Key considerations in the preclinical development of biosimilars.

Biosimilar development requires several steps: selection of an appropriate reference biologic, understanding the key molecular attributes of that reference biologic and development of a manufacturing process to match these attributes of the reference biologic product. The European Medicines Agency (EMA) and the FDA guidance documents state that, in lieu of conducting extensive preclinical and clinical studies typically required for approval of novel biologics, biosimilars must undergo a rigorous similarity evaluation. The aim of this article is to increase understanding of the preclinical development and evaluation process for biosimilars, as required by the regulatory agencies, that precedes the clinical testing of biosimilars in humans.

GABAergic organization of the auditory cortex in the mustached bat (Pteronotus p. parnellii).

The structure and distribution of neurons and axon terminals (puncta) immunostained for gamma-aminobutyric acid (GABA) in the parietotemporal neocortex of the mustached bat (Pteronotus p. parnellii) was studied. The types of GABAergic neurons and puncta (putative terminals) were analyzed, and the immunocytochemical patterns were compared to those in cat auditory cortex (AC). The classic map of mustached bat primary auditory cortex (AI) corresponds to a belt of granular six-layered cortex on the temporal convexity. This area encompasses the Doppler-shifted constant frequency 60 kHz domain (DSCF) described in physiological investigations, as well as its flanking, low-frequency, posterior field (AIp) and the anterior high-frequency region (AIa). Many types of GABAergic neurons correspond to those in cat primary AC. However, the bat had a significantly lower proportion of such cells in five of the six layers. The classes of GABAergic neurons in most layers were small, medium-sized, and large multipolar cells, and bipolar and bitufted neurons. Types found in only one or two layers included horizontal cells (layers I and VI) or extraverted multipolar neurons (layer II). Only layer IV had comparable percentages (∼ 26%), suggesting that the GABAergic influence on lemniscal thalamocortical input is conserved phylogenetically. While the cellular basis for GABAergic cortical processing may reflect shared neural circuits and common modes of inhibitory processing, laminar differences could underlie adaptations specific to microchioptera.