title: A paradigm shift in drug development for treatment of rare multidrug-resistant gram-negative pathogens.
abstract: Multidrug-resistant (MDR) gram-negative pathogens pose a major threat to patients worldwide. Although the organisms remain relatively uncommon overall, their incidence is steadily increasing with associated increases in mortality and pharmacoeconomic impact. As evidenced by the dearth of new products in the pipeline or in clinical use, the conventional paradigm for the development of drugs against such pathogens is generally ineffectual. We advocate the need for a shift in the current paradigm and propose innovative development programs that involve implementation of a graduated approval process. The initial phase of the proposed regulatory paradigm includes early approval of a new drug based on a robust nonrandomized study, buttressed by data from concurrent controls and a pharmacokinetic-pharmacodynamic package generated from nonclinical studies. The postapproval commitment phase will include a randomized controlled trial, when disease prevalence permits, as well as continued assessment of risks and benefits under "real world" settings.
authors.affiliation: Clinical Research, Medicine Development Group, Specialty Care Business Unit, Pfizer, New York, New York, USA.
authors.forename: Demissie
authors.initials: D
authors.lastname: Alemayehu
authors.forename: John
authors.initials: J
authors.lastname: Quinn
authors.forename: Jack
authors.initials: J
authors.lastname: Cook
authors.forename: Mark
authors.initials: M
authors.lastname: Kunkel
authors.forename: Charles A
authors.initials: CA
authors.lastname: Knirsch
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017277:Drug Approval / Q000379:methods*; D055808:Drug Discovery / Q000379:methods*; D024901:Drug Resistance, Multiple, Bacterial; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D017408:Guidelines as Topic; D006801:Humans
chemical_list: D000900:Anti-Bacterial Agents