Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products by the US Food and Drug Administration.

Highly variable (HV) drugs are defined as those for which within-subject variability (%CV) in bioequivalence (BE) measures is 30% or greater. Because of this high variability, studies designed to show whether generic HV drugs are bioequivalent to their corresponding HV reference drugs may need to enroll large numbers of subjects even when the products have no significant mean differences. To avoid unnecessary human testing, the US Food and Drug Administration's Office of Generic Drugs developed a reference-scaled average bioequivalence (RSABE) approach, whereby the BE acceptance limits are scaled to the variability of the reference product. For an acceptable RSABE study, an HV generic drug product must meet the scaled BE limit and a point estimate constraint. The approach has been implemented successfully. To date, the RSABE approach has supported four full approvals and one tentative approval of HV generic drug products.

Simultaneous heart rate and blood pressure variability analysis. Insight into mechanisms underlying neurally mediated cardiac syncope in children.

OBJECTIVES: The purpose of our investigation was to examine serial changes in autonomic nervous system activity along with measurements of hemodynamics and cardiac contractility, in assessing the mechanism(s) that underlie neurally mediated cardiac syncope (NMCS) in children. BACKGROUND: Previous research that used heart rate variability analysis alone to understand changes in autonomic activity that result in NMCS has provided conflicting results. We performed simultaneous heart rate and blood pressure variability analyses to characterize dynamic alterations in sympathetic and vagal tone during tilt-table testing in 23 children with a history of syncope or frequent dizziness. METHODS: Power spectra of heart rate and blood pressure variability were analyzed using autoregressive modeling. Maximum dP/dT of systolic blood pressure and the electrical-mechanical activation time were used to assess cardiac contractility. RESULTS: Tilt-table testing was positive in 12 children and negative in 11. Syncope was associated with decreased heart rate, blood pressure and low-frequency (LF) power. Before episodes of syncope, systolic blood pressure dP/dT decreased, and the electrical-mechanical activation time was prolonged. The decrease in blood pressure LF power exceeded and occurred before the decrease in heart rate LF power. Despite similar early increases in LF power to the initial stress of upright tilting, no significant decline in LF power (heart rate or blood pressure) was observed during negative tilt-table tests. CONCLUSIONS: All of these changes considered in total provide evidence supporting the hypothesis of sympathetic withdrawal/failure, resulting in a decrease in peripheral vascular tone and cardiac contractility, which results in profound hypotension in children with NMCS.