a relatively short time - On the market for approx. 5 years (ie, recent vaccine but sufficient time since launch to have collected sufficient information for the roll-back) - Existing B/R model will be an asset if it can be used for the post-marketing monitoring - Ideally a vaccine for which a major issue with the B/R was detected relatively late, ie some years after launch (It may not be possible to meet all of these constraints simultaneously) Success measures: - How many EU countries could provide all the post-marketing data streams for complete and real-time monitoring locally - Time between actual events (vaccination failure, adverse event) and actual use of the information to update the output of the monitoring model - Ability to start on the first day on which a new vaccine is launched - How rapidly was the B/R confirmed (or signalled as deviating from expectations) - Fit between the study result and what is otherwise known about this vaccine - Precision over time (level of remaining uncertainty) - Integration with other B/R assessment activities - Acceptability (Regulatory Agencies, Public, …)


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Appendix 4: POC proposal influenza (proposal 2) Author: Miriam Sturkenboom (Wp 5) Introduction and background This proposal was made as an example of how we envision proof of concept studies in ADVANCE. Following the consortium meeting in Sitges, where we heard many questions about the proof of concept studies, the Steering committee has met several times to clarify the aims, place and content of proof of concept studies.

ADVANCE Evaluation protoco IMI ADVANCE objective Assess IMI ADVANCE platform for data availability on a seasonal annual vaccine covering different populations and vaccines across countries, plus the effect of repeated vaccination, need to use surveillance data for effectiveness and the new guidance for safety surveillance. To test the use of different methods (as established in WP 4 and I-MOVE) for evidence generation on safety, effectiveness, burden of disease, vaccination coverage and B/R assessment using a near-real time scenario in view of the new influenza vaccine safety guidance. POC Scenario: Seasonal vaccine with annual changes in composition, different matches against circulating viruses, different burden of disease on an annual level and use of different vaccines and target populations across countries. IMI ADVANCE Innovation components: - Integration of data streams Surveillance networks - Identification of target populations of interest: Morbidity based (risk groups)

- Elderly - Children (some countries) - Pregnant women

- Individual level linkage methods and processes

- Different care level for outcomes (primary, secondary) - Linkage of virological data - Ability for comply with EMA guidelines on safety surveillance

IMI ADVANCE Innovation components: Description of the state of art Human influenza viruses are subject to frequent antigenic changes and therefore are reformulated each year to optimise antigenic match between the vaccine and circulating virus strains. The seasonal influenza vaccine is a trivalent vaccine, containing strains of the A subtypes and one strain of B virus. In February, The World Health Organization (WHO) issues recommendations which strains should be included in the seasonal vaccine for the northern hemisphere. Once these recommendations have been made, vaccine producers need at least six months to manufacture and distribute the seasonal vaccine.


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“Seasonal influenza vaccines present several specific challenges for pharmacovigilance. These include mass immunisation in large population cohorts in a relatively short and fixed time period each year, seasonal factors (e.g. differentiating seasonal peaks in background illness from vaccine-induced effects) and multiplicity of seasonal vaccine products on the market with need for product-specific surveillance. There have also been examples when product-specific (or batch-specific) changes in quality specifications, arising from changes to a manufacturing process during the product life-cycle,have led to an unexpected change in reactogenicity or other adverse immune response. Furthermore, recent expansion of national vaccination programmes to include additional target groups (e.g. healthy children and all pregnant women) has created a greater need for information and reassurance on balance of risks and benefits. Due to these challenges, pharmacovigilance systems for influenza vaccines need capability to rapidly detect and evaluate potential new safety concerns each influenza season. The aim is to mitigate risks before the peak period of seasonal immunisation (i.e. at least within the first month after the start of immunisation)”23 Currently the effectiveness of influenza vaccines in Europe is assessed on an annual basis by the I-MOVE consortium using test negative case control studies based on surveillance data, and cohort studies in large linked databases. Safety of influenza vaccines is not studied systematically, although this will now change given the EMA guidelines on influenza vaccine safety monitoring annually. - Validity [Are the POC results consistent with the current knowledge?] Given the wealth of available evidence on coverage, burden of disease, effectiveness/impact and risk assessment, available study results and, ECDC and national statistical reports will be used to assess validity of the results obtain in this POC, including: -Burden of disease: Calendar time and magnitude of influenza (number of cases, incidence rate) - Vaccination coverage: Age specific and target population specific influenza vaccine coverage, over calendar time (VENICE). - Risk: Safety outcomes as specified by EMA, obtained from manufacturers - Effectiveness and impact: Effectiveness estimation from I-MOVE - Stakeholder feed-back and evaluation on the quality, acceptance of the results for B/R assessment and B/R decision making. - Timeliness [Is the POC approach in ADVANCE able to deliver the results faster than what is expected by current practices? - time to data availability, time to results] - Calendar lag time from protocol development start to protocol sign off - Calendar lag time from protocol submission to data source approval and or IRB to approval - Calendar lag time from protocol data approval to data available for analyses - Calendar lag time from data available for analyses to results available - Calendar lag time from results available to final study report sign off - Person time (Person-Days) effort in any of the periods listed above Process parameter evaluation:

i) Time: – Process time of all steps in workflow locally and centrally (list to be created) j) Cost: resources (person time, machine time) needed to run the POC study through the

different workflow steps (list to be created) k) Acceptability of study proposal, workflow and report by stakeholders (stakeholder feedback

survey).

23 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/04/WC500165492.pdf


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l) Compliance: with legislation, standards, approvals to run the study m) Quality of process, data management, data integrity, privacy and security, validation of the

writing, validation of the programming, number of amendments to the protocols, number of errors than need correction.

n) Transparency: what information can be made public (protocol, authors), how much time after it was done, is the information understandable, the decision-making processes (minutes, agendas), whose interests are involved / who benefits.

o) Flexibility / adaptability: how flexible we are to address the new influenza guidance p) Accesibility of data to different stakeholders


Scientific Research protocol Scientific question: What is the benefit-risk of influenza vaccination in the targeted population? In different years seasons (i.e. …….) compared to non-vaccination? Scientific research objective: to assess

a) Burden of influenza disease from the databases over time and different populations b) Influenza vaccination coverage in target groups c) To estimate vaccine effectiveness in various populations of interest, with and

without use of surveillance data d) The risk for safety outcomes of interest. e) The B/R in the target populations f) Variability in BoD, coverage, effectiveness, safety and B/R between vaccins within a

country and across countries g) B/R for re-vaccination in target groups h) Effect of perspective (regulator, manufacturer, public health, health care provider

and patient) on B/R ratio Population: those targeted for influenza vaccination in a given population by age, comorbidities, target risk groups (i.e. pregnant women), Exposure: Influenza vaccination (all brands/products) Outcome: BoD: effectiveness outcomes Coverage: influenza vaccine Effectiveness: Laboratory: laboratory confirmed Influenza Clinical: influenza like illness, all respiratory illness, hospitalisations, death Safety: Fever, including high grade fever; Vomiting and nausea; Malaise; Headache; Irritability (for under 5-year-old vaccinees); Crying (for under 5-year-old vaccinees); Decreased appetite; Injection site reactions4 (e.g. pain, erythema, swelling) including severity and persistence; Rash; Myalgia/arthralgia; Events indicative of allergic and hypersensitivity reactions, including ocular symptoms. For live attenuated, intranasal vaccines, the following additional AEIs are of interest: Nasal congestion/rhinorrhoea; Wheezing; Oropharyngeal pain; Cough; Epistaxis Rare events: Guillain Barre Syndrome, Narcolepsy, asthma exacerbations Data sources: EHR databases Disease surveillance networks (EISN data from ECDC). VENICE coverage data Vaccination records from same or linkable database (registries).


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Study designs I-MOVE standard protocols for effectiveness Recommendations from EMA for safety


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Appendix 5: Pertussis (proposal 3) Author: Germano Ferreira (WP 5)

ADVANCE Evaluation protocol IMI ADVANCE Objective: [Alignment of these POC proposal with ADVANCE mission] The objective of this POC proposal is to assess IMI ADVANCE platform for data availability on a routinely used vaccine in established vaccination programs covering different populations, different schedules across countries and in various combinations with other disease valences. To assess the methods for evidence generation on safety, effectiveness, burden of disease and vaccination coverage using a near-real scenario to inform benefit-risk assessment. To evaluate the acceptability of the results and evidence by stakeholders for decision making on B/R. POC Scenario: Established vaccination/vaccine with changes in vaccine constitution and formulation over time (trivalent to hexavalent combinations), schedule differences between countries and expansion of recommendation to new target populations at risk with subsequent new safety concerns and health outcomes of interest to be monitored. IMI ADVANCE Innovation components: Descrption of the state of art Pertussis is an acute bacterial respiratory infection caused by Bordetella pertussis. Clinical characteristics are proctated coughing that can last for weeks, starting with catarrhal stage followed by intense paroxysmal coughing spells. Infants under 1 year of age are at the highest risk for complications, including pneumonia and seizures. The infection presents with mild in adults and adolescents. Humans are the only host, and control through immunization available since the 50’s has been showed efficient. However neither natural infection nor vaccination confers life-long protection. Pertussis persists an infection of global public health importance. Countries with established vaccination programs with high vaccination coverage for pertussis have reported a resurgence of pertussis cases, in particular adolescents and adults, and infants less than 6 months of age. Recent changes to the vaccination recommendations include: additional booster dose for children 1-6 years, preferred at 2 years of age (SAGE); vaccination of adolescents and close members of the household to protect the infant - “cocooning” (France, Australia, US); and in 2011, the US started the advice for vaccinating pregnant women who have not previously received the recommended adult dose; updated in 2012 to recommend routine pregnant women pertussis-containing vaccine. Immunization of pregnant women is now routine in several other countries including the UK. Albeit the early debate in the 1940-1950’s on the quality of evidence generated by US and Canadian field trials, from 1956 onwards several clinical and field effectiveness studies demonstrated the effectiveness of the pertussis-containing vaccines in reducing the outbreaks and protecting children against the infection. Safety concerns emerged for the first generation of Wholecell (wP) pertussis vaccines with particular relevance to neurological complications in the 1970’s. The benefit of the vaccination was then challenged, and the adverse publicity reduced vaccination coverage from 79% to 31% in 1978. A rich stream of evidence on safety and benefits, risk and effectiveness were produced at the time.


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In the 1990s schedule changes were introduced namely the compressed schedule to increase vaccination coverage, with an impact in reducing the number of infant cases between 6 and 11 years of age. Acellular pertussis vaccines were developed to tackle waning immunity in adults and was introduced in pertussis containing vaccines booster, given the high reactogenicity of wP when administered as a booster. Acellular pertussis component is now routinely available in combinations for primary series in children with 3 or 5 aP pertussis components in combinations with Haemophilus influenzae b Hib and inactivated polio vaccine (IPV). A wealth of evidence and information is available on safety and risk assessment as well as benefit both effectiveness and impact from various stakeholder perspectives, namely academia, public health, and vaccine manufacturers. Recently introduced screening and diagnostic procedures, including serology tests, have increased the performance of differential diagnosis of pertussis in adolescents and adults. Diagnosis confirmation relies on laboratory testing. Pertussis is a reportable infectious disease in most European countries with national level surveillance networks in various countries. Innovation beyond the current state of the art - Integration of data streams Surveillance networks Laboratory sentinel networks - Identification of target populations of interest in available data sources: Very early ages (<12 months of age) Pregnant women Family and household cluster - Individual or aggregated level linkage methods and processes for data integration Mother - Child linkage Family cluster Disease surveillance, Laboratory sentinel, Vaccination registries, Safety spontaneous reports - Assessment of B/R of combination vaccines for which safety profiles are “mixed” and the benefit is individual disease specific.

- Validity

[Are the POC results consistent with the current knowledge?]

Given the wealth of available evidence on coverage, burden of disease, effectiveness/impact and risk assessment, available study results and national statistical reports will be used to assess validity of the results obtain in this POC, including:

-Burden of disease: Calendar time and magnitude of pertussis outbreaks (number of cases, incidence rate)

- Vaccination coverage: Age specific and target population specific pertussis containing vaccination coverage, over calendar time.

- Risk: Risk assessment of the incidence of Health outcomes of interest

- Effectiveness and impact: Effectiveness estimation compared with available study results for infants (disease, hospitalization, death); pregnant women, adult and adolescent.

Impact assessment on the pertussis control in infant cases, mortality, hospitalization.


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- Stakeholder feed-back and evaluation on the quality, acceptance of the results for B/R assessment and B/R decision making.

- Timeliness

[Is the POC approach in ADVANCE able to deliver the results faster than what is expected by current practices? - time to data availability, time to results]

- Calendar lag time from protocol development start to protocol sign off

- Calendar lag time from protocol submission to data source approval and or IRB to approval

- Calendar lag time from protocol data approval to data available for analyses

- Calendar lag time from data available for analyses to results available

- Calendar lag time from results available to final study report sign off

- Person time (Person-Days) effort in any of the periods listed above

Process parameter evaluation: q) Time: – Process time of all steps in workflow locally and centrally (list to be created)

r) Cost: resources (person time, machine time) needed to run the POC study through the

different workflow steps (list to be created)

s) Acceptability of study proposal, workflow and report by stakeholders (stakeholder feedback

survey).

t) Compliance: with legislation, standards, approvals to run the study u) Quality of process, data management, data integrity, privacy and security, validation of the


v) Transparency: what information can be made public (protocol, authors), how much time after it was done, is the information understandable, the decision-making processes (minutes, agendas), whose interests are involved / who benefits.

w) Flexibility / adaptability: how flexible we are to address the new influenza guidance

x) Accesibility of data to different stakeholders


POC Successes or areas for further development: - Identification of an appropriate size population of infants 6 months, 12 months, of age; population of pregnant women and mother child linkage, general population of adults and adolescents - Identification and validation of vaccine exposure in the existing / available data sources, including brand level and combination type detail, and date of vaccination; in the populations of interest. - Identification and validation of pertussis diagnostic / disease occurrence in the available data sources, including the reproduction of the observed disease clusters in public health surveillance data. - Approval of access to required data streams - Estimating valid and consistent measures of BoD, Effectiveness, Safety (Risk), Coverag with those currently available from previous research. - Evidence and results delivered faster than currently established approaches.

Scientific Research protocol [Aligned with ENCEPP checklist for study protocols Appendix 1]

Scientific question: What is the benefit-risk of pertussis vaccination in the various target populations and vaccine combinations?


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Scientific research objectives: The POC study objectives are aligned with the four pillars of the B/R assessment, namely disease burden, vaccination coverage, effectiveness-impact, risk assessment. The specific objectives are the following:

a) To estimate burden of pertussis disease in populations of interest and identification of outbreaks over time.

b) To estimate pertussis vaccination coverage and schedule compliance in various populations and countries, and various combinations.

c) To estimate pertussis vaccine effectiveness in different populations of interest, including the indirect effects of maternal immunization in protecting the newborn; and duration of protection (effectiveness over time), and effect on mild and severe forms of disease.

d) To compare the results of generated evidence with existing evidence on Burden, Coverage and Effectiveness/impact of pertussis vaccination

e) To assess the risk for established safety outcomes, namely:

f) To assess the B/R in the populations of interest, namely: infants, pregnant women, children and adults.

Design: Multi country - distributed database study. Populations: Newborns and infants from 0 to 12 months of age Pregnant women Children adolescent and adult recommended for booster vaccination Exposure: Any vaccine containing Pertussis component (DTP, DTaP, Penta, Hexa). Outcome: BoD: - Pertussis disease - clinical diagnostic - Pertussis disease - laboratory confirmation - “Pertussis-like disease” - syndromic definition - Severe pertussis disease - Clinical, outcomes and health utilization Effectiveness/Impact: - Pertussis disease - clinical diagnostic - Pertussis disease - laboratory confirmation - “Pertussis-like disease” - syndromic definition - Severe pertussis disease - Clinical, outcomes and health utilization Coverage: - Vaccination containing Pertussis component (DTP, DTaP, Penta, Hexa) Safety: - Safety outcomes of interest: Newborn: Congenital malformations Infant: TO BE DEFINED Children-Adults: TO BE DEFINED Data sources: WP3 input for available potential datasources WP5 for fingerprinting for feasibility assessment of data sources of potential interest


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Clinical development (approval) data for deriving the expectations around the B/R (TBC) HER/claims databases available for all needed information on real-world Disease surveillance network data including laboratory sentinel networks Vaccination registry data individual or aggregated. Methods: WP4 input required Use all available sources to estimate coverage, how well can sales data be used? How to plot Safety: systemic reactogenicity (frequent); type of vaccine, coadministration. Different types of design: case control and self-controlled case series, propensity score matched approaches. What type of estimates for B/R? relative risks or absolute risks. First events only. Look at absolute risks and relative transferability. BoD: surveillance data in infants test access to that, can we reproduce the outbreaks? Seroprevalence data for adults. Number of hospitalization cases Effectiveness PRO-ACT Preferences target groups necessary to make explciti Vaccine choice [Why Pertussis?]: PROS - Well established B/R profiles and wealth of evidence on safety, benefit, coverage and burden of disease - Vaccine preventable disease of Public health interest - observed clusters and outbreaks across Europe in recent years - Large use (universal vaccination) - multiple manufacturers and brand combinations available CONS - Unavailable or potentially biased control group of unvaccinated - Single disease based B/R assessment versus combination vaccine B/R assessment - Changes of vaccine constitution over time to be accounted for. - Input required/expected from WPs to further complete the POC proposal for GS in September 2014 - WP1 Governance model; guidelines and best practices criteria; quality

- WP1 Code of conduct ENCEPT criteria applicable, suitable for vaccine research and databases used in the POC; quality parameters to be observed, measured.

- WP2 Potential synergies with other project burden of disease - WP3 Ethics and data access parameters and requirements - WP3 Data sources identification / data gaps - WP3 specify use cases and align with those covered in the POC - WP4 methods - WP5 IT infrastructure and quality assurance metrics Support Background Literature: Vaccination coverage assessment in EU/EEA, Venice consortium: http://venice.cineca.org/

http://venice.cineca.org/


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1. Juretzko P, von Kries R, Hermann M, Wirsing von König CH, Weil J, Giani G. Effectiveness of Acellular Pertussis Vaccine Assessed by Hospital‐Based Active Surveillance in Germany. Clinical Infectious Diseases [Internet]. 2002 Jul 15 [cited 2014 Feb 11];35(2):162–7. Available from: http://cid.oxfordjournals.org/lookup/doi/10.1086/341027

2. Amirthalingam G, Gupta S, Campbell H. Pertussis immunisation and control in England and Wales, 1957 to 2012: a historical review. Euro Surveill [Internet]. 2013 [cited 2014 Aug 22];18(38):20587. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20587

3. Glanz JM, Narwaney KJ, Newcomer SR, Daley MF, Hambidge SJ, Rowhani-Rahbar A, et al. Association Between Undervaccination With Diphtheria, Tetanus Toxoids, and Acellular Pertussis (DTaP) Vaccine and Risk of Pertussis Infection in Children 3 to 36 Months of Age. JAMA Pediatr. 2013 Sep 9;

4. Shakib JH, Korgenski K, Sheng X, Varner MW, Pavia AT, Byington CL. Tetanus, Diphtheria, Acellular Pertussis Vaccine during Pregnancy: Pregnancy and Infant Health Outcomes. J Pediatr. 2013 Jul 26;

5. Amirthalingam G, Andrews N, Campbell H, Ribeiro S, Kara E, Donegan K, et al. Effectiveness of maternal pertussis vaccination in England: an observational study. Lancet. 2014 Jul 15;

6. Donegan K, King B, Bryan P. Safety of pertussis vaccination in pregnant women in UK: observational study. BMJ. 2014;349: g4219.

7. Quinn HE, Snelling TL, Macartney KK, McIntyre PB. Duration of Protection After First Dose of Acellular Pertussis Vaccine in Infants. PEDIATRICS [Internet]. 2014 Mar 1 [cited 2014 Aug 6];133(3):e513–e519. Available from: http://pediatrics.aappublications.org/cgi/doi/10.1542/peds.2013-3181

8. Wang K, Fry NK, Campbell H, Amirthalingam G, Harrison TG, Mant D, et al. Whooping cough in school age children presenting with persistent cough in UK primary care after introduction of the preschool pertussis booster vaccination: prospective cohort study. BMJ [Internet]. 2014 Jun 24 [cited 2014 Jul 4];348(jun24 18): g3668–g3668. Available from: http://www.bmj.com/cgi/doi/10.1136/bmj.g3668

9. Lasserre A, Laurent E, Turbelin C, Hanslik T, Blanchon T, Guiso N. Pertussis incidence among adolescents and adults surveyed in general practices in the Paris area, France, May 2008 to March 2009. Euro Surveill [Internet]. 2011 [cited 2014 Aug 27];16(5):19783. Available from: http://eurosurveillance.org/images/dynamic/EE/V16N05/art19783.pdf


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Appendix 6: POC proposal rotavirus (proposal 4)

IMI-ADVANCE POC study proposal: Rotavirus Author: P95 Epidemiology and Pharmacovigilance Services IMI ADVANCE objective Assess IMI ADVANCE platform for data availability on rotavirus (RV) vaccine, RV gastroenteritis (GE) and adverse events following immunizations (AEFIs) in children, in order to establish the usefulness of the system in the performance of a real-time population based benefit-risk assessment of a novel vaccine. To test the feasibility of linking and integrating different databases across countries. POC Scenario: Rotavirus vaccines are being introduced in the national immunizations schedules in Europe. Although the available vaccines are considered safe and effective, there have been some concerns about an increased risk of intussusception in vaccinated children in studies carried out in the United States, Mexico, Brazil and Australia. There is little or no post-licensure data in Europe. Moreover, there is limited information on the long term effect of rotavirus vaccination on the occurrence of IS. A compensatory decrease, following an initial increase, cannot be excluded. IMI ADVANCE Innovation components: - Integration of data streams Primary Health Care databases from different countries Combining information from clinical trials with information available in the postmarketting setting - Identification of target populations of interest: Children - Individual level linkage methods and processes Different care level for outcomes (primary, secondary) Linkage of virological data if available Ability to comply with EMA guidelines on safety surveillance Validity [Are the POC results consistent with the current knowledge?] There is data available for burden of disease of rotavirus in Europe, as well as several studies concerning the risk of intussusception that can be used for the validation of the results in this POC, including:

Burden of disease: Number of cases and incidence rate

Vaccination coverage: Age specific.

Risk: Safety outcomes as specified by EMA, obtained from manufacturers, focusing on intussusception.

Effectiveness and impact: Effectiveness estimation from post-licensure studies

Stakeholder feed-back and evaluation on the quality, acceptance of the results for B/R assessment and B/R decision making.

Timeliness [Is the POC approach in ADVANCE able to deliver the results faster than what is expected by current practices? - time to data availability, time to results]

Calendar lag time from protocol development start to protocol sign off

Calendar lag time from protocol submission to data source approval and or IRB to approval

Calendar lag time from protocol data approval to data available for analyses

Calendar lag time from data available for analyses to results available


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Calendar lag time from results available to final study report sign off

Person time (Person-Days) effort in any of the periods listed above Process parameter evaluation:

y) Time: – Process time of all steps in workflow locally and centrally (list to be created) z) Cost: resources (person time, machine time) needed to run the POC study through the

different workflow steps (list to be created) aa) Acceptability of study proposal, workflow and report by stakeholders (stakeholder feedback

survey). bb) Compliance: with legislation, standards, approvals to run the study cc) Quality of process, data management, data integrity, privacy and security, validation of the


dd) Transparency: what information can be made public (protocol, authors), how much time after it was done, is the information understandable, the decision-making processes (minutes, agendas), whose interests are involved / who benefits.

ee) Flexibility / adaptability: how flexible we are to address the new influenza guidance ff) Accesibility of data to different stakeholders

[Check list of the parameter matrix checklist] Scientific research protocol Description of the state of art Rotaviruses are the main cause for acute gastroenteritis hospitalizations worldwide. The first rotavirus vaccine (rhesus reassortant tetravalent vaccine, Rotashield, Wyeth Vaccines) was introduced in the United States immunization schedule in 1998, and was withdrawn a year later due to an increase in the number of cases of intussusception in vaccinated children. Since 2006, 2 new vaccines are available, RV5 (pentavalent bovine-human reassortant vaccine, Rotateq, Merck) and RV1 (attenuated monovalent human rotavirus vaccine, Rotarix, GSK Biologicals). Although in pre-licensure trials there was no association found with intussusception, several post-licensure studies have shown an increased risk of intussusception among vaccinated children, albeit much lower than the risk found for RRV-TV. These vaccines are widely used worldwide, although few European countries have introduced it in their immunization schedules to date (Austria, Belgium, Estonia, Finland, Germany, Luxembourg, United Kingdom as of 15 August 2014). The challenge with rotavirus vaccines (and other vaccines) is the identification of rare adverse events in the pre-licensure and post-licensure phase. Powering pre-licensure trials to detect rare adverse events is costly and time-consuming. It would be therefore extremely useful if routine data collection could be used to determine early in the post-licensure period the risk profile of the vaccine, by comparing incidence rates of the events of interest in the pre and post-licensure periods. Scientific question: What is the benefit-risk of RV vaccination in children? Scientific research objective: To assess

i) The Burden of RV disease j) RV vaccination coverage k) To estimate RV vaccine effectiveness in children l) The risk for safety outcomes of interest m) The B/R in children n) Variability in BoD, coverage, effectiveness, safety and B/R across countries


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o) Effect of perspective (regulator, manufacturer, public health, health care provider and patient) on B/R ratio

Population: those targeted for rotavirus vaccination Exposure: RV vaccination (all brands/products) Outcome: BoD: Number of medically attended acute GE due to Rotavirus, pre and post-licensure Coverage: RV vaccine Effectiveness: Laboratory: laboratory confirmed RV Clinical: Medically attended acute GE (hospitalizations/consultations) Safety: Diarrhea, irritability, abdominal pain, hematochezia Rare events: intussusception. Data sources

EHR databases

VENICE coverage data

Vaccination records from same or linkable database (registries) Study design Multi-country, database study. Evaluation of the burden of disease/impact of vaccination will be carried out following ECDC’s generic protocol for the evaluation of the impact of rotavirus vaccination. Methods Support background literature Anderson EJ, Sederdahl BK. Intussusception risk increased after rotavirus vaccination but outweighed by benefits. Evid Based Med. 2014. Buttery JP, Standish J, Bines JE. Intussusception and rotavirus vaccines: consensus on benefits outweighing recognized risk. Pediatr Infect Dis J. 2014; 33:772-773. Clark A, Jit M, Andrews N, Atchison C, Edmunds WJ, Sanderson C. Evaluating the potential risks and benefits of infant rotavirus vaccination in England. Vaccine. 2014; 32:3604-3610. Noel G, Minodier P, Merrot T. Intussusception risk after rotavirus vaccination in U.S. infants. N Engl J Med. 2014; 370:1766. Quinn HE, Wood NJ, Cannings KL, et al. Intussusception Following Monovalent Human Rotavirus Vaccine in Australia: Severity and Comparison of Using Healthcare Database Records versus Case-Confirmation To Assess Risk. Pediatr Infect Dis J. 2014. Rha B, Tate JE, Weintraub E, et al. Intussusception following rotavirus vaccination: an updated review of the available evidence. Expert Rev Vaccines. 2014:1-10. Pediatric REC. The paediatric burden of rotavirus disease in Europe. Epidemiol Infect. 2006;134:908-916. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med. 2006;354:11-22. Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med. 2006;354:23-33.


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VENICE II Consortium (WP4). Vaccination coverage assessment in the EU/EEA, 2011. Available at http://venice.cineca.org/Final_Vaccination_Coverage_Assesment_Survey_2011_1.pdf European Centre for Disease Prevention and Control. Impact of rotavirus vaccination - Generic study protocol. Stockholm: ECDC; 2013. Available at http://www.ecdc.europa.eu/en/publications/publications/rotavirus-impact-vaccination-april-2013.pdf

http://venice.cineca.org/Final_Vaccination_Coverage_Assesment_Survey_2011_1.pdf

http://www.ecdc.europa.eu/en/publications/publications/rotavirus-impact-vaccination-april-2013.pdf

http://www.ecdc.europa.eu/en/publications/publications/rotavirus-impact-vaccination-april-2013.pdf


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Appendix 7: Zoster proposal (proposal 5) Author: Simon de Lusignan Context Shingles, also known as herpes zoster, is a painful skin rash caused by the reactivation of the chickenpox virus (varicella-zoster virus) in people who have previously had chickenpox. It begins with a burning sensation in the skin, followed by a rash of very painful fluid-filled blisters that can then burst and turn into sores before healing. Often an area on just one side of the body is affected, usually the chest but sometimes the head, face and eye. (NHS Choices) Once a person has recovered from chickenpox, the varicella zoster virus lies dormant in the nerve cells and can reactivate at a later stage. Reactivation of the virus is thought to be associated with immunosuppression as a result of a decline in cell mediated immunity due to old age, immunosuppressant therapy or HIV Infection. The burden of disease amongst adults aged 70 and above is considerably high as the risk and severity of shingles increase with age.i Aim:

The aim of this proof of concept (POC) study is to conduct a vaccine study to compare validity, reliability and timeliness of using different methods and data sources to collect data. The study will also evaluate the differences in privacy and ethics procedures between jurisdictions, data sources and types of data. Potential blockers/ failures will inform next wave of studies and the experiences gathered will be a value addition to the investigators guide within the ADVANCE framework.

Design:

This is multi-country study.

Population:

Adults aged 70 to 79 years

Exposure:

Vaccines used for prevention of shingles (Zostavax)

Scientific Questions What are the validity, reliability and timeliness measures of different data collection methods across different countries? What are the barriers of accessing data using these different methods? Method: Data related to shingle vaccination are collected using the following methods.

Interview by researcher of person identified as vaccinated from their medical record (gold standard)

o In person o Data collected though telephone interviews o Online data collection (i.e. using a website or video conferring software such as

Skype)

Family Practice (Primary Care) collected data (routinely collected data – generally from computerised medical records.


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For each method, data from about 50 patients are collected from multiple practices. The practices will be cluster randomized. Practice agreements will be put in place to collect data weekly or two weekly after vaccination. Data sources: As described in the method.


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Appendix 8: HPV proposal P95 (proposal 6)

IMI-ADVANCE POC Study proposal: HPV P95 Epidemiology and Pharmacovigilance Services IMI ADVANCE objective Assess IMI ADVANCE platform for data availability on cervical cancer screening uptake, human papillomavirus (HPV) vaccination coverage and HPV-related burden of disease covering different European countries. As a separate point of interest, the frequency of detection of preneoplastic lesions, including treatment methodology of these lesions, combined with obstetrical data in these women, would make it possible to investigate the potential impact of HPV vaccination on the prevalence of preterm births, a potential benefit of HPV vaccination, that has not been thoroughly investigated so far. POC Scenario: IMI ADVANCE Innovation components: Description of the state of art The HPV vaccines that are currently commercially available, Gardasil (SPMSD) and Cervarix (GSK), were designed to prevent cervical cancer. For cervical cancer it has been shown that there is a nearly 100% association with the (persistent) presence of high-risk HPV types 1. However, a causal role of HPV in the development of a number of other cancers has been decribed, including vulvar, vaginal, anal, penile and oropharyngeal cancer, although the association was less than for cervical cancer (estimated contribution of HPV to various cancer sites is as follows: anal cancer = 88%, vulvar cancer = 25%, vaginal cancer = 70%, penile cancer = 30%, and oropharyngeal cancer = 26%). The HPV vaccines also prevent preneoplastic lesions. In the past, a clear link between treatment of precancerous cervical lesions (cervical intraepithelial neoplasia (CIN) grade 2 and worse) and obstetrical complications later in life (preterm birth) was shown 2,3. Prevention of CIN2+, and hence, reduction in number of preterm births, would be a strong argument in favor of vaccination. However, treatment techniques are much less aggressive nowadays 4, reducing the effect of vaccination. Furthermore, socio-economic factors may be a confounder, further reducing the impact of vaccination. The effect of treatment is also volume-related, the larger the number of treatments performed (per physician/hospital), the lower the risk of preterm birth. Finally, although non-cancerous HPV related diseases, both the frequently occurring genital warts and the rarely occurring recurrent respiratory papillomatosis (RRP) have a high morbidity. Because of the long lag time between HPV infection and the development of HPV-related cancer, the benefit can only be estimated. Insight in the HPV vaccine coverage, combined with the burden of disease for HPV related diseases, as well as data from the original RCTs, will enhance the accuracy of the estimate. On the other hand, cervical cancer screening uptake in combination with treatment and follow-up, will allow estimation of the additional benefit of vaccination for the prevention of preterm births. Innovation beyond the current state of the art - Integration of data streams Public health networks involved in screening Vaccination registries Laboratory sentinel networks Hospital databases


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Cancer registry databases - Identification of CIN treatment method of choice: cold knife LEEP LLETZ - Individual or aggregated level linkage methods and processes for data integration Vaccination Screening Treatment Obstetrics - Validity [Are the POC results consistent with the current knowledge?] Study outcomes will be compared with published data on the different topics, including:

- Vaccination coverage - Burden of HPV-related diseases - Uptake cervical cancer screening - Frequency of preterm births - Treatment method of choice

- Timeliness [Is the POC approach in ADVANCE able to deliver the results faster than what is expected by current practices? - time to data availability, time to results] - Calendar lag time from protocol development start to protocol sign off - Calendar lag time from protocol submission to data source approval and or IRB to approval - Calendar lag time from protocol data approval to data available for analyses - Calendar lag time from data available for analyses to results available - Calendar lag time from results available to final study report sign off - Person time (Person-Days) effort in any of the periods listed above Process parameter evaluation:

gg) Time: Process time of all steps in workflow locally and centrally (list to be created) hh) Cost: resources (person time, machine time) needed to run the POC study through the

different workflow steps (list to be created) ii) Compliance: with legislation, standards, approvals to run the study jj) Quality of process, data management, data integrity, privacy and security, validation of the

writing, validation of the programming, number of amendments to the protocols, number of errors that need correction.

kk) Transparency: what information can be made public (protocol, authors), how much time after it was done, is the information understandable, the decision-making processes (minutes, agendas), whose interests are involved / who benefits.

ll) Accesibility of data to different stakeholders [Check list of the parameter matrix checklist] POC Successes or areas for further development: Europe-wide HPV vaccination coverage Europe-wide cervical cancer screening uptake Combination of CIN treatment data with obstetrical follow-up Approval of access to required data streams


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Scientific Research protocol [Aligned with ENCEPP checklist for study protocols Appendix 1] Scientific question: In the absence of long-term follow-up, can an accurate estimate of the benefit of HPV vaccination on HPV-related diseases be provided? Scientific research objectives: The specific objectives are the following:

g) To estimate the benefit of HPV vaccination on HPV-related diseases, based on vaccine coverage in combination with burden of disease

h) To estimate the excess number of preterm births in women with previous treatment of cervical lesions, preferably specified per treatment modality

i) To define the time trend of preterm births, both in general and treatment-related Design: Multi country - distributed database study. Comparator: no comparison required Start of data collection: End of data collection: Population: Different populations in different databases: girls/young women in the appropriate age range for HPV vaccination, women in the appropriate age range for cervical cancer screening, HPV-related cancers in cancer registries Exposure: HPV vaccination Outcome: HPV related disease Data sources: Ideally, the database(s) would contain the following variables: HPV vaccination status, HPV-related disease, participation in screening, screening outcome, treatment of CIN, date of treatment, treatment method, institution where treatment was performed, number of treatments performed in this institution per year, number of births, number of preterm births, socio-economic status (indication of income?), … Methods: WP4 input required Vaccine choice: Given that the population vaccinated with HPV vaccines is currently too young (vaccine available since 2006, age at vaccination +/- 12) to be included in cervical cancer screening (starting at 25 or 30, depending on country), and too young to already have developed serious HPV-related diseases, combination of databases will be necessary to obtain a reliable estimate of the benefit of HPV vaccination for the prevention of HPV related diseases. Furthermore, the vaccinated women are still fairly young to be of child-bearing age, hence the impact of HPV vaccines on the incidence of preterm birth can only be estimated from retrospective analysis.


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As all this asks for the combination of input from different sources, it would seem to be an excellent exercise for ADVANCE.


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Appendix 9: Varicella POC proposal (proposal 7) Author: Anna Cantarutti, PEDIANET Risk of febrile seizures and varicella vaccination in the second year of life: a retrospective cohort and case-control studies in a large population of Italian children 1.0 Rationale, objectives and Methods WHO advocates routine childhood immunisation against varicella in countries where the disease is a relatively important public health and socioeconomic problem, where the vaccine is affordable and where high (85‒90%) and sustained vaccine coverage can be achieved. The latter is important as childhood immunisation with low coverage could theoretically shift the epidemiology of the disease and increase the number of severe cases in older children and adults for whom the disease is more severe. In Europe by October 2012, there were various types of recommendation regarding varicella vaccination in 22 out of 29 EU/EEA countries. In five countries (Cyprus, Germany, Greece, Latvia and Luxembourg) varicella vaccination is universally recommended for children at national level and in two countries (Spain and Italy) at regional level. In Italy it is recommended (and fully reimbursed) in Veneto, Sicily, Puglia, Toscana. Major barriers for implementation of varicella vaccination include lack of awareness on varicella severity, concerns on increased varicella and Herpes Zoster incidence in adults and elderly people after varicella vaccination successful implementation. Data on the effectiveness and impact of varicella vaccination are limited even in countries where the vaccine has been successfully implemented. In 2006 the Veneto region of North East of Italy introduced varicella vaccination, offering free-of-charge immunisation to 14 months and a catch up dose at 12 years in susceptible children. In 2008 the Veneto Region introduced a second varicella dose at 6 years of age. This program has been extremely successful and the vaccination coverage rose from 8.1% in 2004 to around 90% in 2013. Recent unpublished data collected from Pedianet24 a large network of family paediatricians has shown that the indroduction of varicella vaccination has decreased the incidence of varicella by more than 50%. In Veneto, all available licensed vaccines have been used and with the increase of the coverge there has been a shifting from the use of monovalent vaccine to tetravalent vaccines. In 2010 more than 90% of children received tertravalent vaccine (Table 1). Table 1: Varicella vaccination coverage by year and type of vaccine

year Mean Coverage (%)

Monovalent vaccine (% of vaccinated)

Tetravalent vaccine (% of vaccinated)

2004-2005 7 100

2005-2006 17.4 100

2006-2007 53.6 100

24 Set up in 1999 PEDIANET collects the clinical, demographic, prescription and outcome data for children who are under the care of a group of family paediatricians (FPs) e in Italy. Data are generated during routine patient care with the software JuniorBit ® and are stored in different files, which can be linked through a unique (anonymous) numerical identifier. The identification file contains information on the demographic data of the child and the eligibility status (registration status, date of registration, date of death). The prescription file contains information on all drugs (date of prescription, ATC code, product, quantity, dosing regimen, legend duration, indication, reimbursement status) and vaccinations that are prescribed by the paediatricians. Reasons for contact and diagnoses (free text or coded by the ICD-9 system) are collected in the medical file which also includes all anthropometic measurements (weight and height). In addition the database contains information on referrals to specialists, procedures, hospitalisations, medical exams, health status (according to the Guidelines of Health Supervision of the AAP) and centile diagrams. All patients provide written informed consent for their data to be collected and used for research purposes. Pedianet is not only a database, but also a network of about 300 FPs who can be contacted and involved in prospective studies on clinical epidemiology and drug safety. Pedianet database and network has been used for several retrospective and prospective studies on epidemiology, pharmacovigilance and health economics. Pedianet is also involved in 4 major EU funded projects (TEDDY, GRIP, EU-ADR, SOS and Euclid) aiming to the development of integrated infrastructure for epidemiological and post marketing studies. Pedianet studies have been published in major international Journals and study results presented in several International Conferences.


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2007-2008 70 50 50

2008-2009 77 25 75

2009-2010 80 8 92

2010-2011 88 90 10

2011-2012 89 95 5

2012-2013 89 95 5

In 2011 post licensure data indicated a slightly higher incidence of febrile seizures (FS) in children aged 1 to 2 years who received the first dose of MMRV vaccine (Proquad). Although the increased risk was very small, the AAP Committee on Infectious Diseases recomended to use MMR and Varicella separately as the first dose. Similarly, National vaccine safety Committees in Italy and Germany stated that MMRV is not recommended for the first dose. Recent data from Germany and Canada showed that the risk of FS in children younger than 5 is from 2 to 4 times higher when tetravalent vaccine (either proquad or priorix tetra) is given as first dose when compared with MMR+V. Despite the high coverage rate obtained also with MMR+V immunization schedule, tetravalent vaccine is still advantageous if a good safety profile will be confirmed. Because often countries require data generated by national surveys and studies, more data on the association of MMRV and CS are needed in Italy in order to reintroduce the tetravalent vaccine. Veneto is one of the Italian Regions which successfully implemented Varicella vaccination over time and good coverages with both monovalent and tretravalent vaccines were reached (Table1). In this Region there is a well established electronic health record systems and comprehensive information on immunizations (date, type of vaccine etc) are recorded by Regional Administratve databases. Additionally, clinical information on vaccinated and not vaccinated infants and children are routinely collected and captured from the prevaccination period by the Pedianet primary care reserach database. Data from these different databases can be linked on individual patient basis. Therefore, Veneto is the ideal setting where carrying out a retrospective study to evaluate the association of febrile seizure with different type of varicella vaccination on a large paediatric population seen by primary care paediatricians. Objectives Primary To assess the association between varicella vaccine and the occurence of febrile convulsions. Secondary To evaluate the association between febrile seizures and the administration of varicella vaccine as MMR+V or MMRV. To compare the risk of possible risk of febrile seizures in different age groups Study Population About 50,000 children 0-14 years of age followed up by family pediatricians who are part of the Pedianet network and live in the Veneto Region of Italy Cohort study A cohort study will be implemented to estimate the incidence o f febrile convulsions in each study group (MMR vs MMR+V vs MMRV) as well as the relative risk of febrile convulsion associated with the use of different varicella vaccine (tetravalent or monovalent). Cohort definition: All children age 12 - 24 mo of age registered in the Pedianet database will be enrolled. Outcome definition: The first event (for each child) of febrile convulsion, as confirmed by a medical examination and/or recovering after anti-convulsion therapy, will be considered as a


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case. A case of febrile seizure will be considered as associated to vaccination if occurring within 2 weeks after the administration of the vaccine. All cases will be validated by contacting the FP who will contact the infant's parents to collect more information for the case validation. The exact date of the vaccination of all patients enrolled in the study will be confirmed by a cross linkage by the Pedianet database with the Regional database including the exact dates and type of vaccines received by the individual study patients. The cross linkage will be done by the Regional Epidemiologic Service (partner in this project). The generated data will be anonymized and then analyzed in aggregated form by Pedianet. Only children with a confirmed date of immunization and type of vaccine will be included in the study. This information will also be used to confirm the exact vaccination coverage of the children included in the study. Study period:January 2004 to December 2013. Follow-up: Each child will be followed-up from the registration in the Pedianet database until the first of the following dates: the exact date of the first event of febrile convulsion 31december 2013(end of the study) exit from the Pedianet database. Statistical analysis and power of the study Incidence rates will be calculated dividing the number of events by person time at risk. Relative risks and their 95% Confidence intervals will be estimated by means of Poisson regression. For the computation of the power of the study, only the primary analysis – with the following assumption has been taken into consideration: the ratio between the number of children in the exposed and unexposed groups was defined as a function of the coverage, taking into account that each child is exposed only for the 15 days that follow the vaccination; the coverage was alloed to range between 60%(the mean estimated coverage of the study period and 80%. The relative risk to be detected was allowed to range between 2 (very conservative hypothesis) and 7.18. Given these assumptions a conservative number of 500 cases (which will eventually increase) will provide a power of 90% with a median coverage of 70% to evaluate a RR of 2. nested case-control study A nested case-control study will be conducted to assess the relative risk of febrile convulsion associated with the type of vaccine. All children age 12 – 24 mo with a diagnosis of febrile convulsion as confirmed by a medical examination and/or recovering after anti-convulsion therapy and registered in the Pedianet database will be considered as a case. Only the first event of Febrile convulsion will be considered. The index date for cases is defined as the date of first diagnosis of Febrile convulsion after the 12 month birthday after the enrolment in the Pedianet database. Recurrent events will not be examined. Thus, when a subject experiences an episode of febrile convulsion is excluded from the cohort from that date on. For each case, up to 3 controls will be selected matching on gender, months of birth and pediatrician. Controls have to be in the cohort at the index date. A case of febrile seizure will be considered as associated to vaccination if occurring within 2 weeks after the documented administration of different vaccines. Statistical analysis and power of the study Relative risks and their 95% confidence intervals will be estimated by means of a conditional logistic regression. Since the study involves the comparison of three vaccines (and a non-vaccinated group), definition of the sample size is not straightforward. The following approach has been followed:


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the nominal alpha has been corrected to account for multiple comparisons dividing 0.05 by 3 (the three vaccines against the non-vaccinated) or, to be more conservative, by 6 (the number of distinct comparisons among 4 groups); the probability of exposure among controls was allowed to range between 70% and 80% (the mean coverage of the last eight years) divided by 24 (since each child is exposed only for the 15 days that follow the vaccination); the odds ratio to be detected was set to 7.18 but other values were taken into account. Given these assumptions, sample size was calculated with Stata (module SAMPSI_MCC) and the results are shown in the table 2 below: Table 2: power of the study and number of patients needed

Coverage OR Comparisons Cases Controls Sample size

0.8 7.18 6 61 305 366

0.8 5 6 77 385 462

0.8 2 6 273 1365 1638

0.7 7.18 6 44 220 264

0.7 5 6 57 285 342

0.7 2 6 220 1100 1320

0.8 7.18 3 52 260 312

0.8 5 3 65 325 390

0.8 2 3 235 1175 1410

0.7 7.18 3 34 170 204

0.7 5 3 44 220 264

0.7 2 3 167 835 1002

Considering that we will have information on about 500 cases, having 6 controls for each case will allow to run a case control study powerful enough to evaluate an OR of below 2. Timelines and numbers available A preliminary query carried out in the database showed that, from 2004 to 2011, 50 FP in the Veneto Region reported about 500 cases of febrile convulsion in 490 children 12-24 months. Considering that we will include also years 2012 and 2013 in our analysis we can estimated that a total of about 600 cases will be studies Considering in the incidence study to include at least 600 cases with a mean vaccination coverage of 60-70% over the study period it is estimated that we will be able to evaluate an OR lower than 1.5 with a power of 80 % To complement and confirm the incidence rates we will be able to carry out a case-control study. Based on the previous knowledge of high Odds Ratio, the inclusion of the 600 cases in the case control study (along with 1800 controls) occurred to the Pedianet infants from 2004 to 2011 will allow to conduct the analysis to test all the hypotheses. All information on date of vaccinations, case and control definitions will be individually derived by cross linkage with the Regional Reimbursement Immunisation Database (including all vaccinations done by all children living in the Region).


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Appendix 10 POC proposal HPV-UTA (proposal 8) Author: Matti Lehtinen Amended from Vincent Bachaus’ July 15 outline (see below) This proposal uses post-licensure efficacy, effectiveness and pharmacovigilance studies on licensed human papillomavirus vaccines as an example to guarantee deliverable(s) for ADVANCE WP5. This is not in a specific template but can updated to comply with that format later on. Objective: Establish the feasibility of continuously updating the information on the B/R from the first day after prophylactic HPV vaccines were launched. Design: Annual monitoring of deviations from the B/R expectations on population impact and safety based on post-marketing/implementation (vaccination programs) events observed in existing observational databases and disease surveillance networks, starting at licensure of the quadrivalent (6/11/16/18) and bivalent (16/18) HPV vaccines. Scenario: New HPV vaccines on the market/programs and subsequent unexpected new safety concern (signals) in the post-marketing era. Data sources : Published (Dillner et al. BMJ 2010, Lehtinen et al. Lancet Oncol 2012) clinical development (licensure) data for deriving the expectations around the B/R. Available, existing population-based databases for all needed information on real-world (post-marketing) use: e.g. hospital discharge registry, cancer registry, infectious diseases registry Chlamydia trcahomatis (HPV) surveillance network data as a(n) (alternative) source of infection events. Vaccination records from same or linkable database (registries). Method: Annula monitoring (such as the hospital discharge registry, ICD9/10-based) of the B/R difference expectations. Expectation will be based on a B/R model integrating the following information: - Expected vaccine efficacies (VE) extrapolated from clinical measurements of VE against cervical intraepithelial neoplasia (CIN) grade 1/2/3 or prevalence of vaccine type or high-risk HPV infections (Lehtinen and Dillner Nature Rev 2013) - Burden of the preventable disease: CIN+ occurrence, other HPV-related neoplasia occurrence - Risks (safety profile), as known from clinical development: No increased SAEs reported, “signals” - Common metric or weighting scheme for benefits and risks (Baussano I, et al. Int J Cancer 2013, Vänskä et al. PLoS One 2013) The expectation will be expressed as a minimal B/R difference needed for vaccine use; this minimum will be used as the threshold in the monitoring; the model can derive the impact of each new vaccine failure recorded post-launch, as well as any event for new (serious) safety concern.


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If disease event in the vaccinated are counted in observational databases where specificity is <100% then the model should incorporate conversion factors to estimate the expected proportion of true vaccine failures. The B/R model can be based on either the individual/direct effect perspective and/or the population/indirect perspective. Study design: Roll-back of existing (database) information from time of vaccine launch. The study is started with one/two countries Finland/Sweden and will move on to as many countries as possible, taking up lessons from failures and improving (if possible) in an incremental way. Vaccines: Gardasil™ and Cervarix™ vaccines Selected on the following criteria: - Relatively wide usage: 40-85% vaccine coverages in the EU countries - Relatively high probability of exposure to infectious agent in a relatively short time: Genital HPV infections peak between 18 to 22 years of age - On the market for approx. 5 years (ie, recent vaccine but sufficient time since launch to have collected sufficient information for the roll-back) - Two existing B/R models are an asset since they can be used for the post-marketing monitoring - Foe HPV vaccines “major” issues (unexpected deaths, primary ovarian failure syndrome) with the B/R have been suggested relatively late, ie some years after launch (It may not be possible to meet all of these constraints simultaneously) Success measures: - How many EU countries could provide all the post-marketing data streams for complete and real-time monitoring locally: 7+ - Time between actual events (vaccination failure, adverse event) and actual use of the information to update the output of the monitoring model: +/- 3 years - Ability to start on the first day on which a new vaccine is launched: readily doable - How rapidly was the B/R confirmed (or signalled as deviating from expectations): 1-5 years - Fit between the study result and what is otherwise known about this vaccine: New/confirming data - Precision over time (level of remaining uncertainty): Population-based approach - Integration with other B/R assessment activities: HPV screening for cervical cancer - Acceptability (Regulatory Agencies, Public): No problem


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Appendix 11: Combined HPV proposal Authors: Lisen Arnheim-Dahlstrom, Matti Lehtinen, Tom Verstraeten, Kaatje Bollaerts, Marc Baay, Anna Cantarutti, Carlo Giaquinto, Jan Bonhoeffer, Germano Ferreira, Miriam Sturkenboom, Vincent Bauchau This proposal uses post-licensure, effectiveness and safety studies on licensed human papillomavirus vaccines as an example. This is not in a specific template but can updated to comply with that format later on.

Scientific ADVANCE proposal (additional system testing will be done) Objectives 1. Investigate the availability of data to assess HPV B/R 2. Investigate the feasibility of data linkage in different countries to assess HPV B/R 3. Evaluate the reproducibility of the accepted B/R profile of the quadrivalent (6/11/16/18) and bivalent (16/18) HPV vaccines at licensure or at later timepoints, using data collected from secondary databases 4. Establish the feasibility of continuously updating the information on the B/R of HPV vaccines from the first day after prophylactic HPV vaccines were launched. 5. Investigate the effect of HPV vaccination on cervical cancer screening Scenario: New HPV vaccines on the market/programs and subsequently unexpected safety issues may arise in the post-marketing era which could trigger B/R evaluation. Vaccines: Gardasil™ and Cervarix™ - Relatively wide usage: 40-85% vaccine coverages in the EU countries - Relatively high probability of exposure to infectious agent in a relatively short time: Genital HPV infections peak between 18 to 22 years of age - On the market for approx. 5 years (ie, recent vaccine but sufficient time since launch to have collected sufficient information for the roll-back) - For HPV vaccines several “major” issues (unexpected deaths, primary ovarian failure syndrome) with the B/R have been suggested Description of the state of art Several beneficial effects are expected from HPV vaccination. • Cervical cancer: The HPV vaccines that are currently commercially available, Gardasil (SPMSD) and Cervarix (GSK), were designed to prevent cervical cancer. For cervical cancer it has been shown that there is a nearly 100% association with the (persistent) presence of high-risk HPV types 1. • Other cancers: However, a causal role of HPV in the development of a number of other cancers has also been decribed, including vulvar, vaginal, anal, penile and oropharyngeal cancer, although the association was less than for cervical cancer (estimated contribution of HPV to various cancer sites is as follows: anal cancer = 88%, vulvar cancer = 25%, vaginal cancer = 70%, penile cancer = 30%, and oropharyngeal cancer = 26%). • Precancerous lesions. The HPV vaccines also prevent preneoplastic lesions. This effect has clearly been demonstrated for precancerous cervicalm lesions, but can alos be expected for the other cancers. • Prevention of adverse effects of treatment precancerous lesions. In the past, a clear link between treatment of precancerous cervical lesions (cervical intraepithelial neoplasia (CIN) grade 2 and worse) and obstetrical complications later in life (preterm birth) was shown 2,3. Prevention of


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CIN2+, and hence, reduction in number of preterm births, would be an additonal argument in favour of vaccination. • Non-cancerous HPV related diseases. Finally, although not cancerous in nature, both the frequently occurring genital warts and the rarely occurring recurrent respiratory papillomatosis (RRP) are HPV related and have a high morbidity. Because of the long lag time between HPV infection and the development of HPV-related cancer, some benefit could only be estimated at the time of licensure. Insight in the HPV vaccine coverage, combined with the burden of disease for HPV related diseases, as well as data from the original RCTs, will enhance the accuracy of the estimate. On the other hand, cervical cancer screening uptake in combination with treatment and follow-up, will allow estimation of the additional benefit of vaccination for the prevention of preterm births. In addition, as for most vaccines there is an expectation that HPV vaccination will confer indirect ‘herd protection’ effects on the unvaccinated. Extensive safety information has been collected in the clinical trials. At the time of licensure, a number of potential or identified safety concerns were raised, including syncope, autoimmune disorders and adverse pregnancy outcomes. Since licensure a number of additional safety concerns were raised post-licensure these included death, primary ovarian failure, migraine, postural tachycardia, complex regional pain syndrome, multiple sclerosis, and ADEM. Data sources : Published (Dillner et al. BMJ 2010, Lehtinen et al. Lancet Oncol 2012) clinical development (licensure) data for deriving the expectations around the B/R. For the postlicensure data we will use available, existing population-based databases: e.g. hospital discharge registry, cancer registry, laboratory data, infectious diseases registry, primary information data, prescription data. Chlamydia trachomatis (HPV) surveillance network data as a(n) (alternative) source of infection events. Vaccination records from same or linkable database (registries). Methods Important components of the B/R analysis are burden of disease, coverage in the target population, efficacy, effectiveness and safety Burden of disease: The incidence and prevalence of the following HPV related diseases will be estimated in non-vaccinated i. Cervical cancer incidence ii. cervical intraepithelial neoplasia (CIN) grade 1/2/3 iii. CIN treatment (as proxy) iv. Other HPV related neoplasia (Anal/vaginal/penile/head and neck cancer) and if possible, precancerous lesions v. Condylomata vi. Frequency and type of cervical cancer screening. Any other HPV-related cancer screening The following data sources will be used to identify cases: - Cervical cancer incidence and other HPV related cancers: cancer registries/hospital data, primary care databases - CIN grade 1/2/3: screening databases / laboratory databases / pathology registries - CIN treatment (as proxy) cold knife, LEEP, LLETZ: databases with outpatient procedure - Condyloma: drug prescriptions/primary health care/outpatient diagnoses - Screening: screening registries These will be linked to population files to estimate the incidence and prevalence.


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Coverage: Coverage of HPV vaccines will be estimated on a population level as well as exposure on an individual level. On a population level the prevalence to type and 1st, 2nd,3rd dose of HPV vaccine will be estimated by gender and birth year. These data will be obtained from vaccination registries and/drug prescription databases or primary care databases. Effectiveness Effectiveness will be assessed using a cohort approach (for absolute rates) using age/gender/country matched vaccinated and non-vaccinated persons and a test-negative (HPV negative) case control design. The test negative design will avoid most of the confounding factors. Outcomes will be i. CIN level 2 and higher ii. Cervical cancer iii. Precancerous cervical lesions iv. ASCUS: Atypical squamous cells of undetermined significance v. Other HPV related neoplasia (Anal/vaginal/penile/head and neck cancer) vi. Condolymata ii. HPV Type replacement Data sources will be the same as mentioned under burden of disease, but should be able to be linked to vaccination data. Test negative controls may be obtained from chlamydia screening. Vaccine effectiveness will be assessed by vaccine type and dose of HPV. Safety From the clinical trials and postlicensure several safety signals were reported and their impact on the B/R assessment will be investigated. In order to do so we will estimate the relative and excess risk of the following events, using preferably a cohort design of vaccinated and non-vaccinated persons. i. All auto-immune disorders (AID) ii. Pregnancy outcomes: congenital malformation, pre-term birth, still birth, miscarriage iii. Primary ovarian failure (POF) or insufficiency (POI) iv. Migraine v. Postural orthostatic tachycardia syndrome (POTS) vi. Death vii. Others Events will be identified in medical record databases that comprise outpatient data, birth registries and death registries, these need to be linked to vaccination records B/R modeling The BR balance will be assessed using a MCDA approach with MC modelling of the parameter uncertainties. The MCDA model will integrate all of the above identified benefits and risks (Verstraeten et al, ICPE 2014). The balance will be expressed as a minimal B/R difference needed for vaccine use; this minimum will be used as the threshold in the monitoring; the model can derive the impact of each change in any of the outcomes included in the model. If disease event in the vaccinated are counted in observational databases where specificity is <100% then the model should incorporate conversion factors to estimate the expected proportion of true vaccine failures. The B/R model will assess both the individual/direct effect perspective and the population/indirect perspective.

ADVANCE POC evaluation success measures: - How many EU countries could provide all the post-marketing data streams for complete and real-time monitoring locally:


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- Time between actual events (vaccination failure, adverse event) and actual use of the information to update the output of the monitoring model - Ability to start on the first day on which a new vaccine is launched - How rapidly was the B/R confirmed (or signalled as deviating from expectations) - Fit between the study result and what is otherwise known about this vaccine - Precision over time (level of remaining uncertainty): Population-based approach - Integration with other B/R assessment activities: HPV screening for cervical cancer Support Background Literature:

1. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. The Journal of pathology 1999; 189: 12-9.

2. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet 2006; 367: 489-98.

3. Castanon A, Brocklehurst P, Evans H, et al. Risk of preterm birth after treatment for cervical intraepithelial neoplasia among women attending colposcopy in England: retrospective-prospective cohort study. BMJ (Clinical research ed) 2012; 345: e5174.

4. Albrechtsen S, Rasmussen S, Thoresen S, Irgens LM, Iversen OE. Pregnancy outcome in women before and after cervical conisation: population based cohort study. BMJ (Clinical research ed) 2008; 337: a1343.


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Appendix 12: POC Ranking Proposal HPV Pertussis Influenza Zoster Rotavirus

Criteria Weight

Population diversity 1 0 1 1 0 0

Wide use / vaccination program 2 1 1 1 0 0

ADVANCE Vision alignment / innovation 2 1 1 1 1 1

Existing benchmarking data

1 1 1 1 0 1

Feasibility / workload 1 0 1 0 1 1

Multiple Countries 2 1 1 1 0 1

Multiple Vaccine Brands 2 1 1 1 0 1

Social Media 0 0 0 0 0 0

11 13 12 3 8


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Appendix 13: Framing the Benefit-Risk Decision Problem: Pertussis vaccination, v1.3

Authors: Kaatje Bollaerts (P95), Nicoline van der Maas (RIVM), Susan Hahné (RIVM)

DOCUMENT HISTORY NAME DATE VERSION DESCRIPTION

Kaatje Bollaerts 03-02-2015 1.0 Outline

Nicoline van der Maas Susan Hahné

04-02-2015 1.1 Examples

Kaatje Bollaerts, Nicoline van der Maas, Susan Hahné

09-02-2015 1.2 Revision

I. Vincent Bauchau, Jan Bonhoeffer, Miriam Sturkenboom

17-02-2015 review

Kaatje Bollaerts, Nicoline van der Maas

18-02-2015 1.3 revision

Jan Bonhoeffer 19-02-2015 inclusion proposal 4


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The SC has decided that the first POC shall be based on pertussis. Research starts with precisely defining the research question to be answered. Analogously, in decision analysis, we start with clearly describing the decision to be taken and the evidence that is needed to support this decision-making. In this document, we first propose an outline for framing vaccine-related benefit-risk decision problems. This framing builds upon previous work from the IMI-PROTECT Benefit-Risk group and follows the recommendations by the WHO guide for standardization of economic evaluations of immunization programmes2. We will then formulate some benefit-risk decision problems which are specific for pertussis. These problems are formulated independently of data availability and choice of methodology. In a second step, the ADVANCE Steering Committee will select one of these B/R problems for the first Proof-of-Concept study. For this selection, the criteria previously defined for any POC should be applied, such as: known associations, available benchmark data, simple and quick win, … In a third step, the benefit-risk model will be further developed for implementation in the pillar-studies of the POC: i.e. trimming down the outcome tree, collecting value judgements, developing the protocol and statistical analysis plan written to collect and analyse the evidence needed to populate the benefit-risk model. This document concerns framing the benefit-risk problem, which is only the first step of the benefit-risk analysis. The subsequent steps are:

1. Collecting evidence (and optionally, grading evidence): identifying adequate data sources and extracting evidence related to the formulated benefit-risk decision problem

2. Benefit-risk synthesis: integrating (and weighting) the various benefits and risks, potentially including preference elicitation from relevant stakeholders

3. Sensitivity- and scenario analysis (optional): sensitivity analysis propagates and investigates data uncertainty (uncertainty objective in nature) whereas scenario analysis investigates the effect of subjective choices (choice of data source, value function,…)

4. Communication:

Benefit-risk frame for vaccines The decision problem: First, the decision problem requiring the benefit-risk analysis needs to be clearly defined. Vaccine-related decision problems might relate to different points in the life cycle of a vaccine or the roll out of a vaccination programme and might be triggered by certain events. Examples of vaccine-related benefit-risk decision problems, excluding pre-marketing decisions and economic evaluations (which are both out of scope for ADVANCE), are:

1. Whether a request for marketing authorization should be submitted to the regulatory authorities

2. Whether a new safety risk emerging in the post-marketing period shifted the benefit-risk balance and whether the vaccine should be relabelled, restricted or withdrawn from the market

3. Whether there are new indications for vaccination 4. Whether the recommended age of vaccination is optimal 5. Whether the current vaccination schedule can be optimized with respect to the benefit-risk

balance 6. Which vaccination coverage should be targeted 7. Whether vaccination should be (strongly) recommended for specific populations


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Clearly formulating the decision problem will help selecting the appropriate target population, comparators, benefits and risks. This will consequently narrow down and precisely define the evidence required for the benefit-risk analysis. Who is the decision-maker: The decision maker might be the vaccine manufacturer (e.g. requesting marketing authorization), a regulatory body (e.g. approving, restricting, withdrawing a product from the market), a public health authority (e.g. recommending vaccination), but might also be the health care provider (e.g. advising on vaccination) or the potential vaccine recipient (deciding whether they – or their children – will be vaccinated or not). Relevant stakeholders: The relevant stakeholders are the (groups of) people that are potentially and substantially affected by the decision to be made. Immunization and schedule: This entails clearly defining the vaccine (specific brand or not) and its usage (recommended number of doses, recommended age at vaccination, co-administration, combination vaccine) Target population: The target population is the group intended to receive the vaccination. The target population can vary in age, sex, indication, region, specific subpopulations etc. Examples of target populations are neonates, infants, children, adolescents, elderly, males, females, pregnant women, high-risk groups. A special target population are the close contacts of highly susceptible and vulnerable individuals (e.g. cocoon strategy). Comparators A benefit-risk decision always implies a (explicit or implicit) comparison. Meaningful comparators in the context of vaccine-related benefit-risk are: no preventive measure, alternative preventive measure (e.g. HPV screening), alternative vaccine brand/vaccination schedule. An often chosen comparator is the standard of care. Perspective This might be an individual perspective (only taking into account the health outcomes that directly apply to the individual eligible for vaccination) or a societal perspective (broader perspective, taking into account all criteria relevant (partially) immunized population including transmission rates and herd immunity). Time frame and analytic horizon The time frame (the period over which vaccination is applied) and the analytic horizon (the period over which health outcomes occur as a result of vaccination are considered) should be sufficiently long to capture all benefits and risks vaccine-related health outcomes. Health outcomes (criteria) This includes the identification of all favourable and unfavourable effects that occur as a result of vaccination. These health outcomes might encompass direct and indirect effects. In addition to identifying all relevant health outcomes, the adequate time windows for observation for the different health outcomes need to be defined as well (e.g. adverse events within 30 days after vaccination, protective effect 10 years after vaccination). The criteria to the decision can be visually and hierarchically summarized in an outcome tree or value tree. A generic example of an outcome tree for vaccines is given in Figure 1. It is generally advised to start building the value tree including


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all criteria and then subsequently trimming down the tree by excluding criteria that not meet certain predefined conditions (e.g. no difference between comparators, no established effect)3.

Figure 1. Generic example of an attribute tree for vaccines (Risks are organised following the

structure used in Risk-management plans (RMPs) with the addition of indirect risks.).

References

1. Hughes D, Waddinghma, E, Shahrul, M, Goginsky A, Chan E, Downey G, Hallgreen, C, Hockley K, Juhaeri J, Lieftucht A, Metcalfe M, Noel, R, Phillips L, Ahsby D. IMI-PROTECT: Recommendations for the methodology and visualisation techniques to be used in the assessment of benefit and risk of medicines; 2014.

2. WHO guide for standardization of economic evaluations of immunization programmes. Immunization, Vaccines and Biologicals 2008 [cited; Available from:

3. Mussen F, Salek,S., Walker, S. Benefit-risk appraisal of medicines: John Wiley & Sons; 2009.

Benefit-Risk balance

Benefits

Direct effects

…

…

Indirect effects …

Risks

Adverse effects

…

Important identified risks

…

Important potential risks

….

Indirect risks ...


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Pertussis 1: Decision problem:

Is the benefit-risk balance of current paediatric acellular pertussis (aP) combination better than the benefit-risk balance of infant combination vaccines containing whole pertussis (wP) to justify switching from wP to aP?

Decision maker: Public health organisations

Stakeholders: Paediatric population targeted for vaccination and their parents

Immunization: Any vaccine containing aP (any brand) in combination with other antigens

Schedule All infant pertussis vaccination schedules, independent of number of doses and with or without childhood boosters

Target population: Children

Comparator: Whole-cell pertussis- containing vaccines, any brand

Perspective: Broad, societal perspective

Time frame, analytic horizon:

Time frame: As long as possible Analytic horizon: At least 10 years

Health outcomes: Benefits (direct and indirect): - Cases of pertussis - Complications-sequelae:

- Pertussis related Pneumonia, atelectasis - Pertussis related Encephalopathy, seizures -Hoarseness, sinusitis, otitis media, conjunctivitis - Intracranial bleeding (during coughing) - Retinal bleeding - Rib fractures - Carotid artery dissection - Angina - Urinary incontinence - Weight loss - Passing out - Difficulty in sleeping - Death following pneumonia - Death following acute pertussis - Death following encephalopath

Cases of pertussis at primary care, intensive care, hospitalisations and this age-stratified (before first dose, before completion, after completion). The observation period for the pertussis complications is restricted to 6 months after diagnosis. During this period the complications are potentially related to pertussis. Risks (direct): -Fever -Convulsions -Hypotonic hyporesponsive episodes (HHE) -Local reactions (redness, swelling, pain, extensive limb swelling) -Persistent crying -Apnoea (among premature infants) -Bradycardia (among premature infants) These risks are all known risks. Potential risks are not considered. The observation period for the risks is restricted to 48hours (preferably 24hours) after vaccination. This observation period is chosen because adverse events with a probable causal relation mainly occur within this time window. This is an extensive list of health effects related to pertussis vaccination. This list can be subsequently trimmed down.


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Pertussis 2 Decision problem:

Should maternal pertussis vaccination be recommended by public health authorities?


Stakeholders: Pregnant women, their unborn babies and family Midwifes – obstetricians – paediatricians

Immunization Acellular pertussis vaccine,

Schedule Vaccination typically administered once during first, second or third trimester of pregnancy

Target population: Pregnant women

Comparator: No vaccination

Perspective: Societal (family protection


Time frame: as long as possible Analytic horizon: until newborn has finished the primary series.

Criteria: Benefits (direct and indirect): - Cases of pertussis - Complications-sequelae:

- Pertussis related Pneumonia, atelectasis - Pertussis related Encephalopathy, seizures -Hoarseness, sinusitis, otitis media, conjunctivitis - Intracranial bleeding (during coughing) - Retinal bleeding - Rib fractures - Carotid artery dissection - Angina - Urinary incontinence - Weight loss - Passing out - Difficulty in sleeping - Death following pneumonia - Death following acute pertussis - Death following encephalopathy

Benefits within household (vaccinated mother, newborn, other household members). The observation period for the pertussis complications is restricted to 6 months after diagnosis. During this period the complications are potentially related to pertussis. Risks: -Fever -Malaise??(very aspecific) -Local reactions (redness, swelling, pain, extensive limb swelling) These are all known risks. Potential risks are not considered. The observation period for the risks is restricted to 48hours (preferably 24hours) after vaccination. This observation period is chosen because adverse events with a probable causal relation mainly occur within this time window. This is an extensive list of health effects related to pertussis vaccination. This list can be subsequently trimmed down.


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Pertussis 3 Decision problem:

Should pertussis booster vaccines be given to adolescents (10 years and above) and adults?


Stakeholders: Population 10 years and above

Immunization: Acellular pertussis vaccines, usually one dose per booster

Schedule Usually one dose per booster

Target population: 10 years and above

Comparator: No booster



Time frame: As long as possible Analytic horizon: at least 10 years

Criteria: Benefits (direct and indirect): - Cases of pertussis - Complications-sequelae:

- Pertussis related Pneumonia, atelectasis - Pertussis related Encephalopathy, seizures -Hoarseness, sinusitis, otitis media, conjunctivitis - Intracranial bleeding (during coughing) - Retinal bleeding - Rib fractures - Carotid artery dissection - Angina - Urinary incontinence - Weight loss - Passing out - Difficulty in sleeping - Death following pneumonia - Death following acute pertussis - Death following encephalopathy

The observation period for the pertussis complications is restricted to 6 months after diagnosis. During this period the complications are potentially related to pertussis. Cases will be stratified by age-groups (10-18yrs, 19-59yrs, +60yrs) Risks: -Fever -Malaise??(very aspecific) -Local reactions (redness, swelling, pain, extensive limb swelling) These are all known risks. Potential risks are not considered. The observation period for the risks is restricted to 48hours (preferably 24hours) after vaccination. This observation period is chosen because adverse events with a probable causal relation mainly occur within this time window. Cases will be stratified by age-groups (10-18yrs, 19-59yrs, +60yrs) This is an extensive list of health effects related to pertussis vaccination. This list can be subsequently trimmed down.


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Pertussis 4 Decision problem

Comparing the B/R balance of different paediatric vaccine schedules of acellular pertussis combination vaccines including co-administration with other routine paediatric vaccines.

Decision maker National Vaccine Advisory Bodies, PHI, REG, MAN, HCP

Stakeholders Infants, children, adolescents, their care takers and household contacts

Immunization - acellular pertussis combination vaccines - MCV, PCV, MMR, Hep B

Schedule National routine paediatric immunization schedules

Target population Children and adolescents

Comparator Different schedules

Perspective Broad, societal perspective

Time frame, Analytic horizon

As long as possible Life long

Health outcomes Benefits (direct and indirect): Pertussis wild type disease (ICD coded, +/- lab confirmed) within 10 years following the last dose - direct: in the vaccinee

- Complications-sequelae: - Pertussis related Pneumonia, atelectasis - Pertussis related Encephalopathy, seizures - Death following acute pertussis

- indirect: in the household contact - indirect: in the non-vaccinated Risks within 72 hours: - Fever - Seizures - Hypotonic hyporesponsive episodes (HHE) - Persistent crying - Apnoea (among premature infants) - Bradycardia (among premature infants) - Injection site reactions (redness, swelling, pain, extensive limb swelling) Risks within 10 years - Vaccine failure of Pa containing and co-administered vaccine

POC Questions - Are the differences between national pertussis immunization schedules captured/reflected in the dbs?

- Is co-administration captured consistently according to schedule? - Can pertussis effectiveness be demonstrated in the db at the

expected rates? - Can pertussis safety outcomes be demonstrated at the expected

rates? - Can vaccine failure be demonstrated in co-administered vaccines? - Can the B/R of different schedules/co-administrations be

determined?


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Appendix 14: POC outline v1.5

Outline of the proof-of-concept: monitoring the benefit-risk of

pertussis vaccines in children comparing whole cell and acellular formulations

v1.5


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DOCUMENT HISTORY NAME DATE VERSION DESCRIPTION

Denis Macina Nicoline van der Maas

18-03-2015 1.0 First draft sections 3, 4 and 6

Kaat Bollaerts 18-03-2015 1.0 First draft section 2, 5, 6, 7, 9 (WP4), review

Ulrich Heininger 19-03-2015 1.1 Review

Hanne Dorthe Emborg 22-03-2015 1.1 Review

Miriam Sturkenboom 22-03-2015 1.1 First draft section 1 & 8 and review of other sections

Vincent Bauchau 22-03-2015 1.1 Review

Denis Macina Nicoline van der Maas

24-03-2015 1.2 Revised version section 3 and 4

Kaat Bollaerts 24-03-2015 1.2 Revised version section 2 and 5

Harshana Liyanage 25-03-2015 1.2 Revised section 8

Harshana Liyanage, Vincent Bauchau, Denis Macina, Nicoline van der Maas, Hanne Dorthe Emborg, John Weil, Xavier Kurz, Miriam Sturkenboom

25-03-2015 1.2 Teleconference

Miriam Sturkenboom 26-03-2015 1.3

Review, shortening, taking out overlap, recommendations for study groups, figure 1&2, inclusion of comments/discussion TC

Denis Macina, Kaat Bollaerts, Vincent Bauchau, Nicoline van der Maas

27-03-2015 1.3 Review, comments, addition to the introduction

Miriam Sturkenboom 28-03-2015 1.4 Integration of comments, additions and changes to section 7 and 8

Vincent Bauchau, Mendel Haag, Alena Khromava, Denis Macina, Eddy Ziani, Laurence Pagnon, Marianne van der Sande, Patrick Mahy, Simon de Lusignan, Tin Tin, Michael Greenberg, Piotr Kramarz

1/4/2015 Comments

Miriam Sturkenboom, Kaatje Bollaerts

3/4/2015 1.5 Inclusion of comments and decisions SC, addition of sections


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Contents

DOCUMENT HISTORY ................................................................................................................... 120

PURPOSE & INNOVATIONS ......................................................................................................... 122

1. POC SCENARIO ........................................................................................................................... 124

2. KEY BENEFIT-RISK DECISION FRAME ............................................................................... 125

3. STATE OF THE ART KNOWLEDGE ....................................................................................... 127

3.1 PERTUSSIS DISEASE .................................................................................................................. 127 3.1.1 Disease course ........................................................................................................... 127 3.1.2 Diagnosis ................................................................................................................... 127 3.1.3 Complications ............................................................................................................ 127 3.1.4 Treatment .................................................................................................................. 128

3.2 TYPE OF PERTUSSIS VACCINES AND VACCINATION SCHEDULES IN EUROPE .......................................... 128 3.2.1 Pertussis vaccines .............................................................................................................. 128 3.2.2 Vaccination schedules in Europe........................................................................................ 128 3.2.3 Pertussis schedule ..................................................................................................... 128 3.3.3. Recommendation for coverage pillar ............................................................................... 129

3.3 VACCINE BENEFITS ................................................................................................................... 130 3.3.1 Efficacy ...................................................................................................................... 130 3.3.2 Population impact of vaccination program ............................................................... 130 3.3.3 Effectiveness .............................................................................................................. 131 3.3.4 Recommendation for the Benefits pillar ................................................................... 132

3.4 VACCINE RISKS ........................................................................................................................ 132 3.4.1 Safety studies ............................................................................................................ 132 3.4.2 Recommendation for the risk study group ................................................................ 133

4. OUTCOME TREE ......................................................................................................................... 133

5. BENEFIT-RISK DECISION MODEL AND REQUIRED INPUT ...................................... 135

6. TABLE SHELLS OF MINIMAL INFORMATION ON BENEFITS AND RISKS ................ 135

7. PREFERENCE ELICITATION ................................................................................................... 137

8. DATA SOURCES ........................................................................................................................... 137

9. REQUESTS FROM OTHER WORK PACKAGES ................................................................... 140

REFERENCES ................................................................................................................................... 141


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Purpose & Innovations This POC outline document is written as a common background and rationale to guide:

1) The development of specific study protocols for the data collection pillars: coverage, preference, benefit, risk and evidence synthesis pillars (B/R analysis) for the first POC study

2) Formation of study teams 3) Review and approval for participation to the POC (studies) by participating organisations, as

needed

This document should be used alongside the D5.3 POC Research plan, which describes the processes for any POC at a generic level, while this outline document specifies a specific POC and the scientific question, here on pertussis. The evidence required for the B/R analysis will be primarily generated from data sources that are available within the ADVANCE consortium. The feasibility and acceptability of doing so will be part of the POC. However, information from various other sources (literature, trials) will be used as needed and/or as a sensitivity approach. The evidence (typically incidence rates) will be obtained by the different WP5 studies and synthesised in the BR-analysis. There will be 5 study groups: 1) evidence generating: coverage (also looking at schedules, …) 2) evidence generating: safety 3) evidence generating: vaccine effectiveness (primarily direct effects) 4) evidence generating: preference elicitation 5) evidence synthesis: developing and running the benefit-risk model There is a general advice to keep this first POC simple, it is focused on testing the ADVANCE platform alongside a real vaccine B/R question, and to mimick as much as possible a real life situation that may arise in the vaccine life time. It is envisaged that the background sections as well as the outcome definitions, population definition, time windows and required outputs in the different protocols that will be developed will follow the specifications in this outline document. The IMI ADVANCE specific objectives guiding this POC for pertussis are:

1. Establish the feasibility of continuously updating the information on the B/R of a vaccine from the first day after a vaccine is marketed

2. Assess IMI ADVANCE platform for data availability on a routinely used vaccine in established vaccination programs covering different populations, and different schedules across countries.

3. To test and assess the level of collaboration between different stakeholders in collecting evidence and integrating evidence on the benefits and risks of vaccines

4. To assess the methods for evidence generation on safety, effectiveness, preferences and vaccination coverage using a near real-time scenario.

5. To evaluate the acceptability of the results by stakeholders for decision making on B/R. Key innovations to be made through this POC for pertussis are:

1. Integration of different data streams from different institutions and origins


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2. Individual or aggregated level linkage methods and processes for data integration 3. Assigning specific roles and responsibilities for PI, study teams, as much as possible on merit

(qualification, expertise, experience…) which ultimately aims to support the speed and quality of monitoring benefits and risks of vaccines

Specific success measures

1. How many EU countries can provide evidence on coverage, benefits and risks of pertussis vaccine allowing for monitoring locally?

2. What is the added value to work across EU countries? 3. Demonstration that B/R can be monitored more rapidly 4. Demonstration of effective and transparent collaboration across stakeholders 5. Functionality of the platform to generate data and pool data 6. Building capacity on a national level to generate data for benefits and risks of vaccine 7. Level of agreement between the study result and what is otherwise known about this

vaccine 8. Ability to integrate the data that is arriving from heterogenous sources 9. Acceptability of the processes and results (Regulatory Agencies, Public, data providers …)


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1. POC scenario The ADVANCE vision is to deliver “Best evidence at the right time to support decision-making on vaccination in Europe”, and the mission is to establish a prototype of a sustainable and compelling system that rapidly provides best available scientific evidence on vaccination benefits and risks post-marketing for well informed decisions. This will be achieved by developing and testing a code of conduct, rules of governance, technical infrastructures, data sources, methods, and workflows in a European network of stakeholders. From this vision emerges that the ADVANCE platform should be able to provide evidence under different scenarios when data on benefits and risks of vaccines would be requested by different stakeholders. This could happen for example upon inclusion of the vaccine in the vaccination program, or triggers: e.g. when new safety issues occur, when the benefit of the vaccine is questioned or when new populations are targeted. In these scenarios we would want to investigate in ADVANCE how the benefits and risks could also be monitored sequentially (cumulatively when data becomes available) to investigate whether the benefit-risk is changing over time. Pertussis was chosen as the vaccination program for the first POC based on a set of criteria that were established a-priori by the ADVANCE Steering Committee (see D5.3).

The first step is to frame the benefit-risk decision, starting with precisely describing the benefit-risk question to support decision making and the decision maker. This helps selecting the appropriate study design, statistical framework, target population, comparators, perspective, time frame and the outcomes (i.e. benefits and risks) and narrow down and precisely define the evidence required for the benefit-risk analysis. Based on 4 different proposals for benefit-risk decisions with regard to pertussis (see D5.3) the decision problem comparing acellular and whole cell pertussis vaccines was selected as the focus for the first POC study (see section 2), and the exact wording was redefined after discussion in the POC outline group. Based on discussions in the Steering Committee and with the objective to keep the first Proof-of-Concept study simple, it was decided that:

the primary B/R analysis will consider direct effects only. (An attempt to detect indirect effects will be a secondary objective, and the B/R can be adjusted later if appropriate.)

to accept the disparity in the B/R model: safety will be based on the injection of a multivalent vaccine whereas benefits will be only for the pertussis component. This is based on the fact that pertussis may be the most reactogenic component and that this would be a conservative approach.


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2. Key benefit-risk decision frame Decision question:

Has the initial B/R profile in children prior to school-entry booster been maintained after the switch from whole-cell pertussis vaccines (wP) to acellular pertussis vaccines (aP)?


Target audience Paediatric population targeted for vaccination and their parents

Immunization: Any marketed vaccine containing aP and wP (any brand)

Schedule All child pertussis vaccination schedules prior to the current scheduled age for school-entry booster if any, as defined by individual national/local immunization programs, or no later than 6 years of age

Target population: Children from birth until their school-entry pertussis booster if any (4th or 5th dose). The age may differ by country. In the absence of a school-entry booster in the schedule of a given country, the upper age limit is 6 years-old.

Comparator: In this POC we will compare the direct benefits and risks of aP containing vaccines with the direct benefits and risk of wP containg vaccines. Primary data for wP should come from observational databases. Additional data may be derived from the literature, available clinical data, and post-marketing data.



For investigator: retrospective Study subjects: From start of the study period or birth (whichever latest) until: end of study period, the school-entry pertussis booster, death or reaching age 6, whichever date is earliest. Study period: 1990-2015. Repeated monitoring: T=0 is the time of switch of wP to aP in each country, data will be analysed on a cumulative basis since the day of the switch in each country. The frequency of monitoring may be reconsidered by study teams in order to improve statistical properties (dependent on input from WP4). For wP data on benefits and risks will be retrieved prior to switch from clinical trials and observational data if available. It is expected that after switch little additional data on wP will become available (only the last vaccinated subjects prior to switch will add to evidence) but increasingly more for aP (see figure 1)

Health outcomes: Benefits: Pertussis and its complications (changes in assessment/confirmation of pertussis should be carefully considered) Safety: all outcomes which have been proven causally related with aP or wP containing vaccinations as per current (2015) knowledge.


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Figure 1: Graphic representation of Time axes/horizons. For the study a retrospective approach is taken (all benefits and risks we will measure have already occurred). For the decision analysis we will compare benefits and risks between wP and aP. The evidence for wP is accumulated mostly prior to switch, and little after from the last vaccinated persons. Evidence on aP at time of switch will arrive from clinical data mostly and is complemented by the post-marketing data after switch. The arrows show that we will cumulatively assess the increasing amount of evidence on benefits and risks for wP and aP from the moment of switch. The upper part represents the time frame for the study subjects, these will be follow from birth till school-entry booster, age 6 or death, or end of study period, whichever comes first. Rates and risks of benefits and risks will be assessed by type and dose of aP or wP.


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3. State of the art knowledge In this section, currently available data relevant to designing the POC (studies) are summarised, from various data sources (which are not necessarily the same as the data sources to be used for the pillar studies!). For each topic, the review of the state of the art is followed by specific recommendations for the corresponding pillar study.

3.1 Pertussis disease

3.1.1 Disease course

Pertussis, also referred to as whooping cough, is a highly contagious respiratory disease caused by bacteria of the Bordetella genus, mainly B. pertussis, although other Bordetella-species also occur (1, 2). Pertussis is acquired through transmission of large respiratory droplets generated by coughing or sneezing from infected persons (5). Transmission by the indirect route occurs extremely rarely if ever (3). B. pertussis causes respiratory symptoms, along with systemic effects presumably mediated by secreted toxins (3). Infections range in clinical presentation from asymptomatic to severe. They are most severe, even life-threatening, in young infants before they are immunized (4). It is less frequently severe in older children, adolescents, and adults. Typical clinical disease is characterized by 3 phases. After 7-28 days of incubation, the catarrhal phase (1-2 weeks) is largely nonspecific with coryza, eye redness, frequent coughing and sneezing. It is followed by a 1-6 week-long paroxysmal phase during which intense paroxysms of cough may lead to choking, emesis and the characteristic inspiratory whoop (5). In very young infants, cough is often absent and apnea seems more characteristic of the disease (6). Fever is rare in pertussis. The convalescent phase sees declining symptoms over widely variable duration (5).

3.1.2 Diagnosis

According to the European definitions Clinical criteria for the diagnosis of pertussis are: any person with a cough lasting at least two weeks and at least one of the following three: paroxysms of coughing, inspiratory "whooping", post-tussive vomiting, or any person diagnosed as pertussis by a physician, or apnoeic episodes in infants. Laboratory criteria: At least one of the following three: Isolation of Bordetella pertussis from a clinical specimen Detection of Bordetella pertussis nucleic acid in a clinical specimen Bordetella pertussis specific antibody response Serology results need to be interpreted according to vaccination status

3.1.3 Complications

Common but usually self-limiting complications of pertussis include apnea, seizures, vomiting, gastroesophageal reflux, rib fracture, subconjunctival hemorrhages, epistaxis or syncope secondary to the paroxysms (3, 4). According to the Institute of Medicine25 report, apnea and respiratory arrest are the most common complication of pertussis followed by pneumonia and gastroesophageal reflux. Encephalopathy is a rare complication and occurs most often in younger patients. Other complications include seizures, ataxia, aphasia, blindness, deafness, subconjunctival hemorrhages, syncope, and rib fractures. Pertussis is most serious in infants less than 12 months of age, and the risk of death is highest among infants less than 6 months old.

25 http://www.nap.edu/openbook.php?record_id=13164&page=529


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3.1.4 Treatment

Macrolides are the standard of care for both therapies of cases and post-exposure chemoprophylaxis of household and other close contacts, regardless of vaccination status, and for health care workers with a high risk of, or known exposure to pertussis. Timely chemoprophylaxis reduces, but does not eliminate the risk of pertussis. The administration of macrolides early in the course of illness will reduce the duration and severity of symptoms and lessen the infectivity (3).

3.2 Type of pertussis vaccines and vaccination schedules in Europe

3.2.1 Pertussis vaccines

Vaccines against pertussis are available since the 1940s. First, whole cell vaccines (wPs) were used. These WPs contain suspensions of killed Bordetella pertussis organisms (3). The production process varied between different WPs, resulting in differences in antibody responses. Furthermore, due to the use of the whole bacterium, composition and thus immunogenicity, efficacy and reactogenicity of a specific WP could change over time and from one WP to the next. Reactogenicity of the WVC is probably due to their endotoxin lipopolysaccharide (LPS) content (43). In an attempt to reduce reactogenicity acellular pertussis vaccines (APs) were developed. They were used for the first time in 1981 during mass vaccination campaigns in Japan. APs contain purified secreted and surface components of B. pertussis which, based on animal models, are thought to play an important role in pathogenesis and induction of immunity (3). Later on, several APs were manufactured, containing between 1 and 5 different pertussis components (2). All APs contain at least a detoxified pertussis toxin (PT); the second antigen added in all formulations with 2 or more components is filamentous haemagglutinin (FHA); three-component vaccines contain also pertactin (PRN); finally, four- and five-component vaccines contain one or more fimbrial agglutinogens or fimbriae (FIM). Almost all APs are adjuvanted with aluminium salts and combined with diphtheria and tetanus toxoids, possibly additional vaccine valences such as poliovirus, H. influenza type b and/or hepatitis B. (3) Different products are available in the different countries, as part of the coverage pillar protocol it should be investigated what products were used

3.2.2 Vaccination schedules in Europe

Between 2004 and 2015 several countries switched from wP to aP in infancy and children. All other countries in Europe switched to aPs prior to 2006 (starting in the 1990’s for some countries). As of March 2015, all countries except Poland use exclusively APs. In most cases, the switch to aPs was conducted over a narrow age-cohort, while only in very few cases, such as Poland, the switch occurred, or is occurring progressively over years. Different types of vaccines are being used. As part of the coverage pillar the way participating countries switched should be described.

3.2.3 Pertussis schedule

Since the start of the introduction of pertussis vaccine in the 1940’s, many countries have tended to adapt and customize the schedules of their vaccination programs, adding and removing doses, changing ages of primary and booster schedules, with or without catch-up campaigns, and transitioning from wPs to aPs. As a result, pertussis vaccine schedules vary largely across Europe. For detailed information on the schedules currently used in Europe, see figure 2 and for more details see ECDC-website (http://vaccine-schedule.ecdc.europa.eu/Pages/Scheduler.aspx).

http://vaccine-schedule.ecdc.europa.eu/Pages/Scheduler.aspx


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Figure 2: recommended pertussis schedules from ECDC vaccine scheduler website (March 2015)

The WHO standards of childhood pertussis vaccination recommend a 3-dose primary series administered between 6 weeks and 6 months of age, followed by a booster dose, preferably in the second year of life. As previously mentioned, various countries have adapted and customized their vaccination schedules according to their policy considerations. As of March 2015, 19 countries use a three dose schedule for the primary series, either at 2-3-4 months of age (n=9) or 2-4-6 months of age (n=10). Most of these countries give a toddler booster dose towards the end of the first year of life (n=3) or during the second year of life (n=13). In one country this booster dose can be administered before or after the first birthday; two countries do not recommend any toddler booster dose. Seven countries administer a two-dose primary series at three and five month of age, followed by a booster for 12 month-olds. Only France has a two-dose schedule at two and four months of age followed by a booster at 11 months of age. All countries, except Malta, recommend one (n=11), two (n=15) or three (n=4) further AP booster doses between two and 18 years of age. Six countries recommend one or more AP booster doses for all adults and/or elderly. Two countries (United Kingdom and Ireland) only target pregnant women in their last trimester of pregnancy (since late 2012).

3.3.3. Recommendation for coverage pillar

It is difficult to retrieve the exact historic pertussis vaccination schedules over the study period and the exact brands/types of vaccines that were used. This will be part of the work in the Coverage pillar, at least for the countries that participate in the proof of concept study. Information must be retrieved from the country itself (public health/databases). In addition, patterns of coverage over time and switch patterns should be described and analysed against the ecological patterns of pertussis outbreaks /incidence (together with the effectiveness pillar). This should be viewed in the POC spirit of mimicking near-real time monitoring of a new vaccine. In addition, correlations between coverage and pertussis incidence may be the basis for detecting indirect (herd immunity) effect. It could also be interesting to collaborate with WP 1 on the changes in sentiment and plot this against coverage.


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3.3 Vaccine benefits Vaccination with inactivated whole B. pertussis bacteria (WPs) against pertussis was developed and introduced in the 1940s.

3.3.1 Efficacy

Although surveillance observations demonstrated that wPs were efficacious, no formal prospective WP efficacy trials were initially conducted (2). The main body of evidence of vaccine efficacy for both wPs and aPs stems from six trials conducted between 1990 and 1995, which compared a few wPs, some of which are still in use today, to most of the current aPs (45-50). However, differences in the design of these studies and in the outcomes case definitions limit the comparability of the results across trials. For the wPs in these studies, efficacy estimates ranged between 89% and 96%, except for the Connaught USA wPs, for which an efficacy of 36%-48% was calculated (45, 46). Efficacy estimates for aPs that were eventually introduced for broad vaccination programs ranged between 71%-85% The impact of the number of acellular components in APs on the efficacy of the vaccine remains controversial. In addition, the follow up time in these studies was limited to about two years. Data on efficacy in trials could be collected by the benefit pillar as one type of benefit estimates for the B/R model at least at the moment of switch.

3.3.2 Population impact of vaccination program

At the ecological level of evidence, it is widely accepted that introduction of wPs in broad childhood vaccination programs around the world has resulted in dramatic decreases in incidence of childhood pertussis. In the 1980s and 1990s (after large efficacy trials had been performed), acellular pertussis component vaccines were introduced and these replaced wPs vaccines mainly in western countries and Japan. In the context of steadily increasing reported incidence of pertussis since the 1980s, large pertussis outbreaks have been reported since 2009 in several developed countries using aP vaccines such as in the US, the UK and Australia, despite relatively high childhood vaccine coverage (7-10). Conversely, pertussis appears to be much better controlled in other countries like Sweden and France, which have also been using aPs for more than 15 years. Some evidence also suggests that the resurgence of pertussis may not be limited to AP-using countries. The UK introduced aP vaccines in September 2004 with 3 doses in infants at 2,3,4 months of age while the highest number of pertussis cases during the 2012 outbreak were reported outside the cohort of children vaccinated with aP vaccines (adolescents, adults and infants less than 3 months of age) (7). The UK Department of Health introduced immunization of pregnant women to control the outbreak and to reduce the morbidity and mortality among infants too young to be immunized (7, 18). In several analyses of data obtained in this context, Public Health England estimated that vaccinating pregnant women with a TdaP-IPV vaccine in the 3rd trimester of pregnancy had 90-93% effectiveness in protecting unvaccinated infants in the first 2 months of life against pertussis (19, 20). The outbreak of pertussis subsided in 2013, with incidence diminishing from more than 1600 cases at the peak in October 2012 to less than 250 cases per month on average in October through December 2013 (21). Overall, in 2012 in the EU/EEA, ECDC reported incidence rates that varied between 0 and 0.05 per 100,000 in Malta and Hungary respectively to 85 per 100,000 in Norway. A notable increase in reported incidence was observed in 10 of 28 reporting countries, including the countries reporting the highest number of cases overall (i.e. the Netherlands, Denmark, the United Kingdom, Norway) (13). The highest age-specific incidence of pertussis cases, hospitalizations and complications is in infants, aged 0 to 1 year, and mainly before 3 months of age in most countries (38.5 cases per 100,000 in 2011) (14). Most young infants acquire pertussis from adolescents or adults in their own households mainly parents (20-55%) and siblings (19-53%) (15). In contrast (16), other countries such as Germany reported the


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highest age-specific incidence in adolescents (17). Furthermore, in 2012 in the EU, the most affected age group was in fact those 5-14 years of age (13). The improvements in surveillance methods, case-confirmation technology and the increased awareness of disease in these age groups may have contributed to the increased detection of the milder forms of disease that more typically affect them. Sizeable outbreaks have also been reported in wP-using countries such as Argentina, Chile and Uruguay in recent years (11, 12). The vaccine coverage with pertussis vaccines is an important factor for control of the disease and drops in coverage have often resulted in fast and large increases in incidence of disease. The re-introduction of pertussis childhood vaccination with aPs in 1996 in Sweden following a 17-year gap in vaccination after the wPs were abandoned in 1979 showed a large effect on the incidence of disease, demonstrating the effectiveness of aPs in protection against childhood pertussis. Further ecological evidence of the effectiveness of aPs was provided in the IMPACT surveillance network in Canada, with an 85% reduction in pertussis hospitalizations when the aPs were introduced following the use of a poorly efficacious wP (44). As evidenced in numerous publications, the recent resurgence and outbreaks likely result from the combined impact of multiple factors. These include enhanced awareness of disease, increased case reporting (22), rapidly increasing availability of more sensitive diagnostic tests (eg, polymerase chain reaction) (23), differences in vaccination schedules and coverage (24-28) while it is still a matter of controversy whether mutational evolution of circulating pertussis strains are causally related to AP vaccine use (29-32). However, a central hypothesis analyzed to explain the current epidemiologic observations has been the potentially differential immune response (Th1/Th2), and a differential waning and “boostability” of the immunity elicited by APs vaccines compared to WPs (33-42).

3.3.3 Effectiveness

Numerous observational studies have confirmed the immediate effectiveness of most wPs and all aPs used in large vaccination programs. Several studies have also investigated the duration of the protective effectiveness elicited by pertussis vaccines. After reviewing existing literature, Wendelboe et al. estimated that pertussis vaccination conferred protection for four to 12 years (duration of protection) with no great differences between wPs and aPs (51). However, in light of the recent resurgence and outbreaks of pertussis observed in some countries, a number of observational studies have suggested a lower long-term effectiveness of APs compared to WPs. Some investigators assert that APs vaccines given to infants and young children provide shorter duration of protection than do WPs vaccines. However, it is important to highlight that none of the historical and recent evidence puts in question the immediate effectiveness of pertussis immunization in young children. Furthermore, studies in the 2010 California outbreak and in the 2012 Oregon outbreak confirmed that a full acellular pertussis vaccination series elicited high levels of protection lasting until the age of the adolescent booster(33, 52). These latter findings are broadly considered as evidence that the current APs given to infants and young children do not prime recipients as well as WPs did for future boosting, which is always done with APs. Vaccine failure should be defined according to the CIOMS criteria a) Confirmed Vaccination Failure The occurrence of the specific vaccine-preventable disease in a person who is appropriately and fully vaccinated taking into account the incubation period and the normal delay for the protection to be acquired as a result of immunization. This definition requires clinical and laboratory confirmation (or epidemiological link to a confirmed case) that the actual disease is vaccine preventable, i.e. that the pathogen (including, where


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appropriate, type, subtype, variant, etc.) and clinical manifestations are specifically targeted by the vaccine. b) Suspected Vaccination Failure Suspected vaccination failure is defined as the occurrence of disease in an appropriately and fully vaccinated person, but the disease is not confirmed to be the specific vaccine preventable disease, e.g. pneumococcal disease of unknown serotype in a fully vaccinated person. c) Immunological Failure Immunological failure is defined as failure of the vaccinee to develop the accepted marker of protective immune response. This definition requires that there is an accepted correlate or marker for protection, and that the vaccinee has been tested/examined at an appropriate time interval after completion of immunization.

3.3.4 Recommendation for the Benefits pillar

From this benefit review it is recommended that the benefit pillar considers carefully the different type of ‘pertussis definitions’, an analysis might be done considering clinical definitions (ie. Pertussis as defined in medical record) and a separate one that considers laboratory confirmed cases. Special attention needs to be given to the impact changes in awareness and laboratory technology, as well as the varying laboratory test performance according to age, and the cyclical epidemiologic nature of pertussis can have on the detection of cases. Cases should be analyzed in relation with the number of doses received. Complications as listed in section 3.1.3 should be included. Data should be collected in a way that allows for ‘sequential monitoring’

3.4 Vaccine risks

3.4.1 Safety studies

In a study including 15,752 DTwP and 784 DT doses, that was performed in the Los Angeles area in 1978-1979, local redness, swelling and pain occurred in 37.4%, 40.7% and 50.9% of DTwP recipients compared to 7.6%, 7.6% and 9.9% in DT recipients, respectively. Frequencies increased in subsequent doses. Frequency of fever (≥38 C) was 46.5% and 9.3% after DTwP and DT, respectively. Furthermore, high-pitched unusual crying, convulsions and hypotonic hypo-responsive episodes (HHE) following DTwP were reported in 0.1%, 0.06% and 0.06%, respectively. Those events were not reported after DT, probably due to the low number of DT vaccinees. (5) A large study, performed in USA, assessed common reactogenicity of 13 candidate APs compared to the Lederle-WP. For all AEFI, frequencies after APs were lower than after WP. For fever (≥37.8°C) frequency was 4.2% after the first dose of AP compared with 27.3% following WP. The temperature increased by subsequent doses. For local redness, these percentages were 13.5% and 49.4%, for local swelling 8.7% and 39.7%, local pain 3.8% and 27.3%. (55) For more rare and severe AEFI, frequencies differed as well. Persistent crying, very high fever (≥40.5°C), HHE and seizures were respectively 7, 7, 17 and 6 times more likely after WVC compared with AP(56). In a large (n=28,796) questionnaire study carried out in the Netherlands between 2004 and 2007, frequencies of more rare, severe AEFI were higher after the Dutch wP (used till 2005) compared with the aP (introduced from January 1st 2005 onwards) (57). 1.5% of the infants reported prolonged crying ≥3 hours after first dose at two months after WVC compared with 0.4% after aP. Frequencies of very high fever (≥40.5°C) after fourth dose at 11 months were 0.8% (wP) and 0.2% (aP), whereas


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frequencies for febrile convulsions after the fourth dose were 0.06% (WVC) and 0.02% (AP) and for HHE after the first dose 0.12% (WVC) and 0.03% (AP). A review, performed by Jefferson et al in 2003, showed that WPs were associated with a significantly higher incidence of swelling and induration (OR 11.7; 95%CI 8.8-15.4), fever >39 C (OR 3.4; 95%CI 2.1-5.5) and crying for >2 hours (OR 4.7; 95%CI 2.9-7.6) than placebo or DT-vaccinations without pertussis component. Differences in incidence of HHE and convulsions were not statistically significant. APs did not cause a higher incidence of local signs, fever, convulsions, HHE or prolonged crying than placebo or DT (58). Permanent damage to the central nervous system was repeatedly reported as “causally related” to wPs (59). However, the National Childhood Encephalopathy Study and a consecutive huge body of scientific evidence (60) eventually showed there was no association between neurological sequelae and WPs (61). In spite of this the concerns that arose where the motivation to develop the aPs. In an observational study evaluating the safety of hexavalent vaccines (DTaP-IPV-Hib-HepB) involving 78 preterm infants, immunisation triggered transient cardiorespiratory events in 47% of infants (15% apnoea, 21% bradycardia, 42% desaturations). In a retrospective study involving 53 infants, transient apnea or bradycardia was observed in 13% of infants following immunization with pentavalent or hexavalent vaccines. Apnea seems less frequent and less severe following DTaP than whole cell pertussis vaccines (68)

3.4.2 Recommendation for the risk study group

From this safety review it is recommended that the risk study group will include proven causally related reactions to the pertussis containing vaccinations. Reactions may include ‘reactogenicity’, and serious but less frequent adverse reactions to vaccination that may impact the benefit-risk: high fever, febrile convulsions, and hypotonic hypo-responsive episodes (HHE) and extensive limb swelling. Some of these may not be measurable in databases but may be obtained from other sources As per standards used in clinical trials, the time window for considering these events as potentially attributable to the vaccine was considered to be 48 hours after each dose of vaccine. This may be reconsidered after thorough review in the study group All analyses of adverse reactions should be stratified by severity and level of evidence as much as possible. For most direct risks under study, i.e. fever, convulsive seizure, injection site reactions and hypotonic-hyporesponsive episode, Brighton Collaboration case definitions exist (63-67).

4. Outcome tree The outcome tree for a B/R model is a visual, hierarchical display of the key criteria (here health outcomes) relevant to the benefit-risk decision. The outcome tree facilitates communication and enhances common understanding. Observe that in this outcome tree, we are weighing the disease (pertussis) specific benefits against the vaccination risk (comprising all other disease components) as it difficult to assess specificity for Pertussis only as regards safety. The resulting B/R measure will therefore be a conservative one.


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Figure 3. Pertussis outcome tree

aP vs wP

Benefits

Direct

Confirmed pertussis

Complications/sequelae

Hospitalizations

Deaths

Indirect

Confirmed pertussis

Complications/sequelae

Hospitalizations

Deaths

Risks Direct

Injection site reactions

Fever

Somnolence

Persistent crying

Convulsions

HHE

limb swelling


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5. Benefit-risk decision model and required input To our current knowledge, only one benefit-risk model for pertussis immunization exists (70). The model was developed in the late seventies and used a decision tree analysis to support the decision whether or not to include childhood pertussis vaccination in a community-wide vaccination program. This model did not include utilities, but costs. As a first step, a Benefit-Risk model should be developed to compare the benefit-risk balance of aP vaccines with that of wP vaccines in pre-school children using the PrOACT-URL descriptive framework (Problem, Objectives, Alternatives, Consequences, Trade-offs, Uncertainties, Risk tolerance, Linked decisions).

Subsequently, we will build a multi-criteria decision analysis (MCDA). MCDA is a quantitative framework providing a highly structured approach based on the descriptive framework PrOACT-URL.

MCDA allows comparing multiple options by assessing and integrating multiple benefits and risks criteria and consequently includes value judgements or preferences. The use of MCDA in the context of drug BR analysis was first proposed and discussed in detail by Mussen et al (72). MCDA has been extensively evaluated by the PROTECT consortium and both the European Medicines Agency and PROTECT (71) recommend further investigation into the real-life use of MCDA for pharmaceutical BR assessment. Stochastic extensions of MCDA (e.g. stochastic multi-criteria acceptability analysis or SMAA (73) allowing for uncertainty in benefit- and risk estimates as well as variability in preferences exist as well.

The benefits and risks listed in the outcome tree (figure 1) are the ‘criteria’ in the MCDA model. For each of the ‘criteria’, the ‘performance’ of the decision ‘alternatives’ (in this case, aP or wP vaccination) is to be measured. For vaccine benefit-risk studies, incidence rates or risks are natural ‘performance’ measures. To facilitate the comparison of the different health outcomes, which vary regarding the duration of the effect, simulation models based on hypothetical birth cohorts will be built. Within the models, we will simulate vaccination and follow-up the cohorts over time. The input parameters for this simulation can be retrieved from various sources. In ADVANCE they should come primarily from the real life data in the consortium that will be generated by the study groups. If this is not possible or for sensitivity analyses, we may use data from other sources such as clinical trial data. Then, using these parameters we will estimate the number of events related to the various health outcomes that would occur in such a cohort given the incidence rates obtained from the data sources and assuming a given vaccination coverage. To summarize the number of events, we will calculate the incremental net health benefit (INHB), or the incremental change in benefits minus the incremental change in risks. The use of INHB has been advocated for benefit-risk analysis because of its natural interpretation and good statistical properties. To be able to calculate the INHB, preference weights are required as well (see Section 7).

6. Table shells of minimal information on benefits and risks

Outcome Measure* Population Time window

Benefits

pertussis Incidence rate Infants and children from birth until before the scheduled age of

In infants and children up to school-entry or age 6: any case at or between any dose of


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school-entry booster or age 6 (whichever earliest)

primary or booster vaccine, dose-specifc.

Complications of pertussis§ leading to hospitalization

Risk (proportion) Cohorts of pertussis cases

any hospitalization with pertussis as primary or secondary diagnosis

Pertussis leading to Death Risk (proportion) Cohorts of pertussis cases

any time between start of pertussis symptoms and death

Risks

Injection site reactions: erythema, edema, induration/ nodule/sterile abscess, pain/tenderness, apnea bradycardia

Risk (proportion) Vaccinated infants/children after every dose

Onset within 48 hrs following each dose of vaccine

Fever Risk (proportion) Vaccinated infants/children after every dose


Somnolence Risk (proportion) Vaccinated infants/children after every dose


Persistent crying, irritability

Risk (proportion) Vaccinated infants after every dose


Febrile or afebrile seizure/convulsion



Hypotonic-hyporesponsive episode



extensive limb swelling Risk Vaccinated infants after every dose


wP and aP vaccination Type and brands used

*Incidences can also be obtained by multiplying baseline rates with measures of effectiveness or relative risks. ** Indirect benefit § diagnoses of pneumonia, apnea/respiratory distress, pneumothorax, cardiopulmonary failures, complications (including some of the preceding ones requiring mechanical ventilation or extracorporeal membrane oxygenation), encephalitis/encephalopathy, seizures, gastroesophageal reflux leading to hospitalization


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7. Preference elicitation Preferences are the relative desirability or acceptability of the health outcomes associated with a given vaccine. Different stakeholder groups (e.g. regulators, public health authorities, health care providers and patients) or different individuals within a stakeholder group might have different preferences and consequently take different decisions. Therefore, it is important to systematically quantify these preferences. Several preference elicitation techniques exist, including structured weighting (swing weighting, analytical hierarchy process, MACBETH), health state or disability weight methods (like used for DALY and QALY calculations), stated preference techniques (best-worst scaling, conjoint analysis/discrete choice experiments) or revealed preference techniques (patient preference trials). These methods have already been applied for vaccine preventable diseases or to elicit vaccine related preferences for a.o. rotavirus, pertussis, influenza, HPV and meningococcal vaccination. For this first POC study, we propose to use structured weighting methods, which would allow us to systematically and rather quickly collect preferences from various stakeholders. In particular, we propose to organize a one-day decision conference inviting representatives of public health and regulatory authorities participating to the ADVANCE consortium to elicit preferences for the pertussis-related health outcomes using swing weighting or Analytic Hierarchy Process. The outcome tree described in Figure 3 is the foundation for selecting and prioritizing the health outcomes for which preferences will be elicited.

8. Data Sources A generic set of data requirements was identified during the technical requirements analysis conducted by Work Package 3. The elements were identified by analysing literature and through expert input. From this generic set, we extracted the relevant data elements required for conducting Pertussis POC by reviewing the POC research plan and event definitions for Pertussis developed by Work Package 5. The data requirements were then used to conduct a high level review of the suitability of databases featured in the ADVANCE pilot metadata database created through the AIRR (ADVANCE International Research Readiness) survey instrument (Table: Completeness of recording for Pertussis and vaccine data fields available). The AIRR survey instrument (pilot stage) captured metadata from 15 databases associated with the consortium and 3 external databases. The requirements presented in this document will be used to develop a study-specific extension of the AIRR survey. Data should be available between 1990 and 2015. Table: Data requirements for Pertussis POC Data requirements Pertussis POC data requirements

Po

pu

lati

on

Date of birth, gendergender, start of follow-up, end of follow-up, identifier

Children of vaccination age: birth before school-entry booster age (as defined locally), with exact person time contributions

Exp

osu

r

e

Date of vaccination, dose, brand, identifier Date, dose, brand

Ou

tco

me

Identifier

Date of diagnoses Required

Diagnosis code Events for risk / benefit outcome & covariates


138

Data requirements Pertussis POC data requirements

Type of care Hospitalization yes/no

Symptoms Crying, somnolence

Laboratory data Pertussis (bacterial, PCR)

Death Date of death


139

Table: Data on recording for pertussis and vaccine data fields available (adapted from AIRR survey)

Partner Name Country

Relevant population

Completeness of

recording for Pertussis26

Pertussis vaccine data fields available27

Vac

c. D

ate

Bat

ch N

o.

Lot

No

.

ATC

Lev

el

Bra

nd

Man

ufa

ctu

.

Bo

dy

site

Faci

lity

Ad

m

vPar

tne

rsvP

artn

ers

dat

abas

es 1. Belgian network

of sentinel general practitioners

Belgium Yes Partially (clinical)

2. Finnish HPV Vaccine Trial Cohort

Finland No

3. HPV-CRT Cohort Finland no

4. Integrated Primary Care Information database (IPCI)

Netherlands

Yes Partially (clinical)

5. L'Azienda Sanitaria Locale (ASLCR)

Italy Yes Complete

6. Nordic HPV Vaccine Trial Cohort

Finland No

7. Osiris, Netherlands Netherlands

Yes Reported cases

8. Paediatric Surveillance Network (Pedisurv)

Belgium Yes Partially (clinical)

9. PEDIANET Italy Yes Partially (clinical)

10. Spanish National Pharmacoepidemiology Database (BIFAP)

Spain Yes Partially complete

11. The Danish Civil and Health Registration System (SSI)

Denmark Yes Complete

12. The Royal College of General Practitioners RSC (RCGP RSC)

United Kingdom

Yes Complete

13. The Health Improvement Network

UK yes Partially (clinical)

Ass

oci

ate

par

tne

rs

dat

abas

es 14. EOF Yellow Card Greece No data

available

15. Hellenic Center for Disease Control & Prevention (KEELPNO)

Greece

16. National School of Public Health (ESDY)

Greece

Databases that are eligible to participate in one or more study groups will be asked to work according to the procedures that have been established in D5.1-5.3, this will be one of the parameters of success. This means that we work according to a distributed model. Data are transformed and linked locally by the data controller into pre-specified common input files (population, events, exposure, and measurements: see D5.1 and D.5.2). The structure is pre-defined, the content (type of events/exposure) depends on the protocols. Data transformation into analytical datasets will be done by standardized programs in SAS and R that will be developed in the study teams. All programmers will work using the common data model.

26 Empty responses indicate that no response for provided for this survey question with respect to Pertussis. 27 Data fields available for all vaccine data in general.


140

9. Requests from other work packages Work package 1:

- Sentiment analysis linked to the coverage

- Communication recommendations about results

- Assessment of the integration of the code of conduct, quality criteria and governance functioning

Work package 3:

- Assess the time to approvals, data base suitability and hurdles with ethics/privacy

- Assess eligibility of databases to provide the requested data

Work package 4:

- Assessing and understanding heterogeneity in benefit and risk estimates from different data sources, using different designs. Special attention should be given to scale of measurement (relative or absolute). While absolute effects are typically required to conduct benefit-risk assessments, these can also be derived from relative measures in conjunction with baseline rates. In addition, additional information that might explain the heterogeneity (input required) should be collected. The additional information can then be used in a meta-regression type of approach.

- Estimating vaccination coverage (by dose, type age and birth cohort) using electronic health care data and comparing/validating these estimates using data from vaccine registers

- Eliciting preferences from experts/ representatives of public health organisations and regulatory authorities using either MCDA swing weighting, MACBETH or the Analytical Hierarchy Process (APH) and comparing these preferences with the disability weights used in DALY calculations. -

- Validation of the pertussis cases (various case definitions) obtained from electronic health care records using surveillance data.

- Sequential monitoring (details to be added)

Work package 5:

- Testing of the infrastructure (OCTOPUS)

- Testing of the programming against a common data model by study team members

- POC research teams, definitions of roles and responsibilities?


141

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i Vaccination against shingles for adults aged 70 and 79 years of age - Q&As for healthcare professionals, Public Health England (2013)

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