Narrow therapeutic index drugs are defined as those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. The US Food and Drug Administration proposes that the bioequivalence of narrow therapeutic index drugs be determined using a scaling approach with a four-way, fully replicated, crossover design study in healthy subjects that permits the simultaneous equivalence comparison of the mean and within-subject variability of the test and reference products. The proposed bioequivalence limits for narrow therapeutic index drugs of 90.00%-111.11% would be scaled based on the within-subject variability of the reference product. The proposed study design and data analysis should provide greater assurance of therapeutic equivalence of narrow therapeutic index drug products.

Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction, Molecular Genetics and Metabolism (2015), doi: 10.1016/j.ymgme.2015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The opinions presented herein are those of the authors and do not reflect the positions of all participants nor the institutions they represent. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT

The Biomarker Qualification Program was established at the Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA) to expedite the integration of promising biomarkers across multiple drug development programs. The first set of biomarkers qualified in 2008 consisted of seven nonclinical safety biomarkers for the detection of acute drug-induced nephrotoxicity in rats, and included urinary kidney injury molecule-1 (KIM-1). This article discusses the use of KIM-1 in drug development and research before and after CDER's qualification of KIM-1. Use was determined by analyzing relevant documents identified by keyword searches using three databases: 1) an FDA internal database, Document Archiving, Reporting, and Regulatory Tracking System (DARRTS); 2) ClinicalTrials.gov; and 3) PubMed. The results indicate increased use of KIM-1 as a biomarker for detection of kidney injury in drug development programs reviewed by CDER, as well as in research following qualification.

BackgroundThe COVID-19 public health emergency limited the U.S. Food and Drug Administration’s ability to conduct on-site good clinical practice (GCP) inspections. Alternative tools therefore have been used by FDA during the pandemic to evaluate the reliability and integrity of clinical trial data for marketing applications. However, no systematic assessment of the pandemic impact on in-person GCP inspections has been conducted. In addition, the alternative tools and their contribution to GCP oversight have not been reported.   MethodsThis retrospective study reviewed databases internal to FDA and identified and characterized alternative tools used in lieu of on-site GCP inspections in fiscal year (FY)*2020 and FY2021. The impact of the pandemic on on-site GCP inspections and the contribution of alternative tools to overall GCP activities** were described. ResultsBetween April 13, 2020, and September 30, 2021, FDA conducted 77 GCP evaluations using alternative tools. Alternative tools were used most commonly for GCP evaluations of non-U.S. clinical investigators in support of mission critical, original New Drug Applications (NDAs). FDA conduced 370 on-site GCP inspections in FY2020 and 451 in FY2021, which represented a 23% and 6% decrease, respectively, compared to the yearly average of 481 on-site GCP inspections in the 5 years preceding the pandemic. The use of alternative tools contributed 10% and 8% to total GCP activities in FY2020 and FY2021, respectively.ConclusionGCP evaluations using alternative tools have played a significant role in GCP activities supporting the review of marketing applications during the COVID-19 public health emergency. KeywordsCOVID-19 pandemic, public health emergency, remote regulatory assessment (RRA), good clinical practice, remote inspection, FDA. *Fiscal year is defined as from October 1 to September 30.**GCP activities in this paper refers to on-site inspections and GCP evaluations using alternative tools conducted by the Office of Regulatory Affairs or the GCP Assessment Branch in the Division of Clinical Compliance Evaluation in the Office of Scientific Investigations in support of marketing applications submitted to the Center for Drug Evaluation and Research at FDA.