Scaled average bioequivalence methods for highly variable drugs: Leveling-off soft limits and the EMA's 2010 guideline (some ways to improve its type I error control).

The regulatory EMA's reference scaled average bioequivalence (RSABE) approach for highly variable drugs suffers from some type I error control problems at the neighborhood of the 30% coefficient of variation (CV), where the bioequivalence (BE) limits change from constant to linearly scaled. This paper analyses BE inference methods based on the "Leveling-off" (LO) soft sigmoid expanding BE limits that were proposed as an appealing surrogate for the EMA's limits and compares both approaches, on the replicated and partially replicated crossover designs. The initially proposed version of the LO method also has type I error inflation problems, albeit attenuated. But given its more mathematically regular character, it is more suitable for analytical corrections. Here we introduce two improvements over LO, one based on the application of Howe's method and the other based on correcting the estimation error. They further reduce the type I error inflation, although it does not disappear completely. Finally, the effect of heteroscedasticity on the above results is studied. It leads to inflation or deflation of the type I error, depending on the design and the type of heteroscedasticity (variability of the test product greater than that of the reference product or the opposite). The replicated design is much more stable against these effects than the partially replicated design and maintains these improvements much better.

Controlling type I error in the reference-scaled bioequivalence evaluation of highly variable drugs.

Reference-scaled average bioequivalence (RSABE) approaches for highly variable drugs are based on linearly scaling the bioequivalence limits according to the reference formulation within-subject variability. RSABE methods have type I error control problems around the value where the limits change from constant to scaled. In all these methods, the probability of type I error has only one absolute maximum at this switching variability value. This allows adjusting the significance level to obtain statistically correct procedures (that is, those in which the probability of type I error remains below the nominal significance level), at the expense of some potential power loss. In this paper, we explore adjustments to the EMA and FDA regulatory RSABE approaches, and to a possible improvement of the original EMA method, designated as HoweEMA. The resulting adjusted methods are completely correct with respect to type I error probability. The power loss is generally small and tends to become irrelevant for moderately large (affordable in real studies) sample sizes.

Consumer's risk in the EMA and FDA regulatory approaches for bioequivalence in highly variable drugs.

The 2010 US Food and Drug Administration and European Medicines Agency regulatory approaches to establish bioequivalence in highly variable drugs are both based on linearly scaling the bioequivalence limits, both take a 'scaled average bioequivalence' approach. The present paper corroborates previous work suggesting that none of them adequately controls type I error or consumer's risk, so they result in invalid test procedures in the neighbourhood of a within-subject coefficient of variation osf 30% for the reference (R) formulation. The problem is particularly serious in the US Food and Drug Administration regulation, but it is also appreciable in the European Medicines Agency one. For the partially replicated TRR/RTR/RRT and the replicated TRTR/RTRT crossover designs, we quantify these type I error problems by means of a simulation study, discuss their possible causes and propose straightforward improvements on both regulatory procedures that improve their type I error control while maintaining an adequate power. Copyright © 2015 John Wiley & Sons, Ltd.

Wireless fast-scan cyclic voltammetry measurement of histamine using WINCS--a proof-of-principle study.

Histamine is among the most poorly understood biogenic amines, yet the histaminergic system spreads throughout the brain and has been implicated in functions as diverse as homeostasis and synaptic plasticity. Not surprisingly then, it has been linked to a number of conditions including minimally conscious state, persistent vegetative state, epilepsy, addiction, cluster headache, essential tremor, and Parkinson's disease. We have previously reported that the Wireless Instantaneous Neurotransmitter Concentration Sensing (WINCS) system can monitor dopamine, serotonin, and adenosine using fast-scan cyclic voltammetry (FSCV). Here, we demonstrate the expanded capability of the WINCS system to measure histamine. The optimal FSCV waveform was determined to be a triangle wave scanned between -0.4 and +1.4 V at a rate of 400 V s(-1) applied at 10 Hz. Using this optimized FSCV parameter, we found histamine release was induced by high frequency electrical stimulation at the tuberomammillary nucleus in rat brain slices. Our results suggest that the WINCS system can provide reliable, high fidelity measurements of histamine, consistently showing oxidative currents at +1.3 V, a finding that may have important clinical implications.

Estudio clínico controlado aleatorizado para evaluación del Emdogain como terapia adjunta en el tratamiento de recesiones gingivales / Randomized controlled clinical trial for evaluation of Emdogain in adjunctive therapy in gingival recession treatment

Publicaciones previas han demostrado que las proteínas derivadas de la matriz del esmalte tienen la habilidad de mejorar los parámetros clínicos. El objetivo del presente artículo es comparar clínicamente los resultados con relación a profundidad de bolsa, nivel de inserción clínica al aplicar Emdogain más injerto de tejido conectivo (ITC) con colgajo posicionado coronal (CPC).