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The regulatory standards of the United States Food and Drug Administration (FDA) require substantial evidence of effectiveness from adequate and well-controlled trials, for drugs developed in both adults and children. However, when scientifically justified, relying on extrapolation may be acceptable. Historically, the FDA's extrapolation approach was based on draft guidance published in 2014, which introduced the categories of full, partial, and no extrapolation. The European Medicines Agency (EMA) took a different view on pediatric extrapolation. To better understand the use of extrapolation to support pediatric drug development and approval, we reviewed the pediatric labeling changes published by the FDA, focusing on the labeling updates between 1/1/2015 and 7/31/2021, the period where the extrapolation approach is in transition to harmonize with the EMA. Within this time window, among the 265 drugs and biological products with pediatric labeling changes, 169 (63.8%) were identified where extrapolation was used. This includes 64 (24.2%) labeling changes, where full extrapolation was used, and 105 (39.6%) labeling changes, where partial extrapolation was used. The major disease areas that extrapolation was used include neuroscience (40/53, 75.5%) and infectious disease (20/28, 71.4%). The extrapolation approach was identified in terms of source population beyond the use of adult as well as extrapolation from clinical trials conducted in the same drug class. The use of extrapolation increased the rates of new and expanded pediatric indication in the period. This review gives the most recent landscape of pediatric labeling changes using extrapolation. With the released ICH (International Council for Harmonization) E11A guidance in April 2022, the paper also provides insights for future pediatric drug development programs. [ABSTRACT FROM AUTHOR]

OBJECTIVE. For patients who die in hospitals, the regionalization of tertiary health care services may be increasing the home-to-hospital distance, particularly for younger patients whose care is especially regionalized and for whom access to and use of home hospice services remains limited. The objective of this study was to test the hypotheses that the distance from home at the time of death in a hospital has increased over time and is inversely related to the age of the dying patient. METHODS. A population-based case series was conducted in Washington State of all deaths of state residents from 1989 to 2002. The main outcome measure was driving distance between home residence and location at the time of death. RESULTS. The overall mean distance from home to the hospital where death occurred has increased by 1% annually. Children who died in hospitals were much farther from home than their adult counterparts: the mean distance was 37.4 km for neonates and 50.9 km for children who were aged 1 to 9 years, compared with 19.9 km for adults who were aged 60 to 79 years and 14.0 km for patients who were older than 79 years. Disparities of distance were even greater among patients who were at the 90th percentile for distance (85.6 km for neonates compared with 30.8 for patient who were older than 79 years). CONCLUSIONS. The distance between home residence and the hospital where death occurs is greatest for children and has increased over time. Both of these findings have implications for the design of local and regional pediatric end-of-life supportive care services. KEY WORDS. end of life, palliative care, hospitalization, hospice care, geography.

Background: Prescription omega-3-acid ethyl esters (POM3) reduce triglycerides (TG) and very low-density lipoprotein cholesterol and increase high-density lipoprotein cholesterol (HDL-C) in patients with hypertriglyceridemia. Objective: To examine the effects of POM3 plus atorvastatin versus placebo plus atorvastatin on lipoprotein particle concentrations and sizes, apolipoprotein (Apo) CIII, and lipoprotein-associated phospholipase A2 mass in subjects with mixed dyslipidemia. Methods: After a 4-week diet lead in, men and women with non-HDL-C >160 mg/dL and TG 250-599 mg/dL, while taking no lipid-altering drugs, received double-blind 4 g/d POM3 (n = 118) or placebo (n = 119) with open-label atorvastatin 10 mg/d for 8 weeks, followed by escalation to 20 mg/d atorvastatin for 4 weeks, then 40 mg/d atorvastatin for 4 weeks. Results: Total low-density lipoprotein particle (LDL-P) concentration decreased significantly from baseline, and the reductions did not differ between the POM3 and placebo groups (−659.7 vs −624.4 nmol/L, P = .181). With POM3, compared with placebo, small LDL-P concentration decreased (P = .026), large LDL-P concentration increased (P < .001), mean LDL-P size increased (P = .001), a larger fraction of subjects switched from LDL subclass pattern B to A, and Apo CIII and lipoprotein-associated phospholipase A2 levels were reduced (P < .001). The incremental effects of POM3 were similar across atorvastatin doses for most variables. Conclusion: This analysis supports the view that LDL-P concentration is not increased by POM3 plus atorvastatin, relative to atorvastatin monotherapy, and is associated with potentially favorable shifts in LDL-P subfractions, Apo CIII and lipoprotein-associated phospholipase A2 in mixed dyslipidemia. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to systematically review the use of MRI for the evaluation of deployment characteristics of vaginal microbicides and to understand the relationship of gel spread with potential influencing factors., Methods: Data from four clinical trials that used MRI to assess the deployment of a vaginal gel were combined. A linear mixed model best represented the spread of gel over time. Significant covariates that influence vaginal gel spread are baseline dimensions of the vagina, time from insertion, gel type, ambulation and volume of gel., Results: These data demonstrate that MRI has outstanding intraperson validity and reproducibility. Therefore, paired design, using linear modeling adjusting for significant covariates, is the most efficient study design for comparison of products or volumes. Division of the vagina into two distinct anatomical regions best explains difference in gel spread, i.e., upper area (above the pelvic diaphragm) and lower area (below pelvic diaphragm)., Conclusion: We conclude that the concept of spread from the cervix to the introits, in one dimension, is inadequate to explain spread of gel due to the complex shape of the vagina.