New science, drug regulation, and emergent public health issues: The work of FDA's division of applied regulatory science.

The U.S. Food and Drug Administration (FDA) Division of Applied Regulatory Science (DARS) moves new science into the drug review process and addresses emergent regulatory and public health questions for the Agency. By forming interdisciplinary teams, DARS conducts mission-critical research to provide answers to scientific questions and solutions to regulatory challenges. Staffed by experts across the translational research spectrum, DARS forms synergies by pulling together scientists and experts from diverse backgrounds to collaborate in tackling some of the most complex challenges facing FDA. This includes (but is not limited to) assessing the systemic absorption of sunscreens, evaluating whether certain drugs can convert to carcinogens in people, studying drug interactions with opioids, optimizing opioid antagonist dosing in community settings, removing barriers to biosimilar and generic drug development, and advancing therapeutic development for rare diseases. FDA tasks DARS with wide ranging issues that encompass regulatory science; DARS, in turn, helps the Agency solve these challenges. The impact of DARS research is felt by patients, the pharmaceutical industry, and fellow regulators. This article reviews applied research projects and initiatives led by DARS and conducts a deeper dive into select examples illustrating the impactful work of the Division.

Management of autoimmune retinopathy treated with intravitreal dexamethasone implant.

PURPOSE: The purpose of this study is to evaluate clinical outcomes of autoimmune retinopathy (AIR) in the patients treated with intravitreal dexamethasone implant (IDI). METHOD: Twenty-one eyes of 11 AIR patients treated with at least 1 injection of IDI were retrospectively reviewed. Clinical outcomes before and after treatment, including best corrected visual acuity (BCVA), optic coherence tomography (OCT), fundus autofluorescence (FAF), full-field electroretinography (ff-ERG), and visual field (VF) at last visit within 6 and/or 12 months, were recorded. RESULTS: Among all the patients, 3 had cancer-associated retinopathy (CAR) and 8 had non-paraneoplastic-AIR (npAIR) with mean followed up of 8.52 ± 3.03 months (range 4-12 months). All patients achieved improved or stable BCVA within 6 and/or 12 months after the treatment. Cystoid macular edema (CME) in 2 eyes and significant retinal inflammation in 4 eyes were markedly resolved after single injection. Central retinal thickness (CFT) in all eyes without CME, ellipsoid zone (EZ) on OCT in 71.4% of eyes, ERG response in 55% of eyes, and VF in 50% of eyes were stable or improved within 6 months after treatment. At last visit within 12 months, both BCVA and CFT remained stable in the eyes treated with either single or repeated IDI; however, progression of EZ loss and damage of ERG response occurred in some patients with single IDI. CONCLUSION: Clinical outcomes, including BCVA and parameters of OCT, ERG, and VF, were stable or improved after IDI in a majority of AIR patients. Local treatment of AIR with IDI was a good option to initiate the management or an alternative for the patients' refractory to the systemic therapy but with limited side effect.

Ocular Adverse Events after Inactivated COVID-19 Vaccination.

PURPOSE: To report the clinical characteristics of ocular adverse events that have occurred, in China, after vaccination with inactivated COVID-19 vaccines. METHODS: A retrospective cross-sectional observational study was conducted of ocular disorders that occurred within 15 days from any dose of an inactivated COVID-19 vaccine. Information on gender, age, the interval between the vaccination and ocular symptoms, laterality, duration of the ocular symptoms, primary visual acuity, and clinical diagnosis were retrospectively collected. RESULTS: Twenty-four patients were involved in the study, including 15 females and 9 males, with a mean age of 41 ± 16 years (range of 8-71 years). The patients all denied a prior history of COVID-19 infection. Ocular adverse events occurred after the first dose of vaccine in 18 patients and, after the second or third doses, in six patients. The interval between vaccination with the inactivated COVID-19 vaccine and ocular symptoms was 6 ± 5 days; six patients were bilaterally involved and 18 patients were unilaterally involved. Regarding the diagnosis, 10 patients were diagnosed with white dot syndrome (WDS), 9 patients were diagnosed with uveitis, and 5 patients were diagnosed with retinal vascular disorders. The ages of patients with WDS were younger than those with uveitis or retinal vascular disorders (32 ± 10 vs. 48 ± 18, p < 0.05). For patients diagnosed with WDS, the best-corrected visual acuity (BCVA) was 0.74 ± 0.73 LogMAR. For patients diagnosed with retinal vascular disorders or uveitis, the BCVA was 1.44 ± 1.26 LogMAR. There was no significant difference (p > 0.05). CONCLUSIONS: A relationship cannot be established between inactivated COVID-19 vaccines and ocular disorders; therefore, further investigation of the clinical spectrum of ocular adverse events after vaccination with an inactivated COVID-19 vaccine is necessary.

Calibration and Validation of a Mechanistic COVID-19 Model for Translational Quantitative Systems Pharmacology - A Proof-of-Concept Model Development for Remdesivir.

With the ongoing global pandemic of coronavirus disease 2019 (COVID-19), there is an urgent need to accelerate the traditional drug development process. Many studies identified potential COVID-19 therapies based on promising nonclinical data. However, the poor translatability from nonclinical to clinical settings has led to failures of many of these drug candidates in the clinical phase. In this study, we propose a mechanism-based, quantitative framework to translate nonclinical findings to clinical outcome. Adopting a modularized approach, this framework includes an in silico disease model for COVID-19 (virus infection and human immune responses) and a pharmacological component for COVID-19 therapies. The disease model was able to reproduce important longitudinal clinical data for patients with mild and severe COVID-19, including viral titer, key immunological cytokines, antibody responses, and time courses of lymphopenia. Using remdesivir as a proof-of-concept example of model development for the pharmacological component, we developed a pharmacological model that describes the conversion of intravenously administered remdesivir as a prodrug to its active metabolite nucleoside triphosphate through intracellular metabolism and connected it to the COVID-19 disease model. After being calibrated with the placebo arm data, our model was independently and quantitatively able to predict the primary endpoint (time to recovery) of the remdesivir clinical study, Adaptive Covid-19 Clinical Trial (ACTT). Our work demonstrates the possibility of quantitatively predicting clinical outcome based on nonclinical data and mechanistic understanding of the disease and provides a modularized framework to aid in candidate drug selection and clinical trial design for COVID-19 therapeutics.

Hospital sewage treatment facilities witness the fighting against the COVID-19 pandemic.

Real-time evaluation of the fighting activities during a sudden unknown disaster like the COVID-19 pandemic is a critical challenge for control. This study demonstrates that the temporal variations of effluents from hospital sewage treatment facilities can be used as an effective indicator for such evaluation. Taking a typical infection-suffering city in China as an example, we found that there was an obvious decrease in effluent ammonia and COD concentrations in line with the start of city lockdown, and its temporal variations well indicated the major events happened during the pandemic control. Notably, the lagging period between the change point of effluent residual chlorine and the change points of COD and ammonia concentration coincided with a period in which there was a deficiency in local medical resources. In addition, the diurnal behavior of effluents from designated hospitals has varied significantly at different stages of the pandemic development. The effluent ammonia peaks shifted from daytime to nighttime after the outbreak of the COVID-19 pandemic, suggesting a high workload of the designated hospitals in fighting the rapidly emerging pandemic. This work well demonstrates the necessary for data integration at the wastewater-medical service nexus and highlights an unusual role of the effluents from hospital sewage treatment facilities in revealing the status of fighting the pandemic, which helps to control the pandemic.

A novel DNA and protein combination COVID-19 vaccine formulation provides full protection against SARS-CoV-2 in rhesus macaques.

The current study aims to develop a safe and highly immunogenic COVID-19 vaccine. The novel combination of a DNA vaccine encoding the full-length Spike (S) protein of SARS-CoV-2 and a recombinant S1 protein vaccine induced high level neutralizing antibody and T cell immune responses in both small and large animal models. More significantly, the co-delivery of DNA and protein components at the same time elicited full protection against intratracheal challenge of SARS-CoV-2 viruses in immunized rhesus macaques. As both DNA and protein vaccines have been proven safe in previous human studies, and DNA vaccines are capable of eliciting germinal center B cell development, which is critical for high-affinity memory B cell responses, the DNA and protein co-delivery vaccine approach has great potential to serve as a safe and effective approach to develop COVID-19 vaccines that provide long-term protection.