Developing, Planning and Conducting an Interim Analysis: Lessons From the DEVOTE Cardiovascular Outcomes Trial (Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Patients With Type 2 Diabetes at High Risk of Cardiovascular Events).

Background: In 2013, a randomized, double-blind, active comparator-controlled, event-driven cardiovascular outcomes trial (DEVOTE) was initiated to compare the cardiovascular safety of insulin degludec (degludec) versus insulin glargine 100 units/mL (glargine U100) in patients with type 2 diabetes at high risk of cardiovascular events. The FDA agreed that an interim analysis could form the basis for an early regulatory approval. We report here the operational model developed to support the DEVOTE interim analysis and the results.

Global regulatory standards for the approval of biosimilars.

On March 23, 2010, President Barack Obama signed into law the Patient Protection and Affordable Care Act, which contains the Biologics Price Competition and Innovation Act. Biosimilars have an important role in the United States health care system, and this new law creates an abbreviated approval pathway for biosimilar products in the U.S.

The influence of homogenisation conditions on biomass-adsorbent interactions during ion-exchange expanded bed adsorption.

Expanded bed adsorption (EBA) is an integrative step in downstream processing allowing the direct capture of target proteins from cell-containing feedstocks. Extensive co-adsorption of biomass, however, may hamper the application of this technique. The latter is especially observed at anion exchange processes as cells or cell debris are negatively charged under common anion exchange conditions.

Expanded bed adsorption as a primary recovery step for the isolation of the insulin precursor MI3 process development and scale up.

Expanded bed adsorption (EBA) was evaluated for the isolation of the human insulin precursor MI3, expressed and secreted by the yeast Saccharomyces cerevisiae. The isoelectric point of the insulin precursor (pH 5.3) makes cation exchange a prime candidate for direct adsorption.

Rational combinatorial chemistry-based selection, synthesis and evaluation of an affinity adsorbent for recombinant human clotting factor VII.

The selection, synthesis and chromatographic evaluation of a synthetic affinity adsorbent for human recombinant factor VIIa is described. The requirement for a metal ion-dependent immunoadsorbent step in the purification of the recombinant human clotting factor, FVIIa, has been obviated by using the X-ray crystallographic structure of the complex of tissue factor (TF) and Factor VIIa and has directed our combinatorial approach to select, synthesise and evaluate a rationally-selected affinity adsorbent from a limited library of putative ligands. The selected and optimised ligand comprises a triazine scaffold bis-substituted with 3-aminobenzoic acid and has been shown to bind selectively to FVIIa in a Ca(2+)-dependent manner.