Elements of Regulatory Dissonance: Examining FDA and EMA Product Labeling of New Vaccines (2006-2018).

With the ongoing globalization of the pharmaceutical industry, efforts to harmonize technical requirements of registering drugs and biologics, including vaccines, have produced a number of useful guidelines utilized around the world. However, such efforts have not been extended to the regulatory review process or product labeling. Prescribing information and patient information leaflet are two types of such product labeling documents. This study examined the differences in the languages of these documents between the United States (US) and European Union (EU). The key documents examined were the U.S. Food & Drug Administration's (FDA) Package Inserts (PIs), U.S. Centers for Disease Control and Prevention's (CDC) Vaccine Information Statements (VISs), and the European Medicines Agency's (EMA) Summary of Product Characteristics (SmPCs) and Package Leaflets (PLs). Prescribing information and patient information leaflet languages were subsequently organized into ten and seven categories, respectively. Comparison of FDA PIs to EMA SmPCs showed little harmonization between the two regions, and CDC VISs to EMA PLs revealed even less.

A novel pharmacotherapy approach using P-glycoprotein (PGP/ABCB1) efflux inhibitor combined with ivermectin to reduce alcohol drinking and preference in mice.

Alcohol use disorder (AUD) has a major national impact, affecting over 18 million people, causing approximately 88,000 deaths, and costing upward of $250 billion annually in the United States. Unfortunately, FDA-approved AUD pharmaceuticals are few, and clinical benefits are mostly ineffective in patients suffering from AUD. Therefore, the identification of novel targets and/or innovative methods for the development of safe and effective medications represents a critical public health need. Previously, we reported that avermectin compounds (ivermectin [IVM] and moxidectin [MOX]) significantly reduced ethanol intake in male and female mice. However, avermectin compounds are readily effluxed by P-glycoprotein (Pgp/ABCB1) in the blood-brain barrier (BBB), resulting in reduced retention time by the drugs in the central nervous system (CNS). As such, the doses of IVM or MOX and the time frame for significant reductions of ethanol intake are not ideal. Here we evaluate a novel combinatorial strategy involving IVM and tariquidar (TQ), a third-generation efflux inhibitor of Pgp, to reduce the dosing necessary for improving alcohol (ethanol) consumption behavior. We tested male C57BL/6J mice using a two-bottle choice study to evaluate ethanol consumption and preference. We found that injecting 10 mg/kg of TQ 30 min prior to IVM resulted in a five-fold improvement in the efficacy of IVM (dosed at 0.5 mg/kg), resulting in a significant reduction in ethanol intake and preference. Notably, the reduction by IVM was well tolerated, and no adverse effects were identified when tested at doses ranging from 0.50 mg/kg to 2.0 mg/kg. Collectively, our findings indicate that IVM, in combination with TQ, increases its efficacy in the CNS for reducing ethanol consumption. This work demonstrates a novel combinatorial drug strategy that allows new opportunities for drugs with poor CNS retention, such as IVM, to demonstrate improved potency and potentially improved safety.