Evaluation of FDA Labeling Changes Related to PREA Safety-Waivers.

PURPOSE: The Pediatric Research Equity Act (PREA) gives the US Food and Drug Administration (FDA) authority to require pediatric studies for drug and biologics products under certain circumstances and to waive this requirement in some, or all, pediatric ages. When studies are waived for safety, PREA stipulates the safety issue must be described in labeling. This study assessed the rate of including waiver-related safety information in labeling. METHODS: FDA databases were reviewed to determine the number of safety-related pediatric study waivers and issued from December 2003 through August 2020, and corresponding labeling to establish when relevant safety information was included. Descriptive comparisons were conducted across Cohort 1: December 2003-2007, Cohort 2: 2008-2011, Cohort 3: 2012-2015, and Cohort 4: 2016-August 2020. RESULTS: One hundred sixteen safety waivers were issued [Cohort 1 (n = 1); Cohort 2 (n = 38), Cohort 3 (n = 37), and Cohort 4 (n = 40)] for 84 unique drugs or biologics. Most (106 of 116; 91%) waiver-related safety issues were described in labeling [Cohort 1 (1 of 1), Cohort 2 (33 of 38), Cohort 3 (33 of 37), and Cohort 4 (39 of 40)]. Safety waivers were most common in patients ≤ 17 years (n = 40) and least common in patients ≤ 6 months (n = 15). Products for infections (n = 32) were the most common group receiving safety waivers; 17 for non-antiviral anti-infective products including treatments for dermatologic infestations/infections, and 15 for antiviral products. CONCLUSION: The data confirm that FDA consistently describes waiver-related safety information in drug/biologic product labeling since the inception of PREA in December of 2003.

Considerations and Challenges in the Remdesivir COVID-19 Pediatric Development Program.

The US Food and Drug Administration is committed to the development of effective antiviral regimens for pediatric patients with coronavirus disease 2019 (COVID-19), including infants and neonates. On April 25, 2022, the approved indication of remdesivir (RDV) was expanded to include pediatric patients 28 days and older and weighing at least 3 kg with positive results of direct severe acute respiratory syndrome coronavirus 2 viral testing, who are: Hospitalized, or Not hospitalized and have mild to moderate COVID-19 and are at high risk for progression to severe COVID-19, including hospitalization or death. Given the similar course of COVID-19 in adults and pediatric patients, the approval of RDV for use in pediatric patients is supported by the safety and efficacy data from adequate and well-controlled phase 3 trials in adults and adolescents; and by the safety and pharmacokinetic data from a single-arm, open-label, phase 2/3 pediatric clinical trial of 53 pediatric patients at least 28 days of age and weighing at least 3 kg with confirmed severe acute respiratory syndrome coronavirus 2 infection and mild, moderate, or severe COVID-19. At the time of the April 25, 2022, approval action, the US Food and Drug Administration also revoked the emergency use authorization for RDV that previously covered this pediatric population. This article summarizes key issues and regulatory considerations involved in the RDV COVID-19 pediatric development program, including the evolution of the emergency use authorization issued for RDV as results from registrational studies became available, and discusses lessons learned.

Modeling and simulation of the effect of proton pump inhibitors on magnesium homeostasis. 1. Oral absorption of magnesium.

Prolonged use of proton pump inhibitors has reportedly caused rare clinically symptomatic hypomagnesemia. A review of the literature suggests PPI drugs may impair intestinal magnesium absorption. With the goal of preventing PPI-induced hypomagnesemia, an oral absorption-centric model was developed by referencing literature data. Our modeling with human data reveals that magnesium absorption is substantial in the distal intestine. We then perform simulations by referring to the reported reduction in mid to distal intestinal pH caused by one week of oral esomeprazole, and to reported reduction of the divalent cation-sensitive current when the carboxyl side chains of glutamic and aspartic residues in the binding channels of TRPM6/TRPM7 were neutralized. Our simulations reveal that short-term PPI therapy may cause a very small reduction (5%) in the serum magnesium level, which is qualitatively consistent with the reported 1% reduction in magnesium absorption following 1 week of omeprazole in humans. Simulations provide insight into the benefit of frequent but small dose of magnesium supplementation in maintaining the serum magnesium level when magnesium deficiency occurs.

Regulatory aspects of total product life cycle.

Total Product Life Cycle (TPLC) is a conceptual framework for assessing any product or service (medical or otherwise). This article will address how the Center for Devices and Radiological Health of the U.S. Food and Drug Administration utilizes TPLC in a regulatory paradigm. TPLC will help guide the regulation of market-driven evolution of medical devices and radiation-emitting products from conception, through pre-market development, to widespread market use, and finally to obsolescence and replacement by subsequent generations of products.

Consumers report glucose meter problems to FDA.

OBJECTIVE: Glucose meters have unquestionable clinical utility, particularly in management of diabetes mellitus. U.S. Food and Drug Administration (FDA) surveillance activities include monitoring adverse event reports from healthcare professionals, manufacturers, and lay users. METHODS: To gain insight into problems reported to FDA on glucose meters, we analyzed reports received over a 3-year period (2000-2002) from all sources (mandatory and voluntary) and focused on reports from users. RESULTS: The vast majority of in vitro diagnostic device (IVD) reports (84%, n = 18,959) were on glucose meters, with 333 glucose meter reports from users. Among the user reports, the most common problems were false high or low values and erratic values. Unique issues reported included purchase of incorrect glucose meter strips, calibration problems, and misunderstanding how FDA regulates glucose device performance. CONCLUSION: The FDA gains valuable insight from and encourages user reports.