Use of real-world evidence in regulatory decisions for rare diseases in the United States-Current status and future directions.

Following the release of the framework for the Real-World Evidence (RWE) Program, the US Food and Drug Administration (FDA) is actively evaluating and exploring ways to optimize the utility of real-world data (RWD) and RWE to support regulatory decision making. For rare conditions, conducting traditional randomized clinical trials may not always be feasible, and RWD and RWE have played and will continue to play an important role. We use three case examples-cerliponase alfa, asfotase alfa, and uridine triacetate-to illustrate how RWD from disease registries, medical records with chart review, and literature, respectively, have been used to generate RWE to support regulatory decisions for selected rare diseases.

Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman primate model of perinatal asphyxia.

Background: Up to 65% of untreated infants suffering from moderate to severe hypoxic-ischemic encephalopathy (HIE) are at risk of death or major disability. Therapeutic hypothermia (HT) reduces this risk to approximately 50% (number needed to treat: 7-9). Erythropoietin (Epo) is a neuroprotective treatment that is promising as an adjunctive therapy to decrease HIE-induced injury because Epo decreases apoptosis, inflammation, and oxidative injury and promotes glial cell survival and angiogenesis.

Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics.

Objective: To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000-10000 U/L; area under the curve = 117000-140000 U*h/L).

Methods: In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE.

Characteristics of rare disease marketing applications associated with FDA product approvals 2006-2010.

New drug and biologic product marketing applications submitted to FDA's Center for Drug Evaluation and Research (CDER) between 2006 and 2010 were analyzed to identify rare disease application characteristics associated with higher approval rates. The results show that approval rates were similar for rare and common disease applications. Larger company size, prior regulatory experience and priority review designation were associated with higher approval rates.

A phase I/II trial of high-dose erythropoietin in extremely low birth weight infants: pharmacokinetics and safety.

Objectives: High-dose recombinant erythropoietin is neuroprotective in animal models of neonatal brain injury. Extremely low birth weight infants are at high risk for brain injury and neurodevelopmental problems and might benefit from recombinant erythropoietin. We designed a phase I/II trial to test the safety and determine the pharmacokinetics of high-dose recombinant erythropoietin in extremely low birth weight infants.

Pharmacokinetics of high-dose recombinant erythropoietin in plasma and brain of neonatal rats.

Recombinant human erythropoietin (rEpo) is neuroprotective in neonatal models of brain injury. Pharmacokinetic data regarding the penetration of circulating rEpo into brain tissue is needed to optimize neuroprotective strategies. We sought to determine the pharmacokinetics of rEpo given intraperitoneally or subcutaneously in plasma and brain.

Levofloxacin and ciprofloxacin decrease procainamide and N-acetylprocainamide renal clearances.

Ten healthy adults participated in a randomized, crossover drug interaction study testing procainamide only, procainamide plus levofloxacin, and procainamide plus ciprofloxacin. During levofloxacin therapy, most procainamide and N-acetylprocainamide (NAPA) pharmacokinetic parameters, including decreased renal clearances and renal clearance/creatinine clearance ratios, changed (P < 0.05).

Simulations of Levothyroxine Bioavailability Using a Single-Dose Study Protocol.

Computation of oral levothyroxine bioavailability parameters is hampered due to a long pharmacokinetic half-life and the secretion of endogenous levothyroxine hormone. To overcome these difficulties, Berg and Mayor (J Clin Pharmacol 1992; 32: 1135--1140) suggested the use of a single, supraphysiologic levothyroxine oral dosage protocol and measurement of levothyroxine area under the serum concentration versus time curves (AUC) for 48 h after dose administration. Since this protocol is a nonstandard methodology, simulations were performed to assess potential errors associated with the proposed method.