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

Livrables

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.

Report with publications on results of component algorithms

Task 7.7 Quantification of the impact of choosing different algorithms (M9-M60) (ARS, UMCU, GSK, JAN, Sanofi, CNR-IFC, FISABIO, UOSL, ULST, CHUT, UMCG, LAREB in collaboration with the Outcomes Validation Task Force (WP1, 2) and third parties who will provide expertise and/or data). This task will document and quantify the impact of using different algorithms to extract data in health care databases. Moreover, the strategy will ensure support for sensitivity analyses aimed at addressing assumptions on data semantics. Finally, the strategy will aim to ensure compatibility with the OHDSI tools adopted by the EHDEN initiative, to facilitate data sources which are mapped to the OMOP CDMSome examples of data transformation that we envision follow: •Last Menstrual Period (LMP)/ Gestational age/ Gestational age: We will document how the time of start and end of pregnancy can be derived for each pregnancy in each data source and allow for sensitivity analyses (for instance, restricting to women whose LMP is directly recorded).•Drugs: Transforming drug prescriptions or dispensings in time-stamped episodes of treatment requires harmonisation or derivation from existing data, which is currently missing. We will develop standard algorithms using available information and standard sets of assumptions (for instance, that each study subject assumes the drug according to the recorded prescribed dose, or assumes one DDD per day, or assumes one tablet per day, or assumes the dispensed drug uniformly between dispensings) so that dose- and duration- specific analyses may be possible. In particular, standard sets of assumptions will be developed addressing timing of exposure relative to Last Menstrual Period. •Breastfeeding: different case identification algorithms will be tested to identify breastfeeding in different data sources. This will be validated where possible in collaboration with the outcomes taskforce of WP1/2/7. •Maternal child linkage: To study the effects of drugs during pregnancy and lactation on the child, it is essential to link maternal health records with the child. Based on a literature overview and the work from EU-Peristat we will further identify and test methods for both deterministic and probabilistic linkage of mothers and children in each of the DAPs, and cross-validate linkage whenever possible.The process of documenting and testing the study variables will follow the ‘component analysis’ workflow. We will test different case-finding-algorithms for WP1/2 maternal, neonatal and long-term paediatric outcomes, as well as for other key variables (see examples above). The outcomes taskforce of WP1/2/7 will validate the main variables whenever possible using a gold standard. Statistical techniques for outcome validation & misclassification ascertainment will be further explored, including (Bayesian) Latent Class modelling, imputation-based techniques like regression calibration, multiple imputation of measurement error and the simulation extrapolation technique). Component analysis using data from different sources will be used to evaluate impact of different algorithms on population-based incidence rates of events and to produce estimates of validity. Such ‘novel’ validation techniques will be compared with ‘classic’ validation studies in the demonstration projects that will be conducted in WP1. We will also apply existing methods to use the results of validation to correct the EHR-based disease risk estimates for misclassification.

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

Minutes of annual general assembly meetings 3

Task 84 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

Report on stakeholder meeting describing the model for a 21st century pregnancy data collection and signal detection system which should be able to replace traditional pregnancy registries

Task 21 Information and process needs barriers and requirements M136 UKZN NUTH LAREB UMAN UOSL MHRA ENTIS NVS GSK Sanofi AbbVieIn this task we will prepare in collaboration with WP1 content for a stakeholder workshop to establisha What are the information requirements and how do they differ by various stakeholders to enable informed decisions about prescribing dispensing regulating and using drugs in pregnancy and lactationb The requirements to instil Healthcare provider HCP and public confidence that reporting of medication exposed pregnancies is through a trusted secure and confidential system which supports patientprescriber clinical risk benefit assessment as well as regulatory guidance where use of a medicinal product has occurred or is being considered in pregnancy c The barriers that will need to be overcome to implement a harmonised pregnancy pharmacovigilance system for both public and private organisations that will be supported and accepted by various stakeholders d A proposal as to how existing capacity infrastructure and expertise could be better leveraged The output of this workshop will be an agreed model for a 21st century system for early pregnancy safety data collection analysis as an alternative to traditional pregnancy registries Components of this system will be further developed and trialled in demonstration projects within task 25 and based on the findings from these tasks a framework for the operation of a future endtoend PV system established in 26

In vivo data on lactation transfer in one or more animal species

Task 33 In vivo experiments in lactating nonclinical species likely Gttingen minipig andor pig farm breed M4M48 UNIBO Ellegaard Bionotus Covance Lilly NVS Teva The aim is to develop and characterise an improved in vivo model for drug passage from maternal blood to human breast milk The primary criterion when choosing a preclinical animal model must be its translational value which is dependent on its analogies with the human species The literature search performed in Task 31 will be used to inform andor confirm the selection of the appropriate species Currently the use of rodent species leads to the common view that animal data are generally not useful in predicting drug concentrations in human milk 14 However a porcine species may represent a more suitable model with better anatomical and physiological thus metabolic similarities15 These in vivo studies will use innovative designs considering the possibility for microdosing cassette dosing and blood sampling in offspring Such approaches are expected to maximise the amount of data generated in the animal model consistent with the 3R principle Compound selection will be based on the criteria described in task 31 and the compounds already selected in Task 32 Sensitive LCMSMS methods will be developed and validated according to EMAFDA guidelines and EBF recommendations Bioanalytical method details will be shared with WP4 for corresponding model drugs

Annual reports on external communication results for impact assessment -3

Task 53 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 M6M60 NUTH ENTIS LAREB Synergist UPPS EIWH third parties such as EU organisation for GPs gynaecologist midwivespharmacists Pfizer Sanofi NVS AbbVie UCBRationale Based on the ethical discussions in WP7 task 73 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 postmarketing 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 pushpull 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 internationalnational regulatory organisations will implemented to inform the general population pregnant womenwomen 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 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

Minutes of annual general assembly meetings 4

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.

Reports from Advisory Board and Ethic Report 4

Task 86 Implementation of the External Advisory Boards M1M60 UMCU NVS UCBIn 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 schedulingorganising meetings requested and the logistics of those meetings

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).

Test report of FAIR data catalogue 2nd

Task 74 Creation and filling of a FAIR data source catalogues M3M36 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 finegrained access control for researchers FAIR implies access under welldefined conditions Computerreadable terms that minimally describe the data resource eg an ontology term or a bioschemaorg 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

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

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

Final study protocols for demonstration projects submitted to EU PAS register

Task 15 Execute five demonstration projects for established and newly marketed products to tackle methodologicaldata source issues where progress and innovation is needed M12M54 UOSLO JAN Lilly ULST SGUL CHUT THL USWAN UMCG CNRIFC FISABIO FERR INSERM UMAN EMA and Third Parties institutions providing data data expertise and clinical expertise Sanofi NVS Pfizer GSK Merck in collaboration with WP7See also table task 15 Part BThe demonstration projects have been chosen according to the following criteria high public health importance address known knowledge gaps together of sufficient variety including established vs new medications chronic vs acute condition rare vs common condition to innovate in their use of methodological approaches and new data sources Data sources will be selected according to a combination of costeffectiveness in terms of size of population and cost and data quality but in addition priority will be given to use of new data sourcesThe five demonstration projects will each integrate multiple aspects for each therapeutic area ie medication use in pregnancy and in women of childbearing age the impact of maternal disease on maternal perinatal and childhood outcomes and the impact of medications medication classes during pregnancy on outcomes While one therapeutic area will take the lead for each methodological innovation methods will be shared between demonstration projects Each demonstration project follows a general process of subsequent steps Step1 data characterisation M012 WP7 Step 2 protocol writing for each project and approval M1216 Step 3 obtaining data access WP7 Step 4 Data validation and assessing variation in prevalence of adverse outcomes see Task 13 with the addition of validation of exposure and confounder data M1236 Step 5 Statistical analyses starting with detailed Statistical Analysis Plans M1648 and Step 6 Study report or manuscript M4854 WP1 and WP7 will collaborate in the implementation of these demonstration projects according to a detailed process map Appendix after Section 5 to align and optimise the various tasksThe WP1 demonstration project teams will be made up of partners and third parties with substantive methodological and data source expertise and will appoint clinical advisors to advise on treatment practice in Europe Partners will be given the lead on various crosscutting methodological areas eg other than the demo project methodological leads already mentioned UMCG will take the lead for medication utilisation protocols USWAN will take the lead for integration of breastfeeding data when assessing confounding for long term outcomes CNRIFC will take the lead for validating nonprescription exposure data by linkage to prescriptions A joint statistical method working group will be set up including representation of SGUL GSK JAN Pfizer and WP7 UMCU ARS The demonstration projects will follow the ENCEPP Code of Conduct for Scientific Independence and Transparency A list of possible conflicts of interest for PP and EFPIA will be agreed before study teams for demonstration projects are finalised

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

Reports from Advisory Board and Ethic Report 3

Generic PBPK template for predicting drug concentration time profiles in human breast milk

Task 34 Development of a robust PBPK framework to predict drug concentration profiles in human breast milk M13M37 KUL GSK BioNotus UNIBO CHUT NVS Teva CHUVDrugspecific clearance values for excretion into milk will be generated with the in vitro and in vivo models developed in Tasks 32 and 33 along with previously generated in vitroin vivo data111216 and eventually coming from EFPIA partners will be used to feed drugspecific PBPK models Based on these models a generic PBPK template will be developed that encompasses milk excretion of drugs The PBPK models will be developed in an industrysupported platform eg Simcyp from Certara while the utility and added value of alternative platforms will be explored Using the results of a second set of in vitro experiments see Task 32 as input data the predictive performance of the developed PBPK modelling strategy will be thoroughly evaluated This will be achieved by comparing PBPKbased predictions with clinical observations In case adequate in vivo data are available eg regarding systemic maternal exposure for existing drugs a retrograde approach will be used Possible covariates identified with population PK approaches in WP4 will be used to further improve the developed PBPK models

Annual reports on external communication results for impact assessment -1

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

Report with core data elements to collect long term outcomes

Task 23 Core data elements required for the prospective collection and followup of exposed pregnancies M136 UMAN NUTH UOSL LAREB UKZN ENTIS NVS Novo Nordisk Sanofi Teva BMS and WP7 partners This task has two key components1Describe and evaluate existing coding systems schemes and regulatory guidelines of reported medication exposed pregnancies M112 Building on existing EMA and FDA regulatory guidance documents such as ICH E2B R3 format for safety data exchange ICH M1 MedDRA international terminology IDMPSPOR 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 outcomes task force operational across WP1 2 and 7 to standardise and define data collection for assessment of key outcomes maternal foetal perinatal paediatric and stakeholder determined longer term outcomes to include eg neurodevelopment 2Define core data elements for assessment of acute and longterm outcomes eg neurodevelopment immunological cancer and potentially others M136 The recent valproate review and EMA scientific meeting on long term outcomes following pregnancy exposure have underscored the need to develop methods to assess risk of long term outcomes resulting from direct or indirect effects on reproduction Data elements considered necessary to study both acute and longterm outcomes will be established through literature review experience from recent global initiatives eg OTISVAMPSS an Expert Consultation Meeting and the crossWP outcomes task force WP1 2 7 The generated data elements will be tested and validated in demonstration projects see below and go through qualification advice by EMA Recommendations will be developed a for the standardisation of approaches to the collection of neurodevelopmental oncological and immunological data and b for the analysis of neurodevelopmental immunological and oncological outcomes in prospective data collection and in retrospective reports

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

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

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.

Annual reports on external communication results for impact assessment-4

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

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.

Report on data access models and rules

Task 71 Defining the rules and collaboration models for data reuse M1M12 UMCU SGUL KI iHD EIWH GSKThis task will inquire from relevant data sources identified by WP1 and 2 the access rules in terms of data sharing policies privacy and ethics and governance rules as well as possibilities to speed this up public health access vs research access In addition we will inquire about recognition rules Both monetary and nonmonetary recognition examples will be collected and compiled into a set of reward models that will be offered during the project Data will be collected by interview Based on collected data we will convene a focus group with different types and geographies of data access providers to further define the access and reward models A readable summary of these rules will be added to each data source in the ConcePTION FAIR data catalogue Task 73

Report on the methods and results of the communication campaign to stimulate reporting and participation in studies/registries and publication of analysis of communication methods

Task 54 Develop a training programme for continuous education for HCPs M12M48 ENTIS UOSL UMCU Elevate and WP leads SanofiRationale Studies show that HCP have challenges to explain possible risks of drug useexposure during pregnancy and lactation Aim To train HCPs about teratology and longterm 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 elearning 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 evidencebased 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

Landscape analysis & costs analysis

Task 87 Sustainability plan and roadshow M1M60 TTOP UMCU SYNERGIST EIWH A detailed sustainability plan will be created including a business plan where the exact plans for the Conception ecosystem and how this will be continued after the end of the project will be detailed Dedicated sustainability plans will be developed for the community WP6 the tools and infrastructure biobank WP4 the drug information databank WP5 the data source catalogue WP7 and the evidence generation workflows and templates In order to be able to develop the business plan we will make a baseline assessment of the current costs pregnancy registries to comply with regulatory standards The consortium will employ the following proven phased approach to implement a successful sustainability strategy 1 Mapping an environmental assessment will be made including identification and refinement of the needs of endusers inventory of possible strategic partners assessment of organisational needs and investigation of best practices amongst comparable initiatives 2 brainstorming and business case development 3 validating Together with a selection of key stakeholders and possible funderspayers the business cases will be validated including costeffectiveness modelling 4 planning Positive business cases will be further detailed in a sustainabilitybusiness plan 5 roadshow Key project representatives policy experts will make a roadshow and meet with key fundersdecision makerspayers to realise seed funding initial revenue The success of a sustainable ecosystem will critically depend upon the multistakeholder alignment and support we establish especially via WP6 in financing contributing data and new evidence and in valuing and using this evidence to improve the confident and safe treatment of women We will also leverage partner expertise in establishing and sustaining new not for profit ecosystems and in delivering scalable and interoperable data and information infrastructures for example to sustain the knowledge bank More details provided in section 2

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

Report on E-learning training programme and accreditation plus sustainability plan

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

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.

Final Report on ethical issues

Task 73 Ethical issues M124 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 issues1How 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 continuously be studied to improve the evidence base Currently pregnant and breastfeeding women are typically excluded from research for reasons of risks to the foetuschild and potential liability At the same time the practice of prescription of offlabel medication exposes pregnant and breastfeeding women and their children to risks without learning for future patients2Is there a moral duty around continuous learning in healthcare for pregnant and breastfeeding women and the healthcare professionals involved in their care If so how could such a moral duty be implemented in practice If care and research become integrated in drug use in pregnancy and breastfeeding it will be virtually impossible to escape from this learning environment Ethical evaluation of a moral duty to participate in such a system is essential when regular care becomes inherently intertwined with learning components and3What are the features of a responsible and sustainable LHS for pregnant and breastfeeding women A radical turn to continuous learning from routinely collected data in the field of pregnancy and breastfeeding also requires as set of ethical criteria to render this learning environment responsible and sustainable At least ethical criteria of review informed consent fair inclusion and benefitsharing need rethinking in light of an LHS in this field To address these questions we will take an approach in which the stakeholders perspectives as well as ethical theory on principles such as responsibility solidarity equity and fairness will be translated to the context of the project We will use the method of Reflective Equilibrium Originally the Reflective Equilibrium has its roots in the ideas of the political philosopher John Rawls We will use a version of this method that has been developed by members of the project team and the Department of Medical Humanities of the Julius Centre Van Delden and Van Thiel the normative empirical reflective equilibrium It has proven to be successful in giving guidance to ethical thinking in practical contexts The aim of the Reflective Equilibrium is to produce coherence between empirical conceptual and normative data The empirical and conceptual elements will be brought into Reflective Equilibrium in order to be able to develop a framework for fair inclusion of pregnant women in a Learning Healthcare System To answer the empirical part of the questions we will conduct systematic literature studies and conduct qualitative research structured interviews with relevant stakeholders Maximum variation in context experience and views are essential in order to reach saturation in qualitative research Therefore we will interview the following group of stakeholders which will be drawn from the hospitalcatchment area a Sick pregnant women preexisting eg depression new diseases preeclampsia b Fertile sick women who want to become pregnant c Healthy pregnant women

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.

Publications

Infant exposure to Fluvoxamine through placenta and human milk: a case series - A contribution from the ConcePTION project

Auteurs: Anaëlle Monfort, Evelina Cardoso, Chin B Eap, Céline J Fischer Fumeaux, Myriam Bickle Graz, Mathilde Morisod Harari, Etienne Weisskopf, Peggy Gandia, Karel Allegaert, Hedvig Nordeng, Jean-Michel Hascoët, Olivier Claris, Manuella Epiney, Chantal Csajka, Monia Guidi, Ema Ferreira, Alice Panchaud
Publié dans: Frontiers in Psychiatry, Numéro 14, 2023, ISSN 1664-0640
Éditeur: Frontiers Research Foundation
DOI: 10.3389/fpsyt.2023.1167870

From Inception to ConcePTION: Genesis of a Network to Support Better Monitoring and Communication of Medication Safety During Pregnancy and Breastfeeding

Auteurs: Nicolas H. Thurin,Romin Pajouheshnia,Giuseppe Roberto,Caitlin Dodd,Giulia Hyeraci,Claudia Bartolini,Olga Paoletti,Hedvig Nordeng,Helle Wallach-Kildemoes,Vera Ehrenstein,Elena Dudukina,Thomas MacDonald,Giorgia De Paoli,Maria Loane,Christine Damase-Michel,Anna-Belle Beau,Cécile Droz-Perroteau,Régis Lassalle,Jorieke Bergman,Karin Swart,Tania Schink,Clara Cavero-Carbonell,Laia Barrachina-Bonet,Ainho
Publié dans: Clinical Pharmacology & Therapeutics, 2021, ISSN 0000-0000
Éditeur: Wiley
DOI: 10.1002/cpt.2476

Where are the data linking infant outcomes, breastfeeding and medicine exposure? A systematic scoping review

Auteurs: Jordan S, Komninou S, Lopez Leon S
Publié dans: PLOS ONE, 2023, ISSN 1932-6203
Éditeur: Public Library of Science
DOI: 10.1371/journal.pone.0284128

Families need support to reduce the risk of adverse drug reactions from breastfeeding

Auteurs: Sue Jordan, Emyr Jones, Sophia Komninou, Maria Loane, Christine Damase-Michel
Publié dans: The Pharmaceutical Journal, 2022, ISSN 0031-6873
Éditeur: Pharmaceutical Society of Great Britain

Maternal drugs and breastfeeding: risk assessment from pharmacokinetics to safety evidence - A contribution from the ConcePTION project

Auteurs: Evelina Cardoso, Anaëlle Monfort, Ema Ferreira, Hedvig Nordeng, Ursula Winterfeld, Karel Allegaert, Peggy Gandia, Monia Guidi, Alice Panchaud
Publié dans: Therapie, Numéro 78(2), 2023, Page(s) 149-156, ISSN 0040-5957
Éditeur: John Libbey & Co. Ltd.
DOI: 10.1016/j.therap.2023.01.008

Drug Utilization Studies in Pregnant Women for Newly Licensed Medicinal Products: A Contribution from IMI ConcePTION

Auteurs: Sandra Lopez Leon, Anja Geldhof, Julie Scotto, Keele Wurst, Meritxell Sabidó, Jingping Mo, Ditte Molgaard-Nielsen, Jorieke EH Bergman, Xuan Anh Phi, Sue Jordan
Publié dans: Journal of Pregnancy, 2024, Page(s) 1-13, ISSN 2090-2727
Éditeur: Hindawi Publishing Corporation
DOI: 10.1155/2024/8862801

Transfer of cetirizine/levocetirizine into human breast milk and estimation of drug exposure to infants through breastfeeding: A human lactation study from the ConcePTION project

Auteurs: Hedvig Nordeng; Christine Wegler; Annika Lindqvist Erik Melander, Mikaela Magnusson, Peggy Gandia, Alice Panchaud, Pawel Baranczewski and Olav Spigset
Publié dans: Basic & clinical pharmacology & toxicology, Numéro 134(1), 2023, Page(s) 153-164, ISSN 1742-7843
Éditeur: Wiley-Blackwell
DOI: 10.1111/bcpt.13948

Stimulating solidarity to improve knowledge on medications used during pregnancy

Auteurs: Marieke Hollestelle, Rieke van der Graaf, Miriam Sturkenboom and Hans van Delden
Publié dans: BMC Medical Ethics, Numéro 24(1):44, 2023, ISSN 1472-6939
Éditeur: BioMed Central
DOI: 10.1186/s12910-023-00924-x

Simple and rapid quantification of cetirizine, venlafaxine, and O-desmethylvenlafaxine in human breast milk, and metformin in human milk and plasma with UHPLC-MS/MS

Auteurs: Christine Wegler, Aljona Saleh, Annika Lindqvist, Hedvig Nordeng, John Smeraglia, Pawel Baranczewski
Publié dans: Journal of Chromatography B, 2022, ISSN 0000-0000
Éditeur: Elsevier B.V
DOI: 10.1016/j.jchromb.2022.123340

Improving data collection in pregnancy safety studies: Towards standardisation of data elements in pregnancy reports from public and private partners, a contribution from the ConcePTION project

Auteurs: Favre G., Richardson J.L., Moore A., Geissbühler Y., Jehl V., Oliver A., Shechtman S., Diav-Citrin O., Berlin M., De Haan T., Baud D, Panchaud A, Mor A., Sabidó M., de Souza S., Chambers C., van Rijt-Weetink, Y.R.J., van Puijenbroek E.P., Yates L.M., Stellfeld M., Winterfeld U
Publié dans: Drug Safety, Numéro 47(3), 2023, Page(s) 227-236, ISSN 0114-5916
Éditeur: Adis International Ltd.
DOI: 10.1007/s40264-023-01384-3

Safety of medicines during breastfeeding – from case report to modeling: a contribution from the ConcePTION project

Auteurs: Evelina Cardoso, Monia Guidi, Nina Nauwelaerts, Hedvig Nordeng, Marie Teil, Karel Allegaert, Anne Smits, Peggy Gandia, Andrea Edginton, Shinya Ito, Pieter Anaert, Alice Panchaud
Publié dans: Expert Opinion on Drug Metabolism & Toxicology, 2023, Page(s) 269-283, ISSN 1742-5255
Éditeur: Ashley Publications Ltd.
DOI: 10.1080/17425255.2023.2221847

An inventory of European data sources to support pharmacoepidemiologic research on neurodevelopmental outcomes in children following medication exposure in pregnancy: A contribution from the ConcePTION project

Auteurs: Joanne Given, Rebecca L Bromley, Florence Coste, Sandra Lopez, Maria Loane
Publié dans: PLOS ONE, 2022, ISSN 1932-6203
Éditeur: Public Library of Science
DOI: 10.1371/journal.pone.0275979

Determining the exposure of maternal medicines through breastfeeding: the UmbrelLACT study protocol - A contribution from the ConcePTION project

Auteurs: Martje Van Neste, Nina Nauwelaerts, Michael Ceulemans, Kristel Van Calsteren, An Eerdekens, Pieter Annaert, Karel Allegaert, Anne Smits
Publié dans: BMJ Paediatrics Open, Numéro 8(1), 2024, Page(s) e002385, ISSN 2399-9772
Éditeur: BMJ Publishing Group
DOI: 10.1136/bmjpo-2023-002385

Case Report: Bosentan and Sildenafil Exposure in Human Milk - A Contribution From the ConcePTION Project

Auteurs: Nina Nauwelaerts, Michael Ceulemans, Neel Deferm, An Eerdekens, Bart Lammens, Yeghig Armoudjian, Kristel Van Calsteren, Karel Allegaert, Loes de Vries, Pieter Annaert and Anne Smits
Publié dans: Frontiers in Pharmacology, 2022, ISSN 0000-0000
Éditeur: Frontiers
DOI: 10.3389/fphar.2022.881084

An ethics framework for the transition to an operational learning healthcare system

Auteurs: Marieke J Hollestelle, Rieke van der Graaf, Miriam CJM Sturkenboom, Johannes JM van Delden
Publié dans: Learning Health Systems, 2024, ISSN 2379-6146
Éditeur: Wiley Periodicals LLC
DOI: 10.1002/lrh2.10414

Breastfeeding, pregnancy, medicines, neurodevelopment, and population databases: the information desert.

Auteurs: Sue Jordan, Rebecca Bromley, Christine Damase‐Michel, Joanne Given, Sophia Komninou, Maria Loane, Naomi Marfell, Helen Dolk.
Publié dans: International Breastfeeding Journal, Numéro 17, 2022, Page(s) 55, ISSN 1746-4358
Éditeur: BioMed Central
DOI: 10.1186/s13006-022-00494-5

Building a Sustainable Learning Health Care System for Pregnant and Lactating People: Interview Study Among Data Access Providers

Auteurs: Marieke J Hollestelle; Rieke van der Graaf; Miriam C J M Sturkenboom; Marianne Cunnington; Johannes J M van Delden
Publié dans: JMIR Pediatrics and Parenting, Numéro 7, 2024, Page(s) e47092, ISSN 2561-6722
Éditeur: JMIR Publications Inc
DOI: 10.2196/47092

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

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

Isolation and characterization of mammary epithelial cells derived from Göttingen Minipigs: A comparative study versus hybrid pig cells from the IMI-ConcePTION Project

Auteurs: Chiara Bernardini, Salvatore Nesci, Debora La Mantia, Roberta Salaroli, Nina Nauwelaerts, Domenico Ventrella, Alberto Elmi, Fabiana Trombetti, Augusta Zannoni, and Monica Forni
Publié dans: Research in Veterinary Science, Numéro 172, 2024, Page(s) 105, 244, ISSN 0034-5288
Éditeur: W. B. Saunders Co., Ltd.
DOI: 10.1016/j.rvsc.2024.105244

Sensitive and rapid method for the quantitation of amoxicillin in minipig plasma and milk by LC-MS/MS: A contribution from the IMI ConcePTION project

Auteurs: Yeghig Armoudjian, Yeghig Armoudjian, Qi Lin, Bart Lammens, Johan Van Daele, Pieter Annaert
Publié dans: Journal of Pharmacological and Toxicological Methods, 2023, ISSN 1056-8719
Éditeur: Elsevier BV
DOI: 10.1016/j.vascn.2023.107264

A Learning Healthcare System for pregnant and breastfeeding women: what do women during preconception, pregnancy, and nursing think? – A qualitative study

Auteurs: Marieke J. Hollestelle, Rieke van der Graaf, Sarah Dewi Hartman, Miriam C. J. M. Sturkenboom & Johannes J. M. van Delden
Publié dans: BMC Pregnancy and Childbirth, 2022, ISSN 1471-2393
Éditeur: BioMed Central
DOI: 10.1186/s12884-022-04675-2

Generic Workflow to Predict Medicine Concentrations in Human Milk Using Physiologically-Based Pharmacokinetic (PBPK) Modelling—A Contribution from the ConcePTION Project

Auteurs: Nina Nauwelaerts, Julia Macente, Neel Deferm, Rodolfo Hernandes Bonan, Miao-Chan Huang, Martje Van Neste, David Bibi, Justine Badee, Frederico S. Martins, Anne Smits, Karel Allegaert, Thomas Bouillon, Pieter Annaert
Publié dans: Pharmaceutics, 2023, ISSN 1999-4923
Éditeur: Multidisciplinary Digital Publishing Institute (MDPI)
DOI: 10.3390/pharmaceutics15051469

A Landscape Analysis of Post-Marketing Studies Registered in the EU PAS Register and ClinicalTrials.gov Focusing on Pregnancy Outcomes or Breastfeeding Effects: A Contribution from the ConcePTION Project

Auteurs: Leonardo Roque Pereira, Carlos E. Durán, Deborah Layton, Georgios Poulentzas, Panagiotis-Nikolaos Lalagkas, Christos Kontogiorgis and Miriam Sturkenboom
Publié dans: Drug Safety, 2022, ISSN 0000-0000
Éditeur: Springer Nature
DOI: 10.1007/s40264-022-01154-7

Where are the data to assess the safety of paternal drug exposure? A systematic review of secondary databases: A contribution from IMI concePTION

Auteurs: Sneha Gaitonde, Yola Moride, Elizabeth Suarez, Sandra Lopez-Leon
Publié dans: Pharmacoepidemiology & Drug Safety, Numéro 33, 2024, ISSN 1099-1557
Éditeur: John Wiley & Sons Ltd
DOI: 10.1002/pds.5764

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

Auteurs: Daniel C. Dudman, Fatima Tauqeer, Moninder Kaur, Mary E. Ritchey, Hu Li, Sandra Lopez-Leon
Publié dans: Journal of Neurology, 2021, ISSN 0340-5354
Éditeur: Dr. Dietrich Steinkopff Verlag
DOI: 10.1007/s00415-021-10534-5

Auteurs: Martje Van Neste, Annick Bogaerts, Nina Nauwelaerts, Julia Macente, Anne Smits, Pieter Annaert, Karel Allegaert
Publié dans: Pharmaceutics, Numéro 15(11), 2618, 2023, ISSN 1999-4923
Éditeur: Multidisciplinary Digital Publishing Institute (MDPI)
DOI: 10.3390/pharmaceutics15112618

IMI ConcePTION core data elements for pregnancy pharmacovigilance studies using primary source data collection methods

Auteurs: Jonathan Richardson, Alan Moore, Rebecca Bromley, Michael Stellfeld, Yvonne Geissbühler, Matthew Bluett-Duncan, Ursula Winterfeld, Guillaume Favre, Kenneth Hodson, Alison Oliver, Amalia Alexe, Yrea van Rijt-Weetink, Bita Rezaallah, Eugene van Puijenbroek, David Lewis, Laura Yates
Publié dans: Neurotoxicology and Teratology, Numéro 98, 2023, Page(s) 107, 198, ISSN 0892-0362
Éditeur: Elsevier BV
DOI: 10.1016/j.ntt.2023.107198

Development of a pig mammary epithelial cell culture model as a non‐clinical tool for studying epithelial barrier— a contribution from the imi‐conception project

Auteurs: Chiara Bernardini; Debora La Mantia; Roberta Salaroli; Augusta Zannoni; Nina Nauwelaerts; Neel Deferm; Domenico Ventrella; Maria Laura Bacci; Giuseppe Sarli; Michele Bouisset-Leonard; Pieter Annaert; Monica Forni
Publié dans: Animals, Vol 11, Iss 2012, p 2012 (2021), 2021, ISSN 2076-2615
Éditeur: -
DOI: 10.3390/ani11072012

Validation of a Novel Method to Assess the Clinical Quality of Information in pregnancy-related pharmacovigilance case reports: a ConcePTION project

Auteurs: Yrea R. J. van Rijt-Weetink, Toine C. G. Egberts, Florence P. A. M. van Hunsel, David J. Lewis, Laura M. Yates, Ursula Winterfeld, Eugène P. van Puijenbroek
Publié dans: Drug Safety, Numéro 47, 2024, Page(s) 261-270, ISSN 0114-5916
Éditeur: Adis International Ltd.
DOI: 10.1007/s40264-023-01389-y

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

Auteurs: Sandra Lopez-Leon, Yvonne Geissbühler, Meritxell Sabidó, Moise Turkson, Charlotte Wahlich, Joan K. Morris
Publié dans: Journal of Neurology, 2020, ISSN 0340-5354
Éditeur: Dr. Dietrich Steinkopff Verlag
DOI: 10.1007/s00415-020-09913-1

Neurodevelopmental outcomes in children and adults with Fetal Valproate Spectrum Disorder: a contribution from the ConcePTION project

Auteurs: Bluett-Duncan M., Astill D., Charbak R., Clayton-Smith J., Cole S., Cook P. A., Cozens J., Keely K., Morris J., Mukherjee R., Murphy E., Turnpenny P., Williams J., Wood A. G., Yates L., Bromley R. L.
Publié dans: Neurotoxicology and Teratology, Numéro 98, 2023, Page(s) 107, 201, ISSN 0892-0362
Éditeur: Elsevier BV
DOI: 10.1016/j.ntt.2023.107292

Elements to assess the quality of information of case reports in pregnancy pharmacovigilance data - a ConcePTIONproject

Auteurs: Yrea R.J. van Rijt-Weetink, Khoezik Chamani, Toine C.G. Egberts, Florence P.A.M. van Hunsel, David J. Lewis, Laura M. Yates, Ursula Winterfeld, Eugène P. van Puijenbroek
Publié dans: Frontiers in Drug Safety and Regulation, Numéro 3, 2023, ISSN 2674-0869
Éditeur: Frontiers Media S.A.
DOI: 10.3389/fdsfr.2023.1187888

Expert consensus on neurodevelopmental outcomes in pregnancy pharmacovigilance studies

Auteurs: Bromley R. L., Bickle Graz M., Bluett-Duncan M., Chambers C., Damkier P., Dietrich K., Dolk H., Grant K., Mattson S., Meador K. J., Nordeng H., Oberlander T. F., Ornoy A., Revet A., Richardson J., Rovet J., Schuler-Faccini L., Smearman E., Simms V., Vorhees C., Wide K., Wood A., Yates L., Ystrom E., Supraja T. A., Adams J.
Publié dans: Frontiers in Pharmacology, 2023, ISSN 1663-9812
Éditeur: Frontiers Media S.A.
DOI: 10.3389/fphar.2023.1094698

Core Data Elements for Pregnancy Pharmacovigilance Studies Using Primary Source Data Collection Methods: Recommendations from the IMI ConcePTION Project

Auteurs: Jonathan L. Richardson, Alan Moore, Rebecca L. Bromley, Michael Stellfeld, Yvonne Geissbühler, Matthew Bluett‑Duncan, Ursula Winterfeld, Guillaume Favre, Amalia Alexe, Alison M. Oliver, Yrea R. J. van Rijt‑Weetink, Kenneth K. Hodson, Bita Rezaallah, Eugene P. van Puijenbroek, David J. Lewis, Laura M. Yates
Publié dans: Drug Safety, 2023, ISSN 0114-5916
Éditeur: Adis International Ltd.
DOI: 10.1007/s40264-023-01291-7

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

Auteurs: 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
Publié dans: Biomedicine & Pharmacotherapy, Numéro 136, 2021, Page(s) 111038, ISSN 0753-3322
Éditeur: 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

Auteurs: 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
Publié dans: Animals, Numéro 11/3, 2021, Page(s) 714, ISSN 2076-2615
Éditeur: MDPI
DOI: 10.3390/ani11030714

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