2.1 Study Design

This methodological study explored the degree to which data collected from various DAPs align with the CDE variables and definitions established in the ConcePTION primary data CDE recommendations framework.

2.2 Data Source2.2.1 Data Access Providers (DAPs)

Data access providers were public institutions and pharmaceutical companies collecting various types of data, including clinical data, exposure data, outcome data, and other relevant health information, from pregnant patients and/or healthcare providers regarding disease-modifying therapies for multiple sclerosis during pregnancy, using one of the three following main types of data collection methods:

A.

Pregnancy exposure registries. These registries collect health information on pregnancy and foetal outcomes following exposure to medicinal products during pregnancy. Pregnancy registries typically involve the use of specifically designed data collection forms by various stakeholders, including healthcare professionals (HCPs) and patients who willingly participate and give formal consent, to gather comprehensive health information on pregnancy and foetal outcomes. There are national and international pregnancy exposure registries that may be initiated by pharmaceutical companies, academic groups, research groups or professional scientific societies like the Organisation of Teratology Information Specialists (OTIS), which specialises in providing evidence-based information on the risks of exposures during pregnancy and breastfeeding. Pregnancy registries may focus on a single drug, a drug class or a disease.

B.

Enhanced pharmacovigilance programmes. These programmes collect and process pharmacovigilance data via existing variable fields in the safety database, data collected through sets of targeted checklists or questionnaires, and in some programmes, free-text data from the narratives. In addition, a structured follow-up, a rigorous process of data entry, data quality control and a programmed aggregate analysis is performed. Data are collected initially from ICSRs, used for general adverse event reporting, but are then supplemented by targeted checklists or questionnaires with dedicated pregnancy-related fields. Initial reporting can be by the HCP or directly by the patient. The data are entered in the respective pharmaceutical company safety database.

C.

Teratology Information Services (TIS) from the European Network of Teratology Information Services (ENTIS). ENTIS is a collaborative network of services offering expertise on possible risks related to exposure to medications, and other environmental exposures, during pregnancy and breastfeeding at an individual level. TIS collect patient data both during initial contact and after a follow-up period covering pregnancy outcome using a similar methodology based on structured telephone interviews and/or mailed questionnaires.

The exhaustive list of participating DAPs is presented below:

A.

Pregnancy registries: Gilenya (Novartis), Aubagio (Sanofi), Aubagio (Sanofi, OTIS), The Dutch Pregnancy Drug Register (Lareb)

B.

Enhanced pharmacovigilance programmes: Gilenya PRIM (Novartis), MAPLE-MS (Merck Healthcare KGaA)

C.

TIS: members of ENTIS (Swiss TIS (STIS), UK TIS (UKTIS), Zerfin TIS, Jerusalem TIS)

2.2.2 Data Collection

Between May and November 2022, DAPs were requested to answer a questionnaire concerning their general characteristics and method of data collection including the following items: name, short name, institution/market authorisation holder (MAH), governance, website, initial role, geographical localisation, beginning and end date of data collection, primary reporter, notification, transmission and collection of data, and follow-up approach.

In a second questionnaire, each DAP was requested to answer the following questions for each CDE item (questionnaire presented in Table 1 of the Electronic Supplementary Material (ESM):

Table 1 Description of data sources

- Can this item be taken directly from an existing field in the DAP database? (yes/no)

For yes responses, these items were already available in the DAP database and met the definition of the CDE.

- Can this item be derived by combining data from fields in the DAP database? (yes/no)

For yes responses, these items could be derived, using other variables in order to meet the definition of the CDE (e.g. the pre-pregnancy maternal body mass index [BMI] was not directly available in the DAP database, but could be derived using the maternal pre-pregnancy weight and height that were available in the database).

- Does the DAP collect data, which is similar to this item, but the CDE definition is different from that used in the DAP database? (yes/no)

For yes responses, these items were considered divergent as they were not directly available and could not be derived, but a similar variable was available (e.g. the pre-pregnancy maternal BMI was not directly available and could not be derived, but the maternal BMI at inclusion/entry to the registry was available).

- Is the item missing from the DAP database? (yes/no)

For yes responses, these items referred to variables that were not available.

Following the above answers each CDE item was classified into one of the four following categories: (1) directly matched; (2) derived; (3) divergent; or (4) not available.

It is important to note that the DAPs answered the questionnaire based on their current primary data collection form. This study only focused on the intended data collection step. Data quality (i.e. data accuracy, data completeness) and data processing issues (i.e. data storage, data formatting, other technical issues) were not considered.

Given the fundamental role of E2B(R3) in the data exchange of global pharmacovigilance data, the degree to which ICH E2B(R3) fields align with the ConcePTION primary data pregnancy exposure CDE was also investigated.

2.3 Statistical Analysis

A descriptive analysis of the CDE variables collected, classified in four categories, was performed for each DAP and overall. Results were presented as absolute numbers (n) and proportions (%).