Systemic Barriers and Potential Concerns from Reporting Serious Adverse Drug Reactions.

About 1-10% of all serious adverse drug reactions (sADRs) are reported to the Food and Drug Administration (FDA) ( Moore T, Bennett C. Underreporting of Hemorrhagic and Thrombotic Complications of Pharmaceuticals to the U.S. Food and Drug Administration: Empirical Findings for Warfarin, Clopidogrel, Ticlopidine, and Thalidomide from the Southern Network on Adverse Reactions (SONAR). Semin Thromb Hemost. 2012;38(08):905-907. https://doi.org/10.1055/s-0032-1328890 ). Prevailing opinion suggests that low reporting rates reflect time constraints.

Maximum Accuracy Machine Learning Statistical Analysis-A Novel Approach.

Logistic regression is a statistical tool of paramount significance in the field of epidemiology1 and ranks as one of the most frequently published multivariable analyses for designs involving a single binary dependent variable and one or more independent variables in the fields of public health2,3 and medical4 research.

Investigating Severe Adverse Reactions: Examples of the ANTICIPATE Methodology at Work.

Severe adverse drug reactions (sADRs) are important causes of morbidity and mortality. The Southern Network on Adverse Drug Reactions (SONAR), a National Cancer Institute-funded pharmacovigilance program, has outlined a novel 9-stop methodology, termed ANTICIPATE, that has evaluated this methodology, among persons with chronic kidney disease (CKD).

Catalytic non-thermal plasma treatment of endocrine disrupting compounds, pharmaceuticals, and personal care products in aqueous solution: A review.

Contaminants of emerging concerns such as endocrine-disrupting compounds (EDCs) and pharmaceuticals/personal-care products (PPCPs) constitute a problem since they are not completely eliminated by traditional water and wastewater treatment methods. Non-thermal plasma (NTP) is considered as one of the most favorable treatment methods for the removal of organic contaminants in water and wastewater. The degradation of selected EDCs and PPCPs of various classes was reviewed, based on the recent literature, to (i) address the effect of the main NTP treatment parameters (water quality and NTP conditions: pH, initial concentration, temperature, background common ion, NOM, scavenger, gas type/flow rate, discharge/reactor type, input power, and energy efficiency/yield) on the degradation of contaminants and their intermediates, (ii) assess the influences of different catalysts and hybrid systems on degradation, (iii) describe EDC and PPCP degradation along with their properties, and (iv) evaluate mineralization, pathway, and degradation mechanism of selected EDCs and PPCPs for different cases studied. Furthermore, areas of potential research in NTP treatment for the degradation of EDCs and PPCPs in aqueous solutions are recommended. It could be reasonably predicted that this review is valid for developing our understanding of the fundamental scientific principles concerning the catalytic NTP of EDCs and PPCPs, providing helpful and practical references for researchers and designers on the effective removal of EDCs/PPCPs and the optimized operation of catalytic NTP systems.

Consequences to patients, clinicians, and manufacturers when very serious adverse drug reactions are identified (1997-2019): A qualitative analysis from the Southern Network on Adverse Reactions (SONAR).

BACKGROUND: Adverse drug/device reactions (ADRs) can result in severe patient harm. We define very serious ADRs as being associated with severe toxicity, as measured on the Common Toxicity Criteria Adverse Events (CTCAE)) scale, following use of drugs or devices with large sales, large financial settlements, and large numbers of injured persons. We report on impacts on patients, clinicians, and manufacturers following very serious ADR reporting. METHODS: We reviewed clinician identified very serious ADRs published between 1997 and 2019. Drugs and devices associated with reports of very serious ADRs were identified. Included drugs or devices had market removal discussed at Food and Drug Advisory (FDA) Advisory Committee meetings, were published by clinicians, had sales > $1 billion, were associated with CTCAE Grade 4 or 5 toxicity effects, and had either >$1 billion in settlements or >1,000 injured patients. Data sources included journals, Congressional transcripts, and news reports. We reviewed data on: 1) timing of ADR reports, Boxed warnings, and product withdrawals, and 2) patient, clinician, and manufacturer impacts. Binomial analysis was used to compare sales pre- and post-FDA Advisory Committee meetings. FINDINGS: Twenty very serious ADRs involved fifteen drugs and one device. Legal settlements totaled $38.4 billion for 753,900 injured persons. Eleven of 18 clinicians (61%) reported harms, including verbal threats from manufacturer (five) and loss of a faculty position (one). Annual sales decreased 94% from $29.1 billion pre-FDA meeting to $4.9 billion afterwards (p<0.0018). Manufacturers of four drugs paid $1.7 billion total in criminal fines for failing to inform the FDA and physicians about very serious ADRs. Following FDA approval, the median time to ADR reporting was 7.5 years (Interquartile range 3,13 years). Twelve drugs received Box warnings and one drug received a warning (median, 7.5 years following ADR reporting (IQR 5,11 years). Six drugs and 1 device were withdrawn from marketing (median, 5 years after ADR reporting (IQR 4,6 years)). INTERPRETATION: Because very serious ADRs impacts are so large, policy makers should consider developing independently funded pharmacovigilance centers of excellence to assist with clinician investigations. FUNDING: This work received support from the National Cancer Institute (1R01 CA102713 (CLB), https://www.nih.gov/about-nih/what-we-do/nih-almanac/national-cancer-institute-nci; and two Pilot Project grants from the American Cancer Society's Institutional Grant Award to the University of South Carolina (IRG-13-043-01) https://www.cancer.org/ (SH; BS).

The First 2 Years of Biosimilar Epoetin for Cancer and Chemotherapy-Induced Anemia in the U.S.: A Review from the Southern Network on Adverse Reactions.

Biosimilars are biologic drug products that are highly similar to reference products in analytic features, pharmacokinetics and pharmacodynamics, immunogenicity, safety, and efficacy. Biosimilar epoetin received Food and Drug Administration (FDA) approval in 2018. The manufacturer received an FDA nonapproval letter in 2017, despite receiving a favorable review by FDA's Oncologic Drugs Advisory Committee (ODAC) and an FDA nonapproval letter in 2015 for an earlier formulation. We discuss the 2018 FDA approval, the 2017 FDA ODAC Committee review, and the FDA complete response letters in 2015 and 2017; review concepts of litigation, naming, labeling, substitution, interchangeability, and pharmacovigilance; review European and U.S. oncology experiences with biosimilar epoetin; and review the safety of erythropoiesis-stimulating agents. In 2020, policy statements from AETNA, United Health Care, and Humana indicated that new epoetin oncology starts must be for biosimilar epoetin unless medical need for other epoetins is documented. Empirical studies report that as of 2012, reference epoetin use decreased from 40%-60% of all patients with cancer with chemotherapy-induced anemia to <5% of such patients because of safety concerns. Between 2018 and 2020, biosimilar epoetin use varied, increasing to 81% among one private insurer's patients covered by Medicare whose cancer care is administered with Oncology Analytics and to 41% with the same private insurer's patients with cancer covered by commercial health insurance and administered by the private insurer, to 0% in several Veterans Administration Hospitals, increasing to 100% in one large county hospital in California, and with yet-to-be-reported data from most oncology settings. We conclude that biosimilar epoetin appears to have overcome some barriers since 2015, although current uptake in the U.S. is variable. Pricing and safety considerations for all erythropoiesis-stimulating agents are primary determinants of biosimilar epoetin oncology uptake. IMPLICATIONS FOR PRACTICE: Few oncologists understand substitution and interchangeability of biosimilars with reference drugs. Epoetin biosimilar is new to the market, and physician and patient understanding is limited. The development of epoetin biosimilar is not familiar to oncologists.

Fate and transport of enveloped viruses in indoor built spaces - through understanding vaccinia virus and surface interactions.

The current coronavirus disease 2019 (COVID-19) pandemic has reinforced the necessity of understanding and establishing baseline information on the fate and transport mechanisms of viruses under indoor environmental conditions. Mechanisms governing virus interactions in built spaces have thus far been established based on our knowledge on the interaction of inorganic particles in indoor spaces and do not include characteristics specific to viruses. Studies have explored the biological and kinetic processes of microbes' attachments on surfaces in other fields but not in the built environment. There is also extensive literature on the influence of indoor architecture on air flow, temperature profiles, and forces influencing aerosol transport. Bridging the gap between these fields will lead to the generation of novel frameworks, methodologies and know-how that can identify undiscovered pathways taken by viruses and other microbes in the built environment. Our study summarizes the assessment of the influence of surface properties on the adhesion kinetics of vaccinia virus on gold, silica, glass, and stainless-steel surfaces. We found that on gold the virus layer was more viscoelastic compared to stainless-steel. There was negligible removal of the layer from the stainless-steel surface compared to the others. The results further highlight the importance of converging different fields of research to assess the fate and transport of microbes in indoor built spaces.

Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated Policy Review from the Southern Network on Adverse Reactions.

The EU, the USA, and Japan account for the majority of biological pharmacotherapy use worldwide. Biosimilar regulatory approval pathways were authorised in the EU (2006), in Japan (2009), and in the USA (2015), to facilitate approval of biological drugs that are highly similar to reference products and to encourage market competition. Between 2007 and 2020, 33 biosimilars for oncology were approved by the European Medicines Agency (EMA), 16 by the US Food and Drug Administration (FDA), and ten by the Japan Pharmaceuticals and Medical Devices Agency (PMDA). Some of these approved applications were initially rejected because of manufacturing concerns (four of 36 [11%] with the EMA, seven of 16 [44%] with the FDA, none of ten for the PMDA). Median times from initial regulatory submission before approval of oncology biosimilars were 1·5 years (EMA), 1·3 years (FDA), and 0·9 years (PMDA). Pharmacists can substitute biosimilars for reference biologics in some EU countries, but not in the USA or Japan. US regulation prohibits substitution, unless the biosimilar has been approved as interchangeable, a designation not yet achieved for any biosimilar in the USA. Japan does not permit biosimilar substitution, as prescribers must include the product name on each prescription and that specific product must be given to the patient. Policy Reviews published in 2014 and 2016 in The Lancet Oncology focused on premarket and postmarket policies for oncology biosimilars before most of these drugs received regulatory approval. In this Policy Review from the Southern Network on Adverse Reactions, we identify factors preventing the effective launch of oncology biosimilars. Introduction to the market has been more challenging with therapeutic than for supportive care oncology biosimilars. Addressing region-specific competition barriers and educational needs would improve the regulatory approval process and market launches for these biologics, therefore expanding patient access to these products in the EU, the USA, and Japan.

End of an era of administering erythropoiesis stimulating agents among Veterans Administration cancer patients with chemotherapy-induced anemia.

Erythropoisis stimulating agent (ESA) use was addressed in Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC) meetings between 2004 and 2008. FDA safety-focused regulatory actions occurred in 2007 and 2008. In 2007, black box warnings advised of early death and venous thromboembolism (VTE) risks with ESAs in oncology. In 2010, a Risk Evaluation Strategies (REMS) was initiated, with cancer patient consent that mortality and VTE risks were noted with ESAs. We report warnings and REMS impacts on ESA utilization among Veterans Administration (VA) cancer patients with chemotherapy-induced anemia (CIA). Data were from Veterans Affairs database (2003-2012). Epoetin and darbepoetin use were primary outcomes. Segmented linear regression was used to estimate changes in ESA use levels and trends, clinical appropriateness, and adverse events (VTEs) among chemotherapy-treated cancer patients. To estimate changes in level of drug prescription rate after policy actions, model-specific indicator variables as covariates based on specific actions were included. ESA use fell by 95% and 90% from 2005, for epoetin and darbepoetin, from 22% and 11%, respectively, to 1% and 1%, respectively, among cancer patients with CIA, respectively (p<0.01). Following REMS in 2010, mean hematocrit levels at ESA initiation decreased from 30% to 21% (p<0.01). Black box warnings preceded decreased ESA use among VA cancer patients with CIA. REMS was followed by reduced hematocrit levels at ESA initiation. Our findings contrast with privately- insured and Medicaid insured cancer patient data on chemotherapy-induced anemia where ESA use decreased to 3% to 7% by 2010-2012. By 2012, the era of ESA administration to VA to cancer patients had ended but the warnings remain relevant and significant. In 2019, oncology/hematology national guidelines (ASCO/ASH) recommend that cancer patients with chemotherapy-induced anemia should receive ESAs or red blood cell transfusions after risk-benefit evaluation.

End of an era for erythropoiesis-stimulating agents in oncology.

Erythropoiesis-stimulating agents (ESAs) are available to treat chemotherapy-induced anemia (CIA). In 2007-2008, regulatory notifications advised of venous thromboembolism and mortality risks while the Center for Medicare and Medicaid Services' restricted ESA initiation to patients with hemoglobin <10 g/dl. In 2010, a Risk Evaluation and Mitigation Strategies required consent prior to administration. We evaluated ESA utilization from 2003 to 2012 and obtained private health insurer claims data for persons with lung, colorectal, or breast cancer from 2001 to 2012. ESA use for CIA was determined by an ESA claim after chemotherapy, up to 6 months after treatment. We identified 839,948 commercially insured patients, including 24,785 patients with ESA-treated CIA (3.2%). Darbepoetin use increased 3.9-fold from 2003 to 2007 (12.3% to 48.7%) and then decreased 95% to 2.6% by 2012. Epoetin use decreased 90% from 2003 to 2012 (30.3% to 3.1%). Between 2003 and 2012, mean epoetin dosing decreased 0.8-fold (244,979 in 2003 vs. 196,216 units in 2012), but increased 1.8-fold for darbepoetin-treated CIA (262 in 2003 to 467 µg in 2012). Among CIA patients, transfusions were low (4.5%) in 2002-2007, then increased 2.2-fold between 2008 and 2012. Safety initiatives between 2007 and 2010 facilitated reductions in ESA use combined with changes in coverage. These data show the efficacy of regulatory efforts, publication of adverse events and changes in reimbursement in reducing use of ESAs. Future studies are warranted to optimize deimplementation strategies to improve patient safety.

Emission and dispersal of antibiotic resistance genes through bioaerosols generated during the treatment of municipal sewage.

Wastewater treatment plants act as socio-ecological couplers through the concentration, treatment, and subsequent environmental release of sewage collected from surrounding communities and are often considered hotspots for antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs). While studies have identified the release of ARB/ARGs in treated liquid sewage, little is known about potential dispersal through wastewater bioaerosol emissions. The aim of this study was to better define the contribution of WWTP bioaerosols to potential environmental distribution of ARB/ARGs. Bioaerosols were collected immediately upwind and downwind from the aeration tanks of a municipal wastewater treatment plant and liquid sludge samples were obtained from the aeration tanks. From the bioaerosol and liquid samples, qPCR assays identified 44 ARGs that confer resistance to a wide range of antibiotics. Comparison of the ARG profiles across samples showed that the downwind bioaerosol profile was 68% similar to the profile found in liquid sludge samples. Community 16S rRNA gene sequencing also showed that downwind bioaerosols had similar taxonomic profiles as those generated from liquid sludge while the upwind profiles showed a distinct difference. Preliminary ARG dispersion modeling estimated an ARG emission rate of ~10,620 genes per hour from the liquid sludge and indicated that the bioaerosols have the potential to be carried kilometers away from the WWTP source based on wind speed. The overall results from this study suggest that bioaerosols generated during WWTP processes can aid in the emission and dispersal of bacteria and ARGs, resulting in a possible route of human exposure and deposition into surrounding environments.

Regulatory and Clinical Experiences with Biosimilar Filgrastim in the U.S., the European Union, Japan, and Canada.

Biosimilar filgrastims are primarily indicated for chemotherapy-induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%-40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital-only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the "rebate trap" with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered. IMPLICATIONS FOR PRACTICE: We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing "rebate traps" where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.

Coupling Computational Fluid Dynamics Simulations and Statistical Moments for Designing Healthy Indoor Spaces.

Cross-contamination between occupants in an indoor space may occur due to transfer of infectious aerosols. Computational fluid dynamics (CFD) provides detailed insight into particle transport in indoor spaces. However, such simulations are site-specific. This study couples CFD with statistical moments and establishes a framework that transitions site-specific results to generating guidelines for designing "healthy" indoor spaces. Eighteen cases were simulated, and three parameters were assessed: inlet/outlet location, air changes per hour, and the presence/absence of desks. Aerosol release due to a simulated "sneeze" in a two-dimensional ventilated space was applied as a test case. Mean, standard deviation, and skewness of the velocity profiles and particle locations gave an overall picture of the spread and movement of the air flow in the domain. A parameter or configuration did not dominate the values, confirming the significance of considering the combined influence of multiple parameters for determining localized air-flow characteristics. Particle clustering occurred more when the inlet was positioned above the outlet. The particle dispersion pattern could be classified into two time zones: "near time", <60 s, and "far time", >120 s. Based on dosage, the 18 cases were classified into three groups ranging from worst case scenario to best case scenario.

Quantifying the sensitivity of feedstock properties and process conditions on hydrochar yield, carbon content, and energy content.

Hydrothermal carbonization (HTC) is a wet, low temperature thermal conversion process that continues to gain attention for the generation of hydrochar. The importance of specific process conditions and feedstock properties on hydrochar characteristics is not well understood. To evaluate this, linear and non-linear models were developed to describe hydrochar characteristics based on data collected from HTC-related literature. A Sobol analysis was subsequently conducted to identify parameters that most influence hydrochar characteristics. Results from this analysis indicate that for each investigated hydrochar property, the model fit and predictive capability associated with the random forest models is superior to both the linear and regression tree models. Based on results from the Sobol analysis, the feedstock properties and process conditions most influential on hydrochar yield, carbon content, and energy content were identified. In addition, a variational process parameter sensitivity analysis was conducted to determine how feedstock property importance changes with process conditions.

Sonocatalytic removal of ibuprofen and sulfamethoxazole in the presence of different fly ash sources.

We examined the feasibility of using two types of fly ash (an industrial waste from thermal power plants) as a low-cost catalyst to enhance the ultrasonic (US) degradation of ibuprofen (IBP) and sulfamethoxazole (SMX). Two fly ashes, Belews Creek fly ash (BFA), from a power station in North Carolina, and Wateree Station fly ash (WFA), from a power station in South Carolina, were used. The results showed that >99% removal of IBP and SMX was achieved within 30 and 60min of sonication, respectively, at 580kHz and pH 3.5. Furthermore, the removal of IBP and SMX achieved, in terms of frequency, was in the order 580kHz>1000kHz>28kHz, and in terms of pH, was in the order of pH 3.5>pH 7>pH 9.5. WFA showed significant enhancement in the removal of IBP and SMX, which reached >99% removal within 20 and 50min, respectively, at 580kHz and pH 3.5. This was presumably because WFA contains more silicon dioxide than BFA, which can enhance the formation of OH radicals during sonication. Additionally, WFA has finer particles than BFA, which can increase the adsorption capacity in removing IBP and SMX. The sonocatalytic degradation of IBP and SMX fitted pseudo first-order rate kinetics and the synergistic indices of all the reactions were determined to compare the efficiency of the fly ashes. Overall, the findings have showed that WFA combined with US has potential for treating organic pollutants, such as IBP and SMX, in water and wastewater.

Near-road modeling and measurement of cerium-containing particles generated by nanoparticle diesel fuel additive use.

Cerium oxide nanoparticles (nCe) are used as a fuel-borne catalyst in diesel engines to reduce particulate emissions, yet the environmental and human health impacts of the exhaust particles are not well understood. To bridge the gap between emission measurements and ambient impacts, size-resolved measurements of particle composition and mass concentration have been performed in Newcastle-upon-Tyne, United Kingdom, where buses have used an nCe additive since 2005. These observations show that the noncrustal cerium fraction thought to be associated with the use of nCe has a mass concentration ∼ 0.3 ng m(-3) with a size distribution peaking at 100-320 nm in aerodynamic diameter. Simulations with a near-roadway multicomponent sectional aerosol dynamic model predict that the use of nCe additives increases the number concentration of nuclei mode particles (<50 nm in diameter) while decreasing the total mass concentration. The near-road model predicts a downwind mass size distribution of cerium-containing particles peaking at 150 nm in aerodynamic diameter, a value similar to that measured for noncrustal cerium in Newcastle. This work shows that both the emission and atmospheric transformation of cerium-containing particles needs to be taken into account by regional modelers, exposure scientists, and policymakers when determining potential environmental and human health impacts.

Development of artificial neural network based metamodels for inactivation of anthrax spores in ventilated spaces using computational fluid dynamics.

Linear, quadratic, and artificial neural network (ANN)-based metamodels were developed for predicting the extent of anthrax spore inactivation by chlorine dioxide in a ventilated three-dimensional space over time from computational fluid dynamics model (CFD) simulation data. Dimensionless groups were developed to define the design space of the problem scenario. The Hammersley sequence sampling (HSS) method was used to determine the sampling points for the numerical experiments within the design space. A CFD model, comprised of multiple submodels, was applied to conduct the numerical experiments. Large eddy simulation (LES) with the Smagorinsky subgridscale model was applied to compute the airflow. Anthrax spores were modeled as a dispersed solid phase using the Lagrangian treatment. The disinfectant transport was calculated by solving a mass transport equation. Kinetic decay constants were included for spontaneous decay of the disinfectant and for the reaction of the disinfectant with the surfaces of the three-dimensional space. To enhance the mixing of the disinfectant with the room air, a momentum source was included in the simulation. An inactivation rate equation accounted for the reaction between the spores and the disinfectant. The ANN-based metamodels were most successful in predicting the number of viable bioaerosols remaining in an arbitrary enclosed space. Sensitivity analysis showed that the mass fraction of the disinfectant, inactivation rate constant, and contact time had the most influence on the inactivation of the spores.