title: Drug development for pediatric neurogenic bladder dysfunction: dosing, endpoints, and study design.
abstract: Pediatric drug development is challenging when a product is studied for a pediatric disease that has a different underlying etiology and pathophysiology compared to the adult disease. Neurogenic bladder dysfunction (NBD) is such a therapeutic area with multiple unsuccessful development programs. The objective of this study was to critically evaluate clinical trial design elements that may have contributed to unsuccessful drug development programs for pediatric NBD. Trial design elements of drugs tested for pediatric NBD were identified from trials submitted to the U.S. Food and Drug Administration. Data were extracted from publically available FDA reviews and labeling and included trial design, primary endpoints, enrollment eligibilities, and pharmacokinetic data. A total of four products were identified. Although all four programs potentially provided clinically useful information, only one drug (oxybutynin) demonstrated efficacy in children with NBD. The lack of demonstrable efficacy for the remainder of the products illustrates that future trials should give careful attention to testing a range of doses, using objectively measured, clinically meaningful endpoints, and selecting clinical trial designs that are both interpretable and feasible. Compiling the drug development experience with pediatric NBD will facilitate an improved approach for future drug development for this, and perhaps other, therapeutic areas.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA.
authors.forename: Jeremiah D
authors.initials: JD
authors.lastname: Momper
authors.forename: Alyson
authors.initials: A
authors.lastname: Karesh
authors.forename: Dionna J
authors.initials: DJ
authors.lastname: Green
authors.forename: Mark
authors.initials: M
authors.lastname: Hirsch
authors.forename: Mona
authors.initials: M
authors.lastname: Khurana
authors.forename: Jinoo
authors.initials: J
authors.lastname: Lee
authors.forename: Myong-Jin
authors.initials: MJ
authors.lastname: Kim
authors.forename: Yeruk
authors.initials: Y
authors.lastname: Mulugeta
authors.forename: Hari C
authors.initials: HC
authors.lastname: Sachs
authors.forename: Lynne
authors.initials: L
authors.lastname: Yao
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Burckart
mesh_terms: D000293:Adolescent; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003408:Cresols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003692:Delayed-Action Preparations; D006801:Humans; D007223:Infant; D008333:Mandelic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008387:Marine Toxins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D035964:Oxocins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010665:Phenylpropanolamine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013607:Tablets; D000068737:Tolterodine Tartrate; D001750:Urinary Bladder, Neurogenic / Q000188:drug therapy*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D001559:Benzhydryl Compounds; D003408:Cresols; D003692:Delayed-Action Preparations; D008333:Mandelic Acids; D008387:Marine Toxins; D018727:Muscarinic Antagonists; D035964:Oxocins; D011799:Quinazolines; D013607:Tablets; C549650:tamulamide A; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; C047638:alfuzosin; C005419:oxybutynin
keywords: clinical trial design; neurogenic bladder; pediatric urology; pharmacokinetics