Standardised procedures for performing and reporting safety monitoring studies investigating medications use in pregnancy may help improve data quality and the speed of data generation. The objective of this study was to provide recommendations on the statistical analysis and reporting of single-arm pregnancy medication safety studies using primary source datasets. A Delphi consensus-setting protocol was used to acquire agreement on recommendations from experts with extensive knowledge and experience in conducting studies investigating medication safety in pregnancy. A series of recommendations, along with their scientific justifications and examples of how to calculate and describe exposure and outcome incidences, were critiqued and improved through a series of online Delphi review rounds. Agreement to inclusion scoring was assessed using a five-point Likert scale. Recommendations with a median Likert-scale score of at least 4, where ≥ 80

Introduction: Aligned with the Innovative Medicines Initiative (IMI) ConcePTION project’s goal of advancing drug safety research in pregnancy, we explored the feasibility of employing a standardized list of core data elements (CDEs) and statistical outputs to harmonize data collection and analysis across various study partners. Methods: Study partners from public research institutions and pharmaceutical companies extracted pregnancy safety data on disease-modifying therapies for multiple sclerosis from their databases, mapped them to the CDE framework, and analysed datasets using a common statistical analysis plan (SAP). Questionnaires were used to gather contextual information on data collection practices, including data definitions and infant follow-up, and to evaluate the feasibility and practicality of the proposed methodology. Results: The study demonstrated the feasibility of harmonizing pregnancy safety data using standardized CDEs and a common SAP. All six study partners successfully mapped their data into the CDE framework and produced standardized outputs. Challenges were identified in aligning with recommended definitions, such as classifying ‘prospective cases’ based on differing criteria—pregnancies reported while ongoing, before fetal malformation diagnosis, or before any prenatal screening—and categorizing congenital anomalies using the EUROCAT system. The feasibility questionnaires revealed strong support for the methodology, with all six study partners reporting access to the necessary expertise and all six finding the statistical guidance easy to follow. Conclusions: This study demonstrates the feasibility of employing standardized CDEs and a common SAP to describe pregnancy exposure and outcome data across diverse data providers. The methodology shows promise for improving consistency in pregnancy safety research but requires addressing challenges such as resource constraints and variability in data collection for broader adoption.

Introduction and ObjectiveThe ConcePTION project aims to improve the way medication use during pregnancy is studied. This includes exploring the possibility of developing a distributed data processing and analysis infrastructure using a common data model that could form a foundational platform for future surveillance and research. A prerequisite would be that data from various data access providers (DAPs) can be harmonised according to an agreed set of standard rules concerning the structure and content of the data. To do so, a reference framework of core data elements (CDEs) recommended for primary data studies on drug safety during pregnancy was previously developed. The aim of this study was to assess the ability of several public and private DAPs using different primary data sources focusing on multiple sclerosis, as a pilot, to map their respective data variables and definitions with the CDE recommendations framework.MethodsFour pregnancy registries (Gilenya, Novartis; Aubagio, Sanofi; the Organization of Teratology Information Specialists [OTIS]; Aubagio, Sanofi; the Dutch Pregnancy Drug Register, Lareb), two enhanced pharmacovigilance programmes (Gilenya PRIM, Novartis; MAPLE-MS, Merck Healthcare KGaA) and four Teratology Information Services (UK TIS, Jerusalem TIS, Zerifin TIS, Swiss TIS) participated in the study. The ConcePTION primary data source CDE includes 51 items covering administrative functions, the description of pregnancy, maternal medical history, maternal illnesses arising in pregnancy, delivery details, and pregnancy and infant outcomes. For each variable in the CDE, the DAPs identified whether their variables were: identical to the one mentioned in the CDE; derived; similar but with a divergent definition; or not available.ResultsThe majority of the DAP data variables were either directly taken (85%, n = 305/357, range 73-94% between DAPs) or derived by combining different variables (12%, n = 42/357, range 0-24% between DAPs) to conform to the CDE variables and definitions. For very few of the DAP variables, alignment with the CDE items was not possible, either because of divergent definitions (1%, n = 3/357, range 0-2% between DAPs) or because the variables were not available (2%, n = 7/357, range 0-4% between DAPs).ConclusionsData access providers participating in this study presented a very high proportion of variables matching the CDE items, indicating that alignment of definitions and harmonisation of data analysis by different stakeholders to accelerate and strengthen pregnancy pharmacovigilance safety data analyses could be feasible.

INTRODUCTION AND OBJECTIVE:The risks and benefits of medication use in pregnancy are typically established through post-marketing observational studies. As there is currently no standardised or systematic approach to the post-marketing assessment of medication safety in pregnancy, data generated through pregnancy pharmacovigilance (PregPV) research can be heterogenous and difficult to interpret. The aim of this article is to describe the development of a reference framework of core data elements (CDEs) for collection in primary source PregPV studies that can be used to standardise data collection procedures and, thereby, improve data harmonisation and evidence synthesis capabilities. METHODS:This CDE reference framework was developed within the Innovative Medicines Initiative (IMI) ConcePTION project by experts in pharmacovigilance, pharmacoepidemiology, medical statistics, risk-benefit communication, clinical teratology, reproductive toxicology, genetics, obstetrics, paediatrics, and child psychology. The framework was produced through a scoping review of data collection systems used by established PregPV datasets, followed by extensive discussion and debate around the value, definition, and derivation of each data item identified from these systems. RESULTS:The finalised listing of CDEs comprises 98 individual data elements, arranged into 14 tables of related fields. These data elements are openly available on the European Network of Teratology Information Services (ENTIS) website ( http://www.entis-org.eu/cde ). DISCUSSION:With this set of recommendations, we aim to standardise PregPV primary source data collection processes to improve the speed at which high-quality evidence-based statements can be provided about the safety of medication use in pregnancy.

Background: People with multiple sclerosis (pwMS) have increased comorbid disease (CMD) risk. Most previous studies have not considered overall CMD burden. Objective: To describe lifetime CMD burden among pwMS. Methods: PwMS identified using Swedish registers between 1968 and 2012 ( n = 25,476) were matched by sex, age, and county of residence with general-population comparators ( n = 251,170). Prevalence, prevalence ratios (PRs), survival functions, and hazard ratios by MS status, age, and time period compared seven CMD: autoimmune, cardiovascular, depression, diabetes, respiratory, renal, and seizures. Results: The magnitude of the PRs for each CMD and age group decreased across time, with higher PRs in earlier time periods. Before 1990, younger age groups had higher PRs, and after 1990, older age groups had higher PRs. Male pwMS had higher burden compared with females. Overall, renal, respiratory, and seizures had the highest PRs. Before 2001, 50% of pwMS received a first/additional CMD diagnosis 20 years prior to people without MS, which reduced to 4 years after 2001. PwMS had four times higher rates of first/additional diagnoses in earlier time periods, which reduced to less than two times higher in recent time periods compared to people without MS. Conclusion: Swedish pwMS have increased CMD burden compared with the general population, but this has reduced over time.

Patient safety during pregnancy is an important concern. This article presents a method of using an industry safety database to access prospective pregnancy cases. This method, termed here 'PRegnancy outcomes Intensive Monitoring' (PRIM) was developed for fingolimod (Gilenya ™), a treatment option for multiple sclerosis (MS), due to slow enrollment in the company pregnancy registry. The aim of PRIM was to enhance the process of pregnancy data collection and improve data quality, and in particular to enable estimation of the proportion of major congenital malformation and other pregnancy outcomes. To do this, the spontaneous reports of maternal exposure to fingolimod in pregnancy or in the eight weeks immediately before the last menstrual period of patients not enrolled in the pregnancy registry were identified. Follow up checklists were sent at four time points: initial pregnancy report, end of pregnancy, infant attained 3 and 12 months of age. These focused on core data required for derivation of programmed analyses. From 01 Mar 2014 to 28 Feb 2018, a total of 831 prospective maternal exposures with 843 infants were reported, with fetal outcomes reported in 459/843 (54.4 %) of those infants. This enabled the calculation of proportions of pregnancy cases with the main pregnancy outcomes and of fetal cases with malformation. The number of reported pregnancies was significantly higher in PRIM than in the registry, showing that structured use of pharmacovigilance data enables speedier assessment of risks of maternal drug exposure.

Background: Data are limited for mortality and comorbidities in patients with multiple sclerosis (MS).Objectives: Compare mortality rates and event rates for comorbidities in MS (n=15,684) and non-MS (n=78,420) cohorts from the US Department of Defense (DOD) database.Methods: Comorbidities and all-cause mortality were assessed using the database. Causes of death (CoDs) were assessed through linkage with the National Death Index. Cohorts were compared using mortality (MRR) and event (ERR) rate ratios.Results: All-cause mortality was 2.9-fold higher in the MS versus non-MS cohort (MRR, 95% confidence interval [CI]: 2.9, 2.7-3.2). Frequent CoDs in the MS versus non-MS cohort were infectious diseases (6.2, 4.2-9.4), diseases of the nervous (5.8, 3.7-9.0), respiratory (5.0, 3.9-6.4) and circulatory (2.1, 1.7-2.7) systems and suicide (2.6, 1.3-5.2). Comorbidities including sepsis (ERR, 95% Cl: 5.7, 5.1-6.3), ischemic stroke (3.8, 3.5-4.2), attempted suicide (2.4, 13-4.5) and ulcerative colitis (2.0, 1.7-2.3), were higher in the MS versus non-MS cohort. The rate of cancers was also higher in the MS versus the non-MS cohort, including lymphoproliferative disorders (2.2, 1.9-2.6) and melanoma (1.7, 1.4-2.0).Conclusions: Rates of mortality and several comorbidities are higher in the MS versus non-MS cohort. Early recognition and management of comorbidities may reduce premature mortality and improve quality of life in patients with MS. (C) 2015 The Authors. Published by Elsevier B.V.

The aim of this 13-week, multicenter, randomized, double-blind, double-dummy, placebo- and positive-internal (celecoxib)-controlled, parallel-group study was to demonstrate the efficacy, safety, and tolerability of lumiracoxib in primary hip osteoarthritis (OA) patients. Eligible patients (n = 1,262; ACR criteria) were randomized (1:1:1) to receive lumiracoxib 100 mg once daily (o.d.) (n = 427), celecoxib 200 mg o.d. (n = 419), or matching placebo o.d. (n = 416) administered orally. The primary objective was to compare lumiracoxib 100 mg o.d. and placebo with respect to three co-primary efficacy variables: the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index Likert version 3.1 (WOMAC™ LK 3.1) questionnaire, the function subscale of the WOMAC™ LK 3.1 questionnaire, and patient’s global assessment of disease activity (100-mm visual analog scale (VAS)) after 13 weeks of treatment. Of the 1,262 randomized patients, 951 completed the study. All randomized patients were included in the intention-to-treat and safety populations. Lumiracoxib was superior to the placebo (p < 0.001) after 13 weeks for all three co-primary endpoints. By week 13, the patient’s global assessment of disease activity (100-mm VAS) improved by 23.3 mm (±SD, 27.83 mm) with lumiracoxib and 13.3 mm (±26.71 mm) with placebo. The WOMAC™ function score decreased by 10.4 (±13.56) with lumiracoxib and 6.8 (±12.55) with placebo. The WOMAC™ pain scores decreased by 3.4 (±4.16) with lumiracoxib and 2.2 (±3.94) with placebo at week 13. Similar results were observed for secondary endpoints: OA pain intensity and WOMAC™ total score. Lumiracoxib was similar to celecoxib for all three co-primary endpoints. All treatments were well tolerated. In conclusion, lumiracoxib is effective in reducing pain and improving function in hip OA patients. Clinical trial registration information: www.clinicaltrials.gov; NCT00154219