Common Deficiencies of <Emphasis Type="Italic">in vitro</Emphasis> Binding Bioequivalence (BE) Studies Submitted in Abbreviated New Drug Applications (ANDAs)

There are several drug products that bind phosphate or bile acid in the gastrointestinal (GI) tract to exert their therapeutic efficacy. In vitro binding studies are used to assess bioequivalence (BE) of these products. The objective of this study is to identify the common deficiencies in Abbreviated New Drug Applications (ANDAs) for these products. Deficiencies were compiled from ANDAs containing in vitro binding BE studies. The deficiencies were classified into eight categories: Pre-Study Method Validation, During-Study Sample Analysis, Study Design, Study Procedure, Dissolution/Disintegration, Analytical Site Inspection, Data Submission, and Formulations. Within each category, additional subcategories were defined to characterize the deficiencies. A total of 712 deficiencies from 95 ANDAs for 11 drug products were identified and included in the analysis. The four categories with the most deficiencies were During-Study Sample Analysis (27.8%), Pre-Study Method Validation (17.3%), Data Submission (16.7%), and Study Design (15.7%). For the During-Study Sample Analysis category, failure to submit complete raw data or analytical runs ranked as the top deficiency (32.8%). For the Study Design category, using an unacceptable alternate study design (26.8%) was the most common deficiency. Within this category, other commonly occurring deficiencies included incorrect/insufficient number of absorbent concentrations, failure to pre-treat drug product with acid, insufficient number of replicates in study, incorrect calculation of k1 and k2 values, incorrect dosage form or pooled samples used in the study, and incorrect pH of study medium. The review and approval of these products may be accelerated if these common deficiencies are addressed in the original ANDA submissions.     

Severe Herpes Zoster Requiring Intravenous Antiviral Treatment in Allogeneic Hematopoietic Cell Transplantation Recipients on Standard Acyclovir Prophylaxis

Allogeneic hematopoietic cell transplantation (HCT) recipients are at increased risk for varicella zoster virus (VZV) reactivation and associated complications. The incidence, timing, and risk factors for severe herpes zoster (HZ) are not well described in the era of acyclovir (ACV) prophylaxis. We performed a retrospective cohort study of all patients who underwent first allogeneic HCT between October 2006 and December 2015 at our institution. Patients were followed until December 2017 for the development of severe HZ, defined as necessitating administration of i.v. antiviral medication. Out of 2163 patients who underwent allogeneic HCT, 22 (1.0%) developed severe HZ at a rate of 1 per 228 person-years, including dermatomal/multidermatomal disease (n = 5), disseminated skin disease (n = 5), HZ ophthalmicus (n = 4), meningitis/encephalitis (n = 4), pneumonia (n = 2), viremia (n = 1), and erythema multiforme (n = 1). Severe HZ infection occurred in a bimodal distribution during the early peri-HCT period and at 12 to 24 months post-HCT (median, 12.7 months). Twelve patients (54.5%) were compliant with ACV prophylaxis at the time of HZ diagnosis. Eleven patients (50%) died during the study period, only 2 of whom (9.1%) with active VZV infection. Mortality was higher in patients on immunosuppressive therapy (62.5% versus 16.7%; P = .045) and with concurrent graft-versus-host disease (75.0% versus 35.7%; P= .044). These data suggest that severe HZ remains an important consideration despite ACV prophylaxis.