Contemporary Practice and Considerations for Real-World Data Source Identification and Feasibility Assessment.

PURPOSE: There has been rapid growth in the variety and number of real-world data (RWD) sources, as well as the number of regulatory documents that provide guidance for assessing the suitability of RWD sources for pharmacoepidemiology studies. This study aims to assess differences in RWD guidance and variability in current practice for identifying and assessing RWD for studies with regulatory purpose. METHODS: Key criteria for feasibility assessment were mapped against relevant regulatory guidance documents across US, EU, and Asia-Pacific regions. An online survey was designed and deployed to International Society for Pharmacoepidemiology members to understand current practice. Findings were summarized and used to inform key considerations and recommendations. RESULTS: Eleven RWD guidance documents were identified and mapped against 14 RWD assessment criteria. Variability was seen across these documents in guidance for these criteria. Between December 2022 and January 2023, 37 survey respondents reported having used RWD for post-marketing commitments (34, 92%) and/or background epidemiology (28, 76%). RWD were mostly identified through literature (33, 89%) and data landscaping (26, 70%); guidance documents referenced included: Food and Drug Administration (20, 54%), European Network for Centres for Pharmacoepidemiology and Pharmacovigilance (17, 46%), European Medical Agency (16, 43%), and Structured Process to Identify Fit-For-Purpose Data (11, 30%). Challenges for conducting feasibility assessments included RWD accessibility, ability to complete validation, and RWD provider responsiveness. CONCLUSIONS: Existing guidelines are used extensively by researchers, but key criteria for RWD identification and feasibility assessment are not reflected consistently and challenges remain. Recommendations have been made reflecting study findings.

Final analysis of 379 pregnancy outcomes after exposure to dimethyl fumarate in a prospective international registry.

BACKGROUND: Dimethyl fumarate (DMF) has a favorable benefit-risk profile treating people with multiple sclerosis and should be used in pregnant women only if the potential benefits outweigh potential risks to the fetus. OBJECTIVE: Assess pregnancy outcomes in a completed international registry (TecGistry) of women with MS exposed to DMF. METHODS: TecGistry included pregnant women with MS exposed to DMF, with data collected at enrollment, 6-7 months gestation, 4 weeks after estimated due date, and at postpartum weeks 4, 12, and 52. Outcomes included live births, gestational size, pregnancy loss, ectopic/molar pregnancies, birth defects, and infant/maternal death. RESULTS: Of 397 enrolled, median (range) age was 32 years (19-43). Median (range) gestational week at enrollment was 10 (0-39) and at first DMF exposure was 1 (0-13). Median (range) duration of gestational DMF exposure was 5 weeks (0-40). Fifteen (3.8%) spontaneous abortions occurred. Of 360 (89.1%) live births, 323 were full term and 37 were premature. One neonatal death and no maternal deaths occurred. Adjudicator-confirmed EUROCAT birth defects were found in 2.2%. CONCLUSION: DMF exposure during pregnancy did not adversely affect pregnancy outcomes; birth defects, preterm birth, and spontaneous abortion were in line with rates from the general population.

Analysis of Pregnancy Outcomes Following Exposure to Intramuscular Interferon Beta-1a: The AVONEX® Pregnancy Exposure Registry.

BACKGROUND AND OBJECTIVES: There is a lack of well-controlled US studies of intramuscular (IM) interferon beta (IFNß)-1a use in pregnant women with multiple sclerosis; however, in the European Medicines Agency region, IFNß formulations may be considered during pregnancy if clinically needed based on data from European Union cohort registries. The AVONEX Pregnancy Exposure Registry was established to prospectively study the effects of IM IFNß-1a on the risk of birth defects and spontaneous pregnancy loss in a US population. METHODS: Pregnant women with multiple sclerosis exposed to IM IFNß-1a within ~ 1 week of conception or during the first trimester were included. Participants were followed until there was a pregnancy outcome, live-born infants were followed until age 8-12 weeks. Data were collected on IM IFNß-1a exposure, demographics, patient characteristics, medical history, and pregnancy outcomes, including live births (with or without birth defect), spontaneous abortions/miscarriages and fetal death/stillbirth, elective abortions (with and without birth defect), and ectopic pregnancies. A population-based birth defect surveillance program, the Metropolitan Atlanta Congenital Defects Program (MACDP), served as the primary external control group for evaluating the risk of birth defects. RESULTS: Three-hundred and two patients with a median (range) age of 31.0 (16-48) years and a median (range) gestational age at the time of enrollment of 10.1 (4-39) weeks were evaluable. Most patients (n = 278/302; 92%) reported IM IFNß-1a exposure in the week before conception and most (n = 293/302; 97%) discontinued treatment before the end of the first trimester. Of 306 pregnancy outcomes, there were 272 live births, 28 spontaneous abortions of 266 pregnancies enrolled before 22 weeks' gestation (rate 10.5%; 95% confidence interval 7.2-15.0), five elective abortions, and one stillbirth. There were 17 adjudicator-confirmed major birth defects of 272 live births (rate 6.3%; 95% confidence interval 3.8-10.0); the pattern of birth defects observed was not suggestive of a relationship to prenatal IM IFNß-1a exposure. CONCLUSIONS: This large US registry study suggests IM IFNß-1a exposure during early pregnancy was not clinically associated with adverse pregnancy outcomes in women with multiple sclerosis. These findings help inform clinicians and patients in weighing the risks and benefits of IM IFNß-1a use during pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT00168714, 15 September, 2005.

Progressive multifocal leukoencephalopathy outcomes in patients with multiple sclerosis treated with dimethyl fumarate.

Background and objectives: Dimethyl fumarate (DMF), an oral disease-modifying therapy with an established benefit and well-described safety profile, is among the most commonly used therapies for relapsing forms of multiple sclerosis. As of 31 December 2021, >560,000 patients have been treated with DMF, representing >1,190,000 person-years of exposure. Of these, 6413 patients (14,292 person-years) were from clinical trials. Methods and results: Progressive multifocal leukoencephalopathy (PML) has occurred in the setting of lymphopenia (<0.91 × 109/L) in patients treated with DMF. We present detailed clinical characteristics and outcomes of the 12 confirmed PML cases occurring in MS patients on DMF as of 21 July 2021. The PML incidence in DMF-treated patients is 1.07 per 100,000 person-years of DMF exposure. Lymphopenia is the common risk for PML in DMF treatment. Discussion: DMF-related PML is rare but has occurred in the setting of lymphopenia, supporting the current recommendations for absolute lymphocyte count monitoring in all patients, regardless of age and time on therapy.

Interim Analysis of Pregnancy Outcomes After Exposure to Dimethyl Fumarate in a Prospective International Registry.

BACKGROUND AND OBJECTIVES: Oral delayed-release dimethyl fumarate (DMF) is not recommended during pregnancy and should only be used if the potential benefit justifies the potential fetal risk. Although DMF was well tolerated in clinical trials with consistent safety results in postmarketing surveillance, data are limited in pregnant women. The objective was to provide pregnancy outcomes and DMF exposure information from an interim analysis from a prospective, international registry (TecGistry; NCT01911767). METHODS: Women exposed to DMF from the first day of their last menstrual period before conception or during pregnancy were evaluated. Data were obtained at enrollment; 6-7 months' gestation; 4 weeks after estimated due date; and 4, 12, and 52 weeks after birth. Outcomes included live births, gestational size, pregnancy loss, birth defects, and infant or maternal death after delivery. Outcomes were analyzed cumulatively from October 30, 2013 (the start of TecGistry), to April 8, 2020. RESULTS: Of 345 enrolled patients, median (range) age was 32 (20-43) years. The mean (SD) duration of gestational weeks of DMF exposure was 4.9 (3.8). Most infants were full-term at birth (n = 249/274; 91%) and of average gestational size (n = 190/232; 82%). Of 351 outcomes, 277 were live births; 17 (5%) spontaneous abortions (95% confidence interval [CI] 2.6%-7.1%), including 1 (<1%) molar and 1 (<1%) ectopic pregnancy, were reported. There were 8 (2.9% [95% CI 1.3%-5.6%]) adjudicator-confirmed birth defects among the 277 live births. DISCUSSION: Interim results from this large registry indicate that early DMF exposure was not significantly associated with adverse pregnancy outcomes. Outcomes are consistent with previous smaller reports and with the general population. TRIAL REGISTRATION INFORMATION: TecGistry; clinical trial registration number: NCT01911767.

Prevalence of adverse pregnancy outcomes after exposure to interferon beta prior to or during pregnancy in women with MS: Stratification by maternal and newborn characteristics in a register-based cohort study in Finland and Sweden.

BACKGROUND: Previous studies reported no increase in the prevalence of adverse pregnancy outcomes after exposure to interferon-beta (IFN-beta). However, no study has investigated if the prevalence of these outcomes after IFN-beta exposure is modified by maternal and newborn characteristics. Our objective was to describe the stratified prevalence of adverse pregnancy outcomes among women with multiple sclerosis (MS) exposed only to IFN-beta or unexposed to any MS disease modifying drugs (MSDMDs). METHODS: This population-based cohort study using Finnish (1996-2014) and Swedish (2005-2014) register data included pregnancies of women with MS exposed only to IFN-beta 6 months before or during pregnancy (n=718) or unexposed to MSDMDs (n=1397). The outcome prevalences were described stratified by maternal and newborn characteristics, with 95% confidence intervals (CIs). Confounder-adjusted analyses were performed if the prevalence results indicated modified effect of IFN-beta in specific strata. RESULTS: The stratified analysis indicated that the prevalence of serious (anomaly or stillbirth) and other adverse pregnancy outcomes was similar among the exposed and unexposed, with no statistically significant difference. Among women treated for MS >5 years, serious adverse pregnancy outcomes occurred in 4.3% (95%CI: 1.9-8.3%) of pregnancies exposed only to IFN-beta 6 months before or during pregnancy and in 2.7% (95%CI: 1.2-5.0%) of unexposed pregnancies. The confounder adjusted analyses did not support the hypothesis that MS treatment duration before pregnancy would modify the risk of adverse pregnancy outcomes after exposure to IFN-beta 6 months before or during pregnancy. CONCLUSION: The prevalence of adverse pregnancy outcomes was not increased after IFN-beta exposure, when pregnancies of women with MS were stratified by maternal and newborn characteristics. The stratified results were similar to the unstratified results in the same population.

Diagnosed cataracts in patients with cystic fibrosis in a United States administrative database.

BACKGROUND: We estimated the incidence and prevalence of diagnosed cataracts among patients with cystic fibrosis (CF) versus the general population (GP). METHODS: Using a large US health insurance claims database, we identified a CF cohort and a GP cohort matched with respect to age, gender, and calendar year. The prevalence and incidence of diagnosed cataract (primary outcome) for both cohorts were calculated, as well as the incidence rate ratios (IRRs). RESULTS: The prevalence of diagnosed cataracts among patients with CF alive and enrolled in the health plan on August 31, 2012 was 4.8% versus 2.8% in the GP. The incidence in the CF cohort was higher than in the GP and increased with age in both cohorts. The adjusted IRR comparing the CF and GP cohorts was 1.5 (95% CI: 1.2-1.8). CONCLUSIONS: The study suggests that the risk of developing cataract was higher among patients with CF than among the GP.

Validation of current procedural terminology codes for rotavirus vaccination among infants in two commercially insured US populations.

PURPOSE: We validated procedure codes used in health insurance claims for reimbursement of rotavirus vaccination by comparing claims for monovalent live-attenuated human rotavirus vaccine (RV1) and live, oral pentavalent rotavirus vaccine (RV5) to medical records. METHODS: Using administrative data from two commercially insured United States populations, we randomly sampled vaccination claims for RV1 and RV5 from a cohort of infants aged less than 1 year from an ongoing post-licensure safety study of rotavirus vaccines. The codes for RV1 and RV5 found in claims were confirmed through medical record review. The positive predictive value (PPV) of the Current Procedural Terminology codes for RV1 and RV5 was calculated as the number of medical record-confirmed vaccinations divided by the number of medical records obtained. RESULTS: Medical record review confirmed 92 of 104 RV1 vaccination claims (PPV: 88.5%; 95% CI: 80.7-93.9%) and 98 of 113 RV5 vaccination claims (PPV: 86.7%; 95% CI: 79.1-92.4%). Among the 217 medical records abstracted, only three (1.4%) of vaccinations were misclassified in claims-all were RV5 misclassified as RV1. The medical records corresponding to 9 RV1 and 15 RV5 claims contained insufficient information to classify the type of rotavirus vaccine. CONCLUSIONS: Misclassification of rotavirus vaccines is infrequent within claims. The PPVs reported here are conservative estimates as those with insufficient information in the medical records were assumed to be incorrectly coded in the claims. Copyright © 2016 John Wiley & Sons, Ltd.

Topiramate use during pregnancy and major congenital malformations in multiple populations.

BACKGROUND: We measured birth prevalence of major congenital malformations (MCMs) after topiramate use during pregnancy to screen for a possible signal of increased risk. METHODS: Using four healthcare databases, we identified three cohorts of pregnant women: cohort 1, used topiramate during the first trimester; cohort 2, used topiramate or another antiepileptic drug previously but not during pregnancy; and cohort 3, were pregnant and did not use topiramate but had indications for use individually matched to those of users. Cohort 1 was compared with cohorts 2 and 3. MCMs were a code for any major congenital malformation dated within 30 days of the delivery date on the mother's claims or within 365 days after infant birth date, excluding a genetic or syndromic basis, and with procedure or healthcare usage consistent with the MCM diagnosis code in the 365 days after infant birth. RESULTS: Of the 10 specific common MCMs evaluated, 1 (conotruncal heart defects) had a prevalence ratio greater than 1.5 for both primary comparisons, and 4 (ventricular septal defect, atrial septal defect, hypospadias, coarctation of the aorta) had a prevalence ratio greater than 1.5 for one of the two comparisons. Following screening of organ systems with elevated MCMs, the prevalence ratio was greater than 1.5 for patent ductus arteriosus in both comparisons and for obstructive genitourinary defects in one comparison. CONCLUSION: To evaluate a large number of MCMs across many pregnancies, we used crude methods for detecting potential signals. Therefore, these results should be seen as potential signals, not causal.

Social and behavioral risk marker clustering associated with biological risk factors for coronary heart disease: NHANES 2001-2004.

BACKGROUND: Social and behavioral risk markers (e.g., physical activity, diet, smoking, and socioeconomic position) cluster; however, little is known whether clustering is associated with coronary heart disease (CHD) risk. Objectives were to determine if sociobehavioral clustering is associated with biological CHD risk factors (total cholesterol, HDL cholesterol, systolic blood pressure, body mass index, waist circumference, and diabetes) and whether associations are independent of individual clustering components. METHODS: Participants included 4,305 males and 4,673 females aged ≥ 20 years from NHANES 2001-2004. Sociobehavioral Risk Marker Index (SRI) included a summary score of physical activity, fruit/vegetable consumption, smoking, and educational attainment. Regression analyses evaluated associations of SRI with aforementioned biological CHD risk factors. Receiver operator curve analyses assessed independent predictive ability of SRI. RESULTS: Healthful clustering (SRI = 0) was associated with improved biological CHD risk factor levels in 5 of 6 risk factors in females and 2 of 6 risk factors in males. Adding SRI to models containing age, race, and individual SRI components did not improve C-statistics. CONCLUSIONS: Findings suggest that healthful sociobehavioral risk marker clustering is associated with favorable CHD risk factor levels, particularly in females. These findings should inform social ecological interventions that consider health impacts of addressing social and behavioral risk factors.

Topiramate use in pregnancy and the birth prevalence of oral clefts.

PURPOSE: First marketed in the USA in 1996, topiramate (TPM) is an antiepileptic drug later approved for migraine prophylaxis, and in 2012 for weight loss in combination with phentermine. Some studies indicate an elevated prevalence of oral cleft (OC) in infants exposed to TPM in utero. We evaluated the association between TPM use in early pregnancy and the risk of OC. METHODS: This retrospective cohort study used 1997-2011 automated data from four sources: HealthCore and OptumInsight (commercial insurance claims), Truven Health (Medicaid claims), and Kaiser Permanente Northern California Region (electronic medical records). We compared the prevalence of OCs in infants of women exposed to TPM in the first trimester (TPM cohort) with the prevalence in infants of women formerly exposed to TPM or other antiepileptic drugs (formerly exposed [FE] cohort) and infants of women with similar medical profiles (SMPs) to the TPM cohort that were not exposed to TPM (SMP cohort). To control for confounding, we used stratification and standardization for individual variables and propensity score deciles. RESULTS: The birth prevalence of OCs was 0.36% (7/1945) in the TPM cohort, 0.14% (20/13 512) in the FE cohort, and 0.07% (9/13 614) in the SMP cohort. Standardized by site, the prevalence ratio (PR) for TPM versus FE was 2.5 (95% CI: 1.0-6.0) and for TPM versus SMP was 5.4 (95% CI: 2.0-14.6). Adjustment for covariates one at a time or by propensity score yielded similar results. CONCLUSION: Consistent with other recent epidemiologic research, first-trimester TPM exposure was associated with an elevated birth prevalence of OC.

Implementation of permutation testing to determine clustering of social and behavioral risk factors for coronary heart disease, National Health and Nutrition Examination Survey 2001-2004.

PURPOSE: To determine whether social and behavioral risk factors for coronary heart disease, including education, physical activity, fruit/vegetable intake, and smoking, cluster (i.e., co-occur more than expected as the result of chance) in U.S. adults. METHODS: The study included 4305 male and 4673 female subjects aged ≥20 years from the National Health and Nutrition Examination Survey. Risk factors included: ≤high school diploma/general educational development certificate; <150 minutes of moderate/vigorous physical activity per week; <3 or <2 servings of vegetables and fruit, respectively, per day; and smoking cigarettes. Indicator variables were summed into a sociobehavioral risk index (SRI, range 0 [no risk factors] to 4 [all risk factors]). Ratios of observed-to-expected prevalence (under the assumption of independence) of the SRI were assessed. Statistical significance was evaluated by the use of randomly permuted average observed-to-expected SRI ratios and 95% confidence intervals (95% CIs). RESULTS: In male subjects, the ratio of observed-to-expected prevalence of SRI = 0 was 1.70 (permuted ratio = 1.00; 95% CI: 0.92-1.08), and SRI = 4 was 2.10 (permuted ratio = 1.00, 95% CI: 0.86-1.14), demonstrating significant clustering. In females, the ratio of observed-to-expected prevalence of SRI = 0 was 1.67 (permuted ratio = 1.00, 95% CI: 0.92-1.08), and SRI = 4 was 1.86 (permuted ratio = 1.00, 95% CI: 0.85-1.15). CONCLUSIONS: Social and behavioral risk factors for coronary heart disease cluster in this sample of U.S. adults.

Inverse associations between perceived racism and coronary artery calcification.

PURPOSE: To evaluate whether racial discrimination is associated with coronary artery calcification (CAC) in African-American participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study. METHODS: The study included American Black men (n = 571) and women (n = 791) aged 33 to 45 years in the CARDIA study. Perceived racial discrimination was assessed based on the Experiences of Discrimination scale (range, 1-35). CAC was evaluated using computed tomography. Primary analyses assessed associations between perceived racial discrimination and presence of CAC using multivariable-adjusted logistic regression analysis, adjusted for age, gender, socioeconomic position (SEP), psychosocial variables, and coronary heart disease (CHD) risk factors. RESULTS: In age- and gender-adjusted logistic regression models, odds of CAC decreased as the perceived racial discrimination score increased (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.90-0.98 per 1-unit increase in Experiences of Discrimination scale). The relationship did not markedly change after further adjustment for SEP, psychosocial variables, or CHD risk factors (OR, 0.93; 95% CI, 0.87-0.99). CONCLUSIONS: Perceived racial discrimination was negatively associated with CAC in this study. Estimation of more forms of racial discrimination as well as replication of analyses in other samples will help to confirm or refute these findings.

Cross-cultural validation of the hill-bone compliance to high blood pressure therapy scale in a South African, primary healthcare setting.

OBJECTIVES: Hypertension is prevalent, under-diagnosed, and inadequately treated in Black South Africans. However, few studies have addressed barriers to hypertension care and control in this community. The aim of this study was to validate the Hill-Bone Compliance to High Blood Pressure Therapy Scale (HB Comp Scale) for use in a South African primary healthcare setting. This instrument consists of three subscales, medications-compliance, appointment making, and salt intake. METHODS: A demographic questionnaire and the HB scale were translated into the first language of the subjects and then back-translated into English. Hypertensive patients (N=98) were recruited from primary healthcare clinics in Cape Town. Blood pressure was measured with an Omron electronic blood pressure manometer, after 5 min of seated rest. Item-analysis was conducted to determine internal consistency of the HB Comp Scale; Spearman rank order correlations were used to assess the relationship between compliance scores and blood pressure. RESULTS: A modified scale consisting of only 10 items demonstrated reasonable internal consistency (item-total correlations all >.31, and a standardized Cronbach alpha of 0.79), with an average interitem correlation of .26. In addition, the modified scale had significant predictive validity in that noncompliance predicted higher diastolic blood pressures (p=.21, P<.05) and medication noncompliance tended to predict higher systolic blood pressures (p=.20, P<.06). Appointment-making and dietary salt-intake subscales were not internally consistent. CONCLUSIONS: We demonstrated criterion validity and internal consistency for a modified Hill-Bone Compliance Scale, in Black, urban, hypertensive, South African patients. Results compare favorably with those from an urban African-American setting (standardized Cronbach alpha was .74-.84).