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Building an ecosystem for better monitoring and communicating of medication safety in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimised evidence generation

Deliverables

Report describing existing coding systems, schemes and regulatory guidelines of reported medication exposed pregnancies

Task 2.3: Core data elements required for the prospective collection and follow-up of exposed pregnancies (M1-36) (UMAN, NUTH, UOSL, LAREB, UKZN, ENTIS, NVS, Novo Nordisk, Sanofi, AbbVie, Teva and WP7 partners). This task has two key components: 1. Describe and evaluate existing coding systems, schemes and regulatory guidelines of reported medication exposed pregnancies (M1-12): Building on existing EMA and FDA regulatory guidance documents such as ICH E2B (R3) format for safety data exchange, ICH M1 MedDRA international terminology, IDMP/SPOR and ENTIS and OTIS protocols for prospective cohort collection, we will describe the requirements for spontaneous and solicited primary data collection format and coding, and the possibility and methods to map existing formats to those standards (in collaboration with WP7). Recommendations for changes to the current standards for data collection will be proposed where required following a gap analysis and assessment of content. This task will receive input from the out

Report with description of the functionality of the knowledge

Task 5.2 Developing an EU centralised open access digital knowledge bank (M6- 60) (LAREB, Sanofi SCC, ENTIS, ORC, the Synergist, EIWH, NVS, AbbVie, UCB, Pfizer) Rationale: By creating an EU centralised digital knowledge bank providing timely and high-quality general information and summary and interpretation of scientific research in literature and of data collected (from WP1 and WP2) this task will contribute to more harmonised and reliable evidence dissemination for the general public, pregnant or breastfeeding women and HCPs. Official labelling information will also be available in the knowledge bank. Members of ENTIS already have their own systems for keeping up to date knowledge of high quality. Some centres have a national knowledge bank, and some also available on their website. A common model to share the safety information they have collected is not yet in place. At this moment each country collects and interprets the scientific data themselves. By joining forces and introducing work-sharing betwee

Prototype of FAIR data catalogue-1st

Task 7.4: Creation and filling of a FAIR data source catalogue(s) (M3-M36) (BBMRI, UMCG, GSK, JAN, Sanofi, SGUL). A FAIR data source catalogue will be created with specific search features that will be defined based on user requirements. We will use standard metadata models to make data resources findable, understandable, and provide fine-grained access control for researchers (FAIR implies access ‘under well-defined conditions’). Computer-readable terms that minimally describe the data resource (e.g. an ontology term or a (bio)schema.org term) are added for a searchable index of sources. The metadata defines the resource as a whole, the data sets, formats in which the data sets are, variables and provenance. The catalogue will also contain a private negotiation service to arrange data access, and a separate private site for simple analysis of data characterisation tables, which can be used in feasibility services following authentication. The catalogue will be filled by UMCG using the WP1 and 2 data.

Additional third party selection procedure description

Task 8.8: Management demonstration project funds (M1- M60) (UMCU) Within the third party budget funding is set aside to acquire additional data for quality assessment and demonstration studies (322.5K for WP1 (to be managed by ULST) and 150K for WP7 (to be managed by UMCU)). WP8 will manage a transparent procedure adhering to all relevant EU rules and institutional procedures to identify additional third parties/data sources that add value to the consortium. The WP1 and WP7 leadership will play a key role in this process.

Report on lactation characteristics of animal species (rodent, rabbit, (mini)pig, dog, non-human primate, etc; anatomy/histological structures, milk composition, duration of lactation, etc); Selection of the animal species to be used in in vivo studies

Task 3.1: Literature search (M1-M6) (UNIBO, TEVA, KUL, CHUT, ULAUSUNIGE UOSL, Bionotus, Covance, Ellegaard, NVS). First, literature searches will be conducted on: (i) lactation characteristics of non-clinical tox species (anatomy/histological structures, milk composition, duration of lactation); (ii) non-clinical (in vivo and in vitro) lactation models; (iii) computational approaches to determine drug milk excretion; (iv) non-clinical data available on concentration of drugs in milk, pup exposure; (v) human lactation data, in collaboration with WP4, including milk-mediated drug exposure in breastfed infants (as a benchmark for predictions generated in this WP; possible link to WP4 if/when human lactation data would be available). This knowledge mapping effort should reveal the current state-of-the art including limitations and shortcomings. This will aid in defining a consensus and starting points for development and characterisation of fit-for-purpose non-clinical (in vitro human & in vivo animal) and computational (in silico) models (subsequent tasks in this WP). Information gathered will be combined in structured overviews of existing non-clinical and computational models and clinical reference data on lactation and risk assessment of drug exposure in breastfed infants. The structured overview will be an important technical information source for selection of a set of 10 therapeutically relevant model drugs that will be used in subsequent tasks in this WP, i.e. for assessment of model performance and applicability (Task 3.2-3.4). Criteria for selection of model drugs will be: (i) different chemical structures, physicochemical properties; (ii) different modalities (both LMW and biologicals); (iii) clinical relevance including medical need in the pregnant population; (iv) quality and resolution of available reference data; (v) clinical data sets for which a robust popPK model is available; (vi) availability of PK data; (vii) consider the model drugs that would be(come) available from EFPIA partners and, if possible (dependent on timelines), in WP4 (the demonstration projects in WP4 will generate data sets on breast milk concentrations for selected model drugs).

Project management plans

Task 8.1: Internal project management and coordination (M1- M60) (UMCU and all WP leaders) Development of project management communication and quality assurance plans as a support to the consortium with the main goal to facilitate the collaboration between partners and ensure that IMI requirements are respected. Ensure clear internal communication and handle external project correspondence and the day-to-day requests from partners and external bodies; Implement and maintain internal reporting and monitoring procedures; Report progress, the results and the necessary changes to the work plan; develop risk management process; implement and maintain the project infrastructure and internal workspace; guard consortium principles. Furthermore, the project management team will further deal with any legal issues that may arise and install a complaints officer where complaints about research participation by women can be shared in a trusted manner. A complaints procedure will be established

Detailed project plan, plus tracking tools, to be maintained throughout the life of the project

Task 8.1: Internal project management and coordination (M1- M60) (UMCU and all WP leaders) Development of project management communication and quality assurance plans as a support to the consortium with the main goal to facilitate the collaboration between partners and ensure that IMI requirements are respected. Ensure clear internal communication and handle external project correspondence and the day-to-day requests from partners and external bodies; Implement and maintain internal reporting and monitoring procedures; Report progress, the results and the necessary changes to the work plan; develop risk management process; implement and maintain the project infrastructure and internal workspace; guard consortium principles. Furthermore, the project management team will further deal with any legal issues that may arise and install a complaints officer where complaints about research participation by women can be shared in a trusted manner. A complaints procedure will be established

Report on scope and limitations of in vivo and in vitro non-clinical and computational models for drug milk excretion and breastfed infant exposure; Selection of a panel of at least 10 model compounds for initial evaluation of non-clinical models

Task 3.1: Literature search (M1-M6) (UNIBO, TEVA, KUL, CHUT, UNIGE UOSL, Bionotus, Covance, Ellegaard, NVS). First, literature searches will be conducted on: (i) lactation characteristics of non-clinical tox species (anatomy/histological structures, milk composition, duration of lactation); (ii) non-clinical (in vivo and in vitro) lactation models; (iii) computational approaches to determine drug milk excretion; (iv) non-clinical data available on concentration of drugs in milk, pup exposure; (v) human lactation data, in collaboration with WP4, including milk-mediated drug exposure in breastfed infants (as a benchmark for predictions generated in this WP; possible link to WP4 if/when human lactation data would be available). This knowledge mapping effort should reveal the current state-of-the art including limitations and shortcomings. This will aid in defining a consensus and starting points for development and characterisation of fit-for-purpose non-clinical (in vitro human & in vivo animal) and computational (in silico) models (subsequent tasks in this WP). Information gathered will be combined in structured overviews of existing non-clinical and computational models and clinical reference data on lactation and risk assessment of drug exposure in breastfed infants. The structured overview will be an important technical information source for selection of a set of 10 therapeutically relevant model drugs that will be used in subsequent tasks in this WP, i.e. for assessment of model performance and applicability (Task 3.2-3.4). Criteria for selection of model drugs will be: (i) different chemical structures, physicochemical properties; (ii) different modalities (both LMW and biologicals); (iii) clinical relevance including medical need in the pregnant population; (iv) quality and resolution of available reference data; (v) clinical data sets for which a robust popPK model is available; (vi) availability of PK data; (vii) consider the model drugs that would be(come) available from EFPIA partners and, if possible (dependent on timelines), in WP4 (the demonstration projects in WP4 will generate data sets on breast milk concentrations for selected model drugs).

Contact database (stakeholders and key project contacts)

Task 8.2: Enhance and optimise collaboration within the consortium (M1-M60) (UMCU, NVS, UCB and all WP leaders) This task will aim to keep partners involved in the project by stimulating collaboration and information sharing in a systematic manner. The project management team will: Design and maintain of partner-specific templates for collecting input for required EU documents; Coordinate internal and periodic technical reporting; Support timely production of deliverables and reports, and maintain project archive; Guide partners in project administration by providing a guides and FAQs, as well as a webinar if needed; and Coordinate financial and administrative issues: establish and maintain financial records, co-ordinate financial statements submission by all project partners, calculate partner shares according to rules agreed in the Consortium Agreement. In addition, collaboration will be stimulated by newsletters, and periodic team climate assessments (survey). Impact assessment will be conducted annually.

Roadmap of planned project outputs, including qualification advice submissions, mapped to stakeholder needs and planned stakeholder interactions

Task 6.1: Understand stakeholder needs and perceptions and align with project outcomes (M1 – M12) (i~HD, EMA, MHRA, EFGCP, Synergist, KUL, EIWH, FERR, NVS, Takeda, JAN). In this task WP6 will act as a facilitator and coordinator, working with Work Package leaders to gather insights from key stakeholders (regulatory, HCPs, women and patients, maternal health foundations, charities, etc.) on their needs and perceptions, to help achieve project goals and deliver maximum possible value and impact to target audiences. The outputs from task 6.1 will feed into all other work packages. The first step is to determine what input is needed from stakeholders. A stakeholder landscape analysis will be conducted as a resource to the consortium. A variety of tools will be used to gather input from stakeholders, including literature reviews, surveys, interviews, focus groups, and digital tools (e.g. social media outreach, digital listening tools), and to build ongoing dialogue with stakeholders. This task will seek to und

Summary and review of collected SOPs from project partners and literature

Task 4.4: Developing standard documents for pre-examination processes for breast milk handling and biobanking activities (M1-M60) (BBMRI, UPPS, UNIGE, CHUT, UOSL, Pfizer). Building a ‘Breast Milk Biobank Analysis Center’ requires a comprehensive quality management approach, to secure and control all operations associated with conducting clinical trials, biobanking activities, and downstream analysis procedures at multiple process levels. The partners will develop the basic structure of this quality management system from a set of applicable European and International Standards for biobanking and pre-analytical sample handling (CEN/TS 16835, ISO 20387, ISO 9001, ISO 20186 etc.) and the guideline for good clinical practice E6 (R2), ICH-GCP for the protection of donor rights and safety. SOPs from the project partners and from the literature will be reviewed to verify key processes and methods. The collection, processing steps, processing times, storage temperature, freeze-thaw-cycles and so forth, will be

Annual reports on external communication results for impact assessment -1

Task 5.3: Engage HCPs, pregnant and breastfeeding women and general public and to stimulate pregnancy reporting through PV system and participation in research; (with WP2, WP6 and WP7) (M6-M60) (NUTH, ENTIS, LAREB, Synergist, UPPS, EIWH, (third parties such as EU organisation for GPs/ gynaecologist /midwives/pharmacists) Pfizer, Sanofi, NVS, AbbVie, UCB) Rationale: Based on the ethical discussions in WP7 (task 7.3) about the idea of a learning healthcare system where we have a moral duty to generate evidence on the use of medicines in pregnancy, we will translate the learnings from the ethical research into communication programs to stimulate HCPs and pregnant women awareness that they have can play an active role in increasing general knowledge about the safety of drug use during pregnancy and breastfeeding in the post-marketing phase of a drug by contributing to WP2 as well as WP4. Aim: To build awareness and stimulate actual participation from the targeted audience Method: Communications directed to relevant stakeholders will be developed using push-pull strategies and developing value propositions. A combination of very targeted communication on social media and other digital channels together with point of care material will disseminate the message and capture the audiences utilising health literacy methods and tailored messages to stimulate their participation. The campaign overarching messages will build on various awareness messages and value propositions for pregnant women and HCPs. Each exposure will be the opportunity to engage and offer participatory mechanisms. Messages and value propositions will be tested ahead and then will be assessed in terms of participatory rate and ultimately behaviours changes, partly measured through the channels we will deliver (online, apps, etc.) In the same countries as the information materials are tested, communication strategies (including through social media, promotion through pharmaceutical companies, national healthcare systems and international/national regulatory organisations) will implemented to inform the general population, pregnant women/women of reproductive age and healthcare professionals about the importance of reporting to the pregnancy pharmacovigilance system. The effects of the campaign will be measured, both in terms of increased reporting, but also in terms of increased awareness about the importance of reporting among HCPs.

Report on information, privacy and research governance for WP1-5

Task 7.2: Definition governance framework for responsible re-use of data (M3-M12) (i~HD, UMCU, UPPS, EFCGP, EIWH, KI, GSK, JAN, SANOFI). The objective of this task is to ensure, and assure, data access providers and research users that data and samples are treated in full compliance to the GDPR (for personal data), the IMI Secondary Use Code and other codes of practice that protect the privacy of data subjects (especially EHR4CR, EMIF, i~HD and BBMRI-ERIC), that research is conducted in ways that accord with codes of conduct from ENCePP and the ethics policies of ELIXIR, as well as other relevant standards. In achieving this, the partners involved in this task will reuse these existing instruments – some of which they have themselves developed in other initiatives – and carefully combine these and fill any gaps that are relevant to the project, while including the results from task 7.1. We will describe the procedures for a common trusted data management and research ecosystem. The main elements of such

User requirements and meta-data model for the FAIR data catalogue from WP1&2

Task 7.4: Creation and filling of a FAIR data source catalogue(s) (M3-M36) (BBMRI, UMCG, GSK, JAN, Sanofi, SGUL). A FAIR data source catalogue will be created with specific search features that will be defined based on user requirements. We will use standard metadata models to make data resources findable, understandable, and provide fine-grained access control for researchers (FAIR implies access ‘under well-defined conditions’). Computer-readable terms that minimally describe the data resource (e.g. an ontology term or a (bio)schema.org term) are added for a searchable index of sources. The metadata defines the resource as a whole, the data sets, formats in which the data sets are, variables and provenance. The catalogue will also contain a private negotiation service to arrange data access, and a separate private site for simple analysis of data characterisation tables, which can be used in feasibility services following authentication. The catalogue will be filled by UMCG using the WP1 and 2 data.

Report describing the metadata model (variables) for data collection on pregnancy data sources, as basis for the catalogue collection of exposed pregnancies

Task 2.2: Catalogue of industry and publicly held data sources and handling processes (M1-16) (LAREB, ENTIS, NVS, Novo Nordisk, Pfizer, Sanofi, NUTH, UKZN, UMAN, AbbVie) in collaboration with WP7. Regulators, industry and teratology information databases and clinical disease-based registries contain a mixture of prospectively reported pregnancy exposures, retrospective case reports and paternal exposures (industry pregnancy registries and PV databases, UK Epilepsy Pregnancy Registry, adverse event reporting systems, Teratology Information Service registries or databases, non-pregnancy disease registries). In addition, case reports of exposed pregnancies data are collected incidentally as secondary outcomes through various other sources or reported in the published literature (randomised controlled trials, research cohorts and case series, other). Using the WP1 literature mining tool, and through the partner and stakeholder network we will identify data sources with reports of pregnancies. We will create

Spreadsheet containing all additional data sources for the ConcePTION Data Source Catalogue

Task 1.1: Identifying new data sources to update the ConcePTION data source catalogue and assess its functionality for use in demonstration projects (M1-M60) (ULST, Sanofi, SGUL, USWAN, NUTH, CNR-IFC, INSERM, JAN, NVS). In this task we will update and expand the information in the EMA-funded EUROmediSAFE “Inventory of data sources for evaluating the long-term risks for children” which covers perinatal and childhood outcomes, including neuro- and immuno-developmental outcomes, etc., that are linked, or can be linked, to maternal medication exposure. Expansion will include newly identified EU data sources to study a spectrum of pregnancy outcomes, perinatal, neonatal and long-term childhood outcomes (e.g. cancer), databases for medication utilisation studies, hospital inpatient prescription data, breastfeeding data, additional primary care sources (e.g. in UK), rare disease and other disease registries for maternal disease, and additional contextual information (e.g. medication coverage, reimbursement) whe

List with names and expertise of expert delegates group for BBMRI Technical committee

Task 4.4: Developing standard documents for pre-examination processes for breast milk handling and biobanking activities (M1-M60) (BBMRI, UPPS, UNIGE, CHUT, UOSL, Pfizer). Building a ‘Breast Milk Biobank Analysis Center’ requires a comprehensive quality management approach, to secure and control all operations associated with conducting clinical trials, biobanking activities, and downstream analysis procedures at multiple process levels. The partners will develop the basic structure of this quality management system from a set of applicable European and International Standards for biobanking and pre-analytical sample handling (CEN/TS 16835, ISO 20387, ISO 9001, ISO 20186 etc.) and the guideline for good clinical practice E6 (R2), ICH-GCP for the protection of donor rights and safety. SOPs from the project partners and from the literature will be reviewed to verify key processes and methods. The collection, processing steps, processing times, storage temperature, freeze-thaw-cycles and so forth, will be

Interim Report on ethical issues

Task 7.3: Ethical issues (M1-24) (UMCU, EFGCP, EIWH, UPPS, GSK, Sanofi). The approach of ConcePTION to collect data on safety of medicines during pregnancy and breastfeeding is similar to what is increasingly being called a Learning Healthcare System (LHS). In an LHS, care and research are aligned to accelerate research and outcomes for patients and to overcome current problems, such as low inclusion rates and complex informed consent procedures. Taking an LHS approach to knowledge generation in the field of pregnancy and breastfeeding may broaden the opportunities to strengthen the evidence base, among others by learning from routinely collected data. However, applying an LHS approach to the field of pregnancy and breastfeeding comes with at least three open ethical issues: 1. How should we weigh the risks of the current status quo (where women hardly participate in research and we do not learn) versus the benefits and risks of participating in a system where pregnant and breastfeeding women will continuous

Data Management Plan

Task 8.3: Development and updating of data management plan (M1-M60) (UMCU, i~HD, BBMRI) In order to ensure the implementation of FAIR principles on all levels, ACRONYM will develop and further update a data management plan (DMP; in collaboration with WP7). A DMP describes the data management life cycle for all data sets that will be collected, processed or generated by the research project. ACRONYM’s DMP will detail: The handling of research data during and after the end of the project; What data will be collected, processed and/or generated; Which methodology and standards will be applied; Whether data will be shared/made open access, accessible for verification and re-use; How data will be curated and preserved.

Collaborative website (intranet)

Task 8.5: Website, internal document repository and social media (M1-M60) (UMCU) Implementing and maintaining the project infrastructure and the collaborative website (public and closed) as a platform for secured internal information exchange and project documents archive. The public website will include items such as general project information, news and newsletters, events and event outputs, tool information and the key results of the project. The website needs to be a functional, user friendly website. A social media strategy will be developed with WP5 (focus on Twitter and LinkedIn), aiming to promote the project image, inform stakeholders and the general public and to share key results of the project. It will also reinforce the communication activities as described in the communication. The social media strategy will include measurable objectives. The social media strategy will be included in the communication plan and social media activities will be aligned with information on the project’s public web

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