The Work Packages
The overall objective of WP1 is to generate timely evidence about pregnancy outcomes, including perinatal and long-term effects following medication use during pregnancy, to benefit women, their babies and their families. The aim is to move beyond medication exposure pregnancy registries by continuously identifying secondary data sources*, optimising analytic methods and tools, and identifying the strengths and limitations of different approaches to generate actionable evidence on medication use and safety in pregnancy including maternal (pregnancy), perinatal and childhood outcomes.
- To identify the data sources that can be used for medication utilisation and medication safety studies in pregnancy by updating and extending the existing EUROmediSAFE inventory, focusing primarily on existing and new sources in the EU and adding available non-EU data sources;
- To define a standard core set of clinically relevant maternal, perinatal and childhood outcomes that should be consistently evaluated to adequately address regulatory requirements to inform HCPs and patients on medication use during pregnancy (e.g. via medication labels, SmPCs);
- To validate specific maternal, perinatal and childhood outcomes in data sources contributing to demonstration projects;
- To assess the variations in background incidence/prevalence of adverse maternal, perinatal and childhood outcomes in the population and data sources and associated with selected diseases;
- To conduct medication utilisation studies for newly approved medications to establish the most appropriate strategy and innovative methodologies in population databases;
- To conduct medication utilisation studies for selected medications and/or medication classes in pregnant women and women of childbearing age to test the feasibility and validity of innovative approaches, increase population coverage, and inform pregnancy outcome studies;
- To design innovative methodologies to assess the impact of selected medications (classes) used during pregnancy on maternal, perinatal and childhood outcomes and implement these in demonstration projects; and
- To develop methodological guidelines and recommendations for best practice to efficiently generate evidence on use and outcomes of medications in pregnancy based on secondary use of health data and compare this with alternative approaches used in WP2;
*secondary data sources include population healthcare databases for operational healthcare use (prescription data, primary care data, maternity data, hospital discharge data, medical birth registries etc), as well as disease registries and birth cohorts collected for research and surveillance purposes.
The main objective of WP2 is to optimise pharmacovigilance data collection on reported pregnancies and sharing of data plus analytical methodologies to more rapidly and efficiently quantify and characterise risks associated with use of medications during pregnancy and lactation (to complement data generated through the secondary use of routinely collected EHR (electronic health record) data in WP1).
- To identify and characterise existing data sources that capture reported medication exposed pregnancies;
- To develop novel methods and analysis of reported pregnancies;
- To explore and evaluate the role of traditional versus novel data collection systems, methodological approaches and datasets through specific demonstration studies using data from different sources; and
- To develop best practice guidance to support a more timely and efficient multifaceted approach to data collection, analysis and interpretation of reported pregnancies to inform risk-benefit considerations of medication use in pregnancy for both HCPs and pregnant women.
The main goal of this WP will be to develop, characterise, validate and apply a non-clinical testing platform for reliable prediction of drug concentrations in human breast milk along with systemic drug exposure in breastfed infants.
- To map applicability and to identify shortcomings of current in vitro and animal models for studying drug distribution to human breast milk and including prediction of systemic infant exposure;
- Building on state-of-the-art in vitro models (see first objective): (i) to develop a validated (and implementable) human in vitro platform for accurate and rapid determination of plasma-milk transfer rates of drugs (including metabolites) and drug candidates; (ii) to explore the impact of drug-specific properties (e.g. physicochemistry, drug-transporter affinities) in determining the extent and rate of drug excretion in human breast milk;
- Relying on existing expertise with animal lactation models, to develop a relevant animal lactation model (along with an in vitro model) in a species sufficiently related to human lactation physiology to validate extrapolation of the human in vitro and animal in vivo data to human in vivo predictions;
- Relying on non-clinical data generated in this WP, to develop, validate and apply a Physiology-Based PharmacoKinetic (PBPK) modelling platform for predicting drug concentration profiles in human breast milk. PBPK-based predictions will be verified against clinically observed human lactation data (as already generated by EFPIA contributors or generated during this project as deliverables of WP 4). To explore the sensitivity of the PBPK-based predictions regarding drug concentrations in human breast milk to maternal (physiological) factors (e.g. milk composition, drug transporter abundance in mammary epithelial cells);
- To identify based on published data neonatal physiological factors (e.g. related to maturation of gastrointestinal drug absorption processes) determining systemic drug exposure in breastfed infants. The established PBPK platform will be expanded with a PBPK modelling strategy in infants that takes these neonatal factors into account;
- To evaluate and cross-validate the developed non-clinical and computational approaches for their performance to predict medication concentrations in human breast milk and systemic drug exposure of breastfed infants (by comparison with existing human lactation data;
- To propose acceptable (and regulatory recognised) non-clinical data generation protocol for drug milk excretion and breastfed infant exposure (in collaboration with WPs 4 and 6); and
- Based on the scope and limitations of the non-clinical and in silico tools generated in this WP, to provide input to other WPs regarding the use of these new predictive tools as best practices for informing risk assessment on medication use during lactation.
The main aim of WP4 is to establish a central European self-sustaining breast milk and blood biobank and analytical centres able to comply with regulatory quality standards fit for label, capable of measuring medication concentrations in breast milk.
- Set up standards, facilities and operating procedures for collection, reception, long-term storage, withdrawals and management of breast milk and blood samples from participating countries at Uppsala Biobank;
- Develop and implement information and consent procedures and templates for collection, short-term storage, transportation and analysis of samples in different European countries and transfer of personal data across borders;
- Set up operating procedures for sample preparation and handling, and determination of selected drugs and their metabolites concentration in breast milk and plasma in order to estimate pharmacokinetics (PK) of test compounds in breast milk and blood/plasma, and thus population variabilities in exposure to these compounds in order to estimate risk assessments and infants’ exposure to the drug and its metabolites (especially active and toxic). Bioanalytic measurements of human samples to be compliant with regulatory standards;
- Conduct 5 human lactation demonstration studies;
- Analyse drug concentration values in breast milk and share the results with WP3 to allow verification of predictions obtained with physiologically based pharmacokinetics (PBPK); and
- Develop and implement a Governance framework for access to and sharing of samples and data.
The main aim of WP5 is to improve the value, quality and harmonisation of the dissemination of information on the available evidence related to medicine use in pregnancy and the potential effects on the mother, embryo and foetus before and during pregnancy as well as to infants during breastfeeding.
- To compile an inventory of available information about medication use before and during pregnancy and during the breastfeeding period and the tools that are used to disseminate this information;
- To develop an EU centralised publicly accessible and sustainable information knowledge bank for up-to-date information about drug use during pregnancy and lactation;
- To develop and execute general communication methods for increasing awareness about the importance of reporting through PV systems and participation in research during pregnancy and breastfeeding; and
- To develop a blended learning training programme for continuous education for HCPs treating women in the reproductive age for optimal treatment of women before and/or during pregnancy or for breastfeeding women.
WP6 will work to serve the needs of the project acting as a facilitator of the work, connecting information sources from key stakeholder groups and building an internal project infrastructure to integrate and facilitate knowledge sharing to help maximise the impact of project outcomes on stakeholders.
- Chart the landscape of stakeholders, mapped to project outputs;
- to investigate their concerns and evidence needs to make well informed decisions about the safety of drugs in pregnancy and lactation
- to help the WPs to deliver outputs that can meet stakeholder needs.
- Ensure all partners understand the qualification and decision-making pathways of regulatory authorities, including European and national Medicines Agencies, FDA
- to develop resources and facilitate knowledge sharing so that all partners and external stakeholders understand each other’s perspectives and language
- to produce guidance for the consortium and external stakeholders on roles and responsibilities of different regulatory agencies at European and national levels, their decision-making pathways when assessing new evidence.
- Support all other work packages to engage with external stakeholders to get their input to optimise solutions that meet their needs;
- to use consensus building tools to enable positive and successful engagement across stakeholder groups
- to support patient involvement & healthcare professional and public health agency consensus on the value of new forms of evidence and its appropriate impact on decision making.
- Engage with regulatory authorities, with input from other key stakeholders as needed, to facilitate adoption of new methods for generating evidence, in collaboration with WP1-4. Adoption by health authorities will be key to sustainability; and
- Co-create sustainable solutions for raising awareness and enhancing engagement by different stakeholders
- to establish methods, repositories and dissemination channels to convey new evidence to all decision makers
- to design a sustainable model for improving availability of high quality scientific information on drugs used by pregnant and lactating women by engaging the ecosystem toward adoption of the new evidence generation tools.
The main goal of this WP is to provide ethical and governance and quality assessment support for the conduct of distributed data collection and analyses which will support generation of high quality real world evidence on the effects of drugs during pregnancy and lactation. This WP will facilitate the work for WP1 and 2 by providing support in data and analytics generation readiness.
- To identify and describe the rules by which different data access providers will provide access to data, with the purpose to facilitate access;
- To conduct empirical ethical research on involving pregnant women in a learning health care system
- To define and describe information and research governance for use of different sources of data (electronic healthcare, case reports, human and animal biosamples);
- To create a FAIR data source catalogue, allowing to find adequate data sources, negotiate and assess whether they would be fit for purpose;
- To create common data models for distributed analysis and characterise the quality of potential data sources in collaboration with WP1 and WP2;
- To create and run a platform for distributed data analysis supporting WP1 and 2;
- To characterise available data sources and quantify the impact of using different algorithms in WP1 and 2;
- To double code analytical scripts in R and make them available open source; and
- To create a database of reprotox and targets for small molecules to allow for prediction modelling.
The objective of WP8 is to run an effective project management for the ConcePTION consortium and to guarantee the project’s long-lasting effect on rapid and adequate information on the effects of drugs during pregnancy and lactation for women, society and pharmacovigilance.