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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 landscape analysis

Task 5.1: Landscape analysis of available information sources about drug use in pregnancy (M1-24) (UOSL, NVS, LAREB, ENTIS, SCC, the Synergist, EIWH, AbbVie, UCB, Pfizer, Sanofi). The aim in this task is to compile an inventory of key information sources that are available to HCPs and women of child bearing age about drug use before and during pregnancy and during the breastfeeding period and to explore their preferences in receiving/accessing such information. The task is subdivided in three subtasks: Sub-task 5.1.1: Inventory Rationale: Different stakeholders (government, regulatory agencies, TIS, researchers, PV centres, HCP organisations, pharmacists, industry) are disseminating (different kinds of information) about the safety of drug use during pregnancy and lactation utilizing different delivery methods and with different purposes. Objective: To collect information on the current communication methods Methods: For different categories of stakeholders an overview will be made of: 1. The target group(s) of the communication; 2. The scope and purpose of the information; 3. The method(s) of information dissemination; 4. The process and methodology of interpretation of scientific research and how is this translated into up to date knowledge; and 5. Justification for and transparency about which sources are used The data will be collected using the most suitable data collection method including but not limited to desk research, interviews, surveys and digital channels. If stakeholder input is needed, this will be collected during a stakeholder event organised by WP6 in the beginning of the project. The task group will develop a briefing document for that meeting. Sub-task 5.1.2: Information discrepancies Rationale: A wide variety of information sources on medicines is available for women before and during pregnancy and during the breastfeeding period and the general public (which includes the women’s partners). Objective: assessing information discrepancies/conflicts Methods: Based on the landscape analysis above an assessment of the frequency and nature of information discrepancies, including discrepancies in the label, as well as the quality and health literacy level of the information between different sources will be made for at least 10 drugs in at least 3 different countries. The selection of drugs will be made by WP5 participants and stakeholder feedback (see 5.1.1) Sub-task 5.1.3: End-Users’ experiences Objective: To collect information on end users’ experience with the currently available information about the safety of drug use during pregnancy and lactation and to assess what their preferences would be in receiving such information in the future, both regarding content of the information and how it is delivered/made accessible to them. Methods: A survey and/or focus group discussions (in collaboration with stakeholders through WP6), with a good geographical spread within the European countries, with at least two groups (HCPs and patients) in at least 4 countries will be carried out on the following topics: 1) information needs about drug use during pregnancy and lactation and the risks of untreated disease; 2) preferences for receiving this information; 3) perception on the importance of this information 4) channels do they use to access this information; 5) if there is information accessible, how understandable and useful it is; 6) if they use multiple information sources, how do they interpret conflicting information; and 7) socio-demographic, lifestyle, health literacy and health factors related to understanding and perception of this information.

Sampling, storage and handling standards, consent procedures and templates

Task 4.1: Setting up standards, facilities and operating procedures for collection and storage of breast milk and blood/plasma samples (M1-M12) (UPPS, BBMRI, NVS, UCB, Pfizer) A protocol template will be developed that specifies minimum quality requirements for sampling of human breast milk, including maturity of breast milk (established milk supply vs immature milk or very mature milk); volume and timing of sample collection (e.g., relative to start of feeding event and dosing), how samples are to be stored, handled, and shipped up to delivery to the biobank. The standard template will consider measures to reduce patient burden and will be optimised with input from patients, clinicians and regulators, in collaboration with WP6 for stakeholder engagement. For each specific drug, a sampling protocol will be developed including sample type, time for drug administration, type of collection, tube, labelling, centrifugation, information management etc. Instructions for transportation of frozen samples will be set up. Protocols will be tested and implemented for one site/one study at the time in close collaboration with task 4.6. At Uppsala Biobank the samples will be received, checked and registered in the biobank LIMS and stored in low-temperature freezers. The biobank has already established facilities set up for freezers with proper alarm systems and back-up freezers and processes for managing any failures. A process for withdrawals of samples for the needs of the project for analysis at the analytical centre is available at Uppsala Biobank. The process will be adjusted to further suit the project needs and managing the biobank.

Prototype of FAIR data catalogue -2nd

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 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

Report on the core data elements and analytical standards for informing HCP and patients on risks associated with exposure during pregnancy and lactation as agreed during stakeholder consultation meeting

Task 1.2: Define core data elements to allow assessment of medication utilisation and safety in pregnancy to meet regulatory requirements and standards for inclusion in product label. (M1-M12) (CHUT, GSK, ULST, SGUL, UMAN, UOSLO, Novo Nordisk, JAN, Merck, Pfizer, Lilly, NVS, EMA). This task is aimed at reaching agreement with all stakeholders including but not limited to academic, industry, clinical experts, EMA (and other regulators) on • what the core (and additional) maternal, perinatal and childhood outcome data elements are, e.g. major congenital anomalies, foetal deaths, small for gestational age, long term outcomes; • the required number of exposed pregnancies to be tested (pending medication utilisation in pregnant women); • the required analytical methods and including hypotheses to be tested, e.g. doubling risk for outcome x as compared to disease comparator; • appropriate design (e.g. comparator) that would satisfy regulatory requirements (expedited reporting; PSUR; PASS) and • quality standards for inclusion in SmPC/product label to adequately inform HCPs and patients. In collaboration with WP2, WP6 and WP7, multi-stakeholder consultation meetings will be prepared. In advance of the multi-stakeholder meetings, Novo Nordisk will lead the collection of publicly available information on these elements from literature, regulator guidance documents and product labels. Merck and CHUT will write a briefing document and GSK and CHUT will lead the discussion for WP1 during the consultation meeting. JAN and CHUT will write a report summarizing the outcome of the consultation meeting. The agreed data elements and methods will be revisited as part of Task 1.6 in the light of demonstration project results.

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.

Annual reports on external communication results for impact assessment-2

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 existing common data models and proposals for ConcePTION

Task 7.5: Create and operate a platform and common data models for sharing data and remote access (M1-M60) (UMCU, ARS, BBMRI, GSK, JAN, Elevate). A state-of-the-art digital research environment with ISO certified and GDPR proof services for remote collaborations will be subcontracted and operated. Access to the application server will be only allowed using two-factor authentication. The environment will be able to host multiple research projects, each with its own secured area to share data and results and provide access through remote desk tops clients. The infrastructure will offer several analytical tools (e.g. R, SQL database, Shiny, Stata) word processing software, and utilities. To streamline and conduct the data characterisation and distributed data analytics for the different WPs (1 & 2) that want to use the platform for distributed analytics, an operations team will be installed that will coordinate the various tasks This will involve the negotiations for data access and access rules, distribution of instructions and scripts, as well as facilitating the transfer of results to the DRE. For management, documentation and tracking of the different tasks we will operate TASKA which was developed in the IMI-EMIF project. Standard operating procedures & training webinars for DAPs will be developed, whenever necessary. Common data models for data characterisation and demonstration studies will be defined together with WP1 and 2 and based on existing CDMs (EUROlinkCAT, EU-ADR, OMOP, EMIF Use Cases, SENTINEL, PCORnet, LifeCycle) as a starting point, and standard procedures will be developed that run against the chosen CDMs. We envision that different CDMs will be chosen at different steps of the data flow. First, a set of common input files (D2), which will encompass approximately 4 tables (see Figure 3.1b, Part B): for instance, the identifiers of mothers and children with birthdate will be stored (in Population), each event of delivery with be stored (in Events), gestational age with the same date will be stored (in Measurement). Second, datasets of study-specific variables (D3 in the figure): for instance, LMP will be stored as a derived variable from the event of delivery and the gestational age. Third, datasets specific to the study design (D4 in the figure): for instance, if the study design is a case-control, D4 will encompass the dataset of case-sets. Even though we will aim to create syntactically stable CDMs, the content stored in the CDMs, and the values allowed for the different columns, will be data source- and project-specific: for instance, if in a data source Last Menstrual Date is directly recorded this will be stored and used along with the derived LMP. However, the data transformation procedures will be programmed centrally, as far as possible. All the datasets will remain stored within the premises of the DAPs up to D3. D4 will be shared within the study team using the secure remote environment. In case one or more of the study designs of the demonstration projects require that D4 contains information that the DAPs are not allowed to share, the distributed implementation of the statistical analysis (t4) will be developed. For instance, if estimation of a propensity score is needed, a distributed estimation of regression will be implemented, following similar experience in Sentinel To support the semantic and syntactic harmonisation, available tools will be leveraged, which include UMLS OHDSI ontologies and tools, the IDMP standards and Article 57 database, ADVANCE Codemapper and VaccO. DAPs will be trained with e-learning materials to use these tools. Since we are prepared to work both with data sources that have already been mapped to the OMOP structure, as well as data sources which are in the original format, different processes will be supported to map the local data to the common input files, according to whether the local data is in OMOP or not. In particular, if the local data is in OMOP, data so

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 with procedures for evidence retrieval and synthesis for the knowledge bank

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 between the members in a network, timely, uniform and high-quality information will be available to all European countries. Objective: The aim of this task is to develop an EU centralised digital knowledge bank for up to date information of drug use before and during pregnancy and breastfeeding and the risks of untreated disease (in English) for a selection of diseases and drugs that are common in pregnancy by combining information from different sources and providing common knowledge. The knowledge bank will start with information on drugs mostly used by women 15-45 years; drugs on which most often advise has been asked for. After the start the repository can be expanded and continuously be updated. General system requirements: The information in the digital knowledge database will be publicly available. The content of the database will be available (in English) through a website and interfaces will be built so that national translations will be accessible to share with 3rd parties such as other apps and websites in the country. A prerequisite for the digital knowledge databank is that all stakeholders have confidence in the quality and reliability of the information. ENTIS will be responsible for quality control. A peer reviewed system and protocol for screening and interpretation scientific research will be developed to add or change information into the knowledge bank to ensure reliability and that the information is up to date. This task is further sub-divided into the following sub-tasks: Sub-task 5.2.1: Agree upon the functionality of the database Aim: To define the functionalities of the database. This includes; but is not limited to indexing of information, searching information, presenting information and presenting references for the information given. Method: Designing meeting with contributors and partners developing the tool will be organised to agree on the functionality of the database. Stakeholder feedback will be organised in collaboration with WP6. Sub-task 5.2.2: Build a knowledge management database Aim: To build the knowledge bank Method: the knowledge bank will be built by ORCION in an agile way with the possibility to change things if deemed necessary, so that the final product will fit the needs of the end-users. To ensure usability the knowledge bank will be tested in cycles by WP5 members and stakeholders, to make sure that it fits with their needs. Sub-task 5.2.3: Interconnectivity Rationale: Making Translation of information possible to local language /national adaptations of the content is important. In local settings, it is possible that the safety information will need to be accessed at other points in the healthcare system than the central EU webpage, for example in apps or as part of other websites. A system to ensure the quality and reliability of the translation will be developed. Aim: to build Application programming interfaces (API) to allow for interconnectivity with local websites an

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.

Minutes of annual general assembly meetings 1

Task 8.4: Planning and hosting of project & stakeholder meetings (M1- M60) (UMCU, NVS, UCB) In collaboration with WP6 for content of stakeholder meetings: Planning, organising, executing and post- processing of major project meetings such as the annual meetings, work group meetings, weekly coordination team meetings and monthly steering committee meetings monthly, as well as meetings with other IMI consortia and other adjacent projects

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

Minutes of annual general assembly meetings 2

Task 8.4: Planning and hosting of project & stakeholder meetings (M1- M60) (UMCU, NVS, UCB) In collaboration with WP6 for content of stakeholder meetings: Planning, organising, executing and post- processing of major project meetings such as the annual meetings, work group meetings, weekly coordination team meetings and monthly steering committee meetings monthly, as well as meetings with other IMI consortia and other adjacent projects

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.

Description of the operational platform for data sharing and task management plus instructions

Task 7.5: Create and operate a platform and common data models for sharing data and remote access (M1-M60) (UMCU, ARS, BBMRI, GSK, JAN, Elevate). A state-of-the-art digital research environment with ISO certified and GDPR proof services for remote collaborations will be subcontracted and operated. Access to the application server will be only allowed using two-factor authentication. The environment will be able to host multiple research projects, each with its own secured area to share data and results and provide access through remote desk tops clients. The infrastructure will offer several analytical tools (e.g. R, SQL database, Shiny, Stata) word processing software, and utilities. To streamline and conduct the data characterisation and distributed data analytics for the different WPs (1 & 2) that want to use the platform for distributed analytics, an operations team will be installed that will coordinate the various tasks This will involve the negotiations for data access and access rules, distribution of instructions and scripts, as well as facilitating the transfer of results to the DRE. For management, documentation and tracking of the different tasks we will operate TASKA which was developed in the IMI-EMIF project. Standard operating procedures & training webinars for DAPs will be developed, whenever necessary. Common data models for data characterisation and demonstration studies will be defined together with WP1 and 2 and based on existing CDMs (EUROlinkCAT, EU-ADR, OMOP, EMIF Use Cases, SENTINEL, PCORnet, LifeCycle) as a starting point, and standard procedures will be developed that run against the chosen CDMs. We envision that different CDMs will be chosen at different steps of the data flow. First, a set of common input files (D2), which will encompass approximately 4 tables (see Figure 3.1b, Part B): for instance, the identifiers of mothers and children with birthdate will be stored (in Population), each event of delivery with be stored (in Events), gestational age with the same date will be stored (in Measurement). Second, datasets of study-specific variables (D3 in the figure): for instance, LMP will be stored as a derived variable from the event of delivery and the gestational age. Third, datasets specific to the study design (D4 in the figure): for instance, if the study design is a case-control, D4 will encompass the dataset of case-sets. Even though we will aim to create syntactically stable CDMs, the content stored in the CDMs, and the values allowed for the different columns, will be data source- and project-specific: for instance, if in a data source Last Menstrual Date is directly recorded this will be stored and used along with the derived LMP. However, the data transformation procedures will be programmed centrally, as far as possible. All the datasets will remain stored within the premises of the DAPs up to D3. D4 will be shared within the study team using the secure remote environment. In case one or more of the study designs of the demonstration projects require that D4 contains information that the DAPs are not allowed to share, the distributed implementation of the statistical analysis (t4) will be developed. For instance, if estimation of a propensity score is needed, a distributed estimation of regression will be implemented, following similar experience in Sentinel To support the semantic and syntactic harmonisation, available tools will be leveraged, which include UMLS OHDSI ontologies and tools, the IDMP standards and Article 57 database, ADVANCE Codemapper and VaccO. DAPs will be trained with e-learning materials to use these tools. Since we are prepared to work both with data sources that have already been mapped to the OMOP structure, as well as data sources which are in the original format, different processes will be supported to map the local data to the common input files, according to whether the local data is in OMOP or not. In particular, if the local data is in OMOP, data so

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

Reports from Advisory Board and Ethic Report 1

Task 8.6: Implementation of the External Advisory Boards (M1-M60) (UMCU, NVS, UCB) In this task we will manage and prepare all necessary activities for an external advisory board, including Scientific, and Ethical KOLs in collaboration with WP5 and 6. As part of this task, the project management and coordination team will arrange and deal with all technical aspects of scheduling/organising meetings requested and the logistics of those meetings.

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

Report describing communication plan and governance

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.

Description of basic quality management structure for biobanking and pre-analytical handling of human breastmilk specimens

Task 4.4: Developing standard documents for pre-examination processes for breast milk handling and biobanking activities (M1-M60) (BBMRI, UPPS, CHUT, UOSL, Pfizer, CHUV). 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 addressed to optimize SOPs to optimal sample quality for subsequent analytical methods. The open structure of the standardization process allows transparency to all involved or interested parties. Building and hosting a BBMRI Technical committee will allow all partners to join guided standardization activities with the aim to develop standardized documents. Regular committee meetings will be initiated and hosted and will take place via web-conferences and/or f2f project meetings. Based upon project partners outcomes, standardization activities will be carried out jointly with the partners within the BBMRI Technical committee, aiming to result in the contribution to, and the preparation of, one or more standard document(s), with the focus on the standardization of the pre-analytical and analytical management of breast milk, based on collection, processing steps, processing times, storage temperature, freeze-thaw-cycles and analytical method for defined intended use. The transformation of research findings into application/product ideas transferred to the market afterwards is also assisted by such standardization activities, as they support the dissemination and implementation of innovative knowledge. With the aim to spread the awareness concerning standardization activities of the project, information about standards and standardization will be provided, e.g. via presentations at conferences and workshops, contribution to journals and scientific publications. The results may also be published in guidelines for the handling of human breast milk. Standardization activities will be provided on the website of Uppsala Biobank.

Report describing toolbox of methodologies and approaches for WPs to engage stakeholders regarding new evidence on the use of medicines in pregnancy and lactation

Task 6.3: Methodologies and tools for stakeholder engagement and consensus building (M1 – M24) (KUL, i~HD, EMA, EFGCP, Takeda, NVS, Lilly, JAN, Teva). This task will assemble a toolbox of resources (methodologies, instruments, tools, guidelines and training materials) to enable positive and successful engagement across stakeholder groups and to support patient engagement & healthcare professional and public health consensus building, for example about communicating the strength of evidence about safety, how it has been derived, the level of confidence provided by the experimental data. This activity will primarily guide the consortium on which well-established methods may be most suitable for each of the various kinds of engagement, attitude sampling and consensus building. In collaboration with WP5, this task will advise internally on the uses of individual expert interviews, focus group discussions, Delphi study methods, online surveys, webinars and training materials. The toolbox will progressively grow tools in a prioritised way from early in the project and be complete by M24.

Reports from Advisory Board and Ethic Report 2

Task 8.6: Implementation of the External Advisory Boards (M1-M60) (UMCU, NVS, UCB) In this task we will manage and prepare all necessary activities for an external advisory board, including Scientific, and Ethical KOLs in collaboration with WP5 and 6. As part of this task, the project management and coordination team will arrange and deal with all technical aspects of scheduling/organising meetings requested and the logistics of those meetings.

Report explaining the regulatory procedures, their scientific requirements, priorities and decision-making pathways regarding the use of medicines in pregnancy and lactation

Task 6.2: Promote a common understanding of regulatory authorities and their use of evidence (M1 – M18) (i~HD, KUL, EMA, MHRA, NVS, Lilly, Takeda, UCB, JAN, Teva). This task will help all consortium partners and external stakeholders to share a common understanding of the scope, roles and responsibilities of different regulatory agencies at European and national levels, how they work, their statutory powers and in particular their decision-making pathways when assessing new evidence on the use of medicines in pregnancy and lactation. A review and synthesis of regulatory publications and relevant EFPIA partner internal guidelines, supplemented by stakeholder consultations (e.g. interviews, surveys, current FDA and EMA work on patient-focused drug development) will be undertaken with the goal to ensure consortium partners, advisory board members and external stakeholders have a common understanding of the current regulatory frameworks that govern evidence assessment to understand impact of medicines used by pregnant and lactating women. This task will establish glossaries and other explanatory tools for internal and external use and shared with the public. The glossary will specify a standardised nomenclature and terminologies related to use of medicines during pregnancy and lactation that will be used consistently within the project for scientific communication. In collaboration with maternal/patient experts the glossary will include lay terms that can also be used when developing dissemination materials intended for the public.

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

Report on characterisation In vitro human/animal mammary epithelial cell culture models, including comparison between in vitro models

Task 3.2: Development of an improved in vitro model to identify parameters determining the rate and extent of blood-milk excretion (M4-M48) (KUL, NVS, UNIBO, Bionotus, Covance). The aim is to develop and characterise an improved in vitro model for drug passage from maternal blood to human breast milk. The model will be based on cultured human mammary epithelial cells11,12. In parallel, a mammary epithelial cell model corresponding to the species selected for Task 3.3 will be established. Primary cultures of mammary epithelial cells, grown as monolayers or on inserts, will be utilised to determine transfer rate data for the model drugs across mammary epithelial cells13. The literature search performed in Task 3.1 will be used to inform the development of the in vitro models. At least 10 model compounds selected in Task 3.1 will be used in a first wave of in vitro experiments. High-throughput and sensitive LC-MSMS methods will be developed and validated according to EMA/FDA guidelines and EBF recommendations. These methods will be applied for accurate and precise measurement of drugs in in vitro samples. As a secondary objective, the data obtained in Task 3.2 will be compared to data generated on existing models of trans-epithelial transport (e.g., Caco-2 / MDCK / PAMPA) to investigate whether those existing models could predict the mammary cell culture data and could be used as replacement. This would allow utilisation of a large amount of existing data from easy-to-access assays that are commonly found in discovery programs across industry.

Report with planned training programmes, learning goals, target audience, teachers

Task 5.4 Develop a training programme for continuous education for HCPs (M12-M48) (ENTIS, UOSL, UMCU, Elevate and WP leads, Sanofi) Rationale: Studies show that HCP have challenges to explain possible risks of drug use/exposure during pregnancy and lactation. Aim: To train HCPs about teratology, and long-term outcome and methods of evidence generation in Conception and how they can translate this in effective messages for women and their families. Method: With content input from WP1, 2, 3, 4, 7, this task will develop a e-learning training programme which can be used for continuous education of HCPs in English language. We will also apply for EU wide continuous medical accreditation. The focus will be on the basic principles of teratology, knowing where to find the right information and how to interpret it for a patient centred and evidence-based decision. Case discussions regarding the teratological risk assessment following an inadvertent exposure during pregnancy or approach to a pregnant patient in whom pharmacotherapy is necessary or the management of pharmacotherapy in a breastfeeding mother.

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

Test report 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.

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

Public website and social media plan

Task 8.5: Website, internal document repository and social media (M1-M60) (UU, 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. A communications manager will lead the development and operational implementation of communications strategy and plan, with the aim to launch and maintain channels (website, newsletter and Twitter), build audiences and disseminate project activities & results to the wider stakeholder community. This includes developing social media strategy, monitoring and reporting KPIs for all channels, liaison with WP leads to ensure timely communication of results, and task 5.3 to ensure communications activities are aligned in terms of project overall messaging, visual identity, and timing. A communications strategy and plan will be developed, listing project overall communication objectives, audiences, key messages, tools and tactics.

Wiki page with description of tools and GITHUB repository 1st

Task 7.8: Creation & posting of double coded scripts (M12-M48) (UMCU, ARS, USWAN) In this task we will provide a service to double code WP1 study-specific scripts in R, and to document, version and store them. Scripts will be parameterised and documented for reuse. Compatibility with the infrastructure developed by the EHDEN Project will be sought.

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Publications

Online information discrepancies regarding safety of medicine use during pregnancy and lactation: an IMI ConcePTION study

Author(s): Ulrika Nörby, Benedikte Noël-Cuppers, Sashka Hristoskova, Monali Desai, Linda Härmark, Michael Steel, Chantal El-Haddad, Ludivine Douarin
Published in: Expert Opinion on Drug Safety, 2021, Page(s) 1-8, ISSN 1474-0338
Publisher: Ashley Publications Ltd.
DOI: 10.1080/14740338.2021.1935865

A systematic review and meta-analyses on the prevalence of pregnancy outcomes in migraine treated patients: a contribution from the IMI2 ConcePTION project

Author(s): Daniel C. Dudman, Fatima Tauqeer, Moninder Kaur, Mary E. Ritchey, Hu Li, Sandra Lopez-Leon
Published in: Journal of Neurology, 2021, ISSN 0340-5354
Publisher: Dr. Dietrich Steinkopff Verlag
DOI: 10.1007/s00415-021-10534-5

A systematic review and meta-analyses of pregnancy and fetal outcomes in women with multiple sclerosis: a contribution from the IMI2 ConcePTION project

Author(s): Sandra Lopez-Leon, Yvonne Geissbühler, Meritxell Sabidó, Moise Turkson, Charlotte Wahlich, Joan K. Morris
Published in: Journal of Neurology, 2020, ISSN 0340-5354
Publisher: Dr. Dietrich Steinkopff Verlag
DOI: 10.1007/s00415-020-09913-1

A comprehensive review on non-clinical methods to study transfer of medication into breast milk – A contribution from the ConcePTION project

Author(s): Nina Nauwelaerts, Neel Deferm, Anne Smits, Chiara Bernardini, Bart Lammens, Peggy Gandia, Alice Panchaud, Hedvig Nordeng, Maria Laura Bacci, Monica Forni, Domenico Ventrella, Kristel Van Calsteren, Anthony DeLise, Isabelle Huys, Michele Bouisset-Leonard, Karel Allegaert, Pieter Annaert
Published in: Biomedicine & Pharmacotherapy, 136, 2021, Page(s) 111038, ISSN 0753-3322
Publisher: Elsevier Masson
DOI: 10.1016/j.biopha.2020.111038

Animal Models for In Vivo Lactation Studies: Anatomy, Physiology and Milk Compositions in the Most Used Non-Clinical Species: A Contribution from the ConcePTION Project

Author(s): Domenico Ventrella, Nurit Ashkenazi, Alberto Elmi, Karel Allegaert, Camilla Aniballi, Anthony DeLise, Patrick John Devine, Anne Smits, Lilach Steiner, Monica Forni, Michele Bouisset-Leonard, Maria Laura Bacci
Published in: Animals, 11/3, 2021, Page(s) 714, ISSN 2076-2615
Publisher: MDPI
DOI: 10.3390/ani11030714