DrugWAS: Drug-wide Association Studies for COVID-19 Drug Repurposing.

This study aimed to systematically investigate if any of the available drugs in the electronic health record (EHR) can be repurposed as potential treatment for coronavirus disease 2019 (COVID-19). Based on a retrospective cohort analysis of EHR data, drug-wide association studies (DrugWAS) were performed on 9,748 patients with COVID-19 at Vanderbilt University Medical Center (VUMC). For each drug study, multivariable logistic regression with overlap weighting using propensity score was applied to estimate the effect of drug exposure on COVID-19 disease outcomes. Patient exposure to a drug between 3-months prior to the pandemic and the COVID-19 diagnosis was chosen as the exposure of interest. All-cause of death was selected as the primary outcome. Hospitalization, admission to the intensive care unit, and need for mechanical ventilation were identified as secondary outcomes. Overall, 17 drugs were significantly associated with decreased COVID-19 severity. Previous exposure to two types of 13-valent pneumococcal conjugate vaccines, PCV13 (odds ratio (OR), 0.31, 95% confidence interval (CI), 0.12-0.81 and OR, 0.33, 95% CI, 0.15-0.73), diphtheria toxoid and tetanus toxoid vaccine (OR, 0.38, 95% CI, 0.15-0.93) were significantly associated with a decreased risk of death (primary outcome). Secondary analyses identified several other significant associations showing lower risk for COVID-19 outcomes: acellular pertussis vaccine, 23-valent pneumococcal polysaccharide vaccine (PPSV23), flaxseed extract, ethinyl estradiol, estradiol, turmeric extract, ubidecarenone, azelastine, pseudoephedrine, dextromethorphan, omega-3 fatty acids, fluticasone, and ibuprofen. In conclusion, this cohort study leveraged EHR data to identify a list of drugs that could be repurposed to improve COVID-19 outcomes. Further randomized clinical trials are needed to investigate the efficacy of the proposed drugs.

Estimating Baseline Incidence of Conditions Potentially Associated with Vaccine Adverse Events: a Call for Surveillance System Using the Korean National Health Insurance Claims Data.

BACKGROUND: Vaccines against coronavirus disease 2019 (COVID-19) are raising concerns about vaccine safety, particularly in the context of large-scale immunization. To address public concerns, we measured the baseline incidence rates of major conditions potentially related to vaccine-related adverse events (VAEs). We aimed to provide a basis for evaluating VAEs and verifying causality. METHODS: Conditions of interest were selected from the US Vaccine Adverse Event Reporting System Table of Reportable Events and a recent report from a European consortium on vaccine surveillance. We used the National Health Insurance Service database in Korea to identify the monthly numbers of cases with these conditions. Data from January 2006 to June 2020 were included. Prediction models were constructed from the observed incidences using an autoregressive integrated moving average. We predicted the incidences of the conditions and their respective 95% confidence intervals (CIs) for January through December 2021. In addition, subgroup analysis for the expected vaccination population was conducted. RESULTS: Mean values (95% CIs) of the predicted monthly incidence of vasovagal syncope, anaphylaxis, brachial neuritis, acute disseminated encephalomyelitis, Bell's palsy, Guillain-Barré syndrome, encephalopathy, optic neuritis, transverse myelitis, immune thrombocytopenic purpura, and systemic lupus erythematosus in 2021 were 23.89 (19.81-27.98), 4.72 (3.83-5.61), 57.62 (51.37-63.88), 0.03 (0.01-0.04), 8.58 (7.90-9.26), 0.26 (0.18-0.34), 2.13 (1.42-2.83), 1.65 (1.17-2.13), 0.19 (0.14-0.25), 0.75 (0.61-0.90), and 3.40 (2.79-4.01) cases per 100,000 respectively. The majority of the conditions showed an increasing trend with seasonal variations in their incidences. CONCLUSION: We measured the incidence of a total of 11 conditions that could potentially be associated with VAEs to predict the monthly incidence in 2021. In Korea, conditions that could potentially be related to VAEs occur on a regular basis, and an increasing trend is observed with seasonality.

Lifecycle management in pharmaceutical analysis: How to establish an efficient and relevant continued performance monitoring program.

It is the objective of a systematic and holistic Quality-by-Design approach to demonstrate and ensure that an analytical procedure is fit for its intended purpose over its entire lifecycle. Such a lifecycle approach, as proposed for a new USP General Information Chapter includes the three stages Procedure Design and Development, Procedure Performance Qualification, and Continued Procedure Performance Verification, in alignment to manufacturing process validation. A decisive component of this approach is the Analytical Target Profile, which defines the performance requirements for the measurement of a Quality Attribute as the target for selection, development and optimization of the respective analytical procedures. Although the most benefit can be gained by a comprehensive Quality-by-Design approach establishing the Analytical Target Profile in the very beginning of a drug development project, it may also be established retrospectively for analytical procedures long in routine use, in order to facilitate future lifecycle activities such as continual improvements, transfers, monitoring and periodic performance evaluations. In contrast to the first two stages of the analytical lifecycle with usually limited amount of data, the Continued Procedure Performance Verification stage offers the possibility to utilize a much more reliable data base to collect, analyze, and evaluate data that relate to analytical procedure performance. This monitoring program should be aligned as far as possible with other quality systems already in place and may include performance indicators such as Conformity (i.e. out-of specification test results with analytical root-cause), Validity (i.e. failure to meet method acceptance criteria, e.g. system suitability tests), and (numerical) analytical performance parameters (e.g. ranges for replicate determinations, control sample results, etc). In addition to the monitoring of analytical control parameters by means of control charts, average (pooled) performance parameters can be calculated. Over time, a large number of data can be included and thus the reliability of these estimates is increased tremendously. Such reliable estimates for the true performance parameters, e.g. repeatability or intermediate precision are essential to identify systematic effects (also called special cause variation) with good confidence. The intent of the analytical procedure performance evaluation is to identify substandard performance, identify root cause through investigations, and determine when additional activities are required to improve it. Examples are provided for the monitoring and evaluation of performance parameters for the compendial drug substance Furosemide and for biopharmaceutical applications.

Drug Safety Evaluation in China.

PURPOSE OF REVIEW: This review aimed to introduce the regulations management and current situations of drug safety evaluation in China. RECENT FINDINGS: The nationwide implementation of good laboratory practice and good clinical practice guarantees the quality of pre-marketing drug safety evaluation. In recent years, post-marketing drug safety monitoring is changing from passive mode to the combination of active and passive monitoring. A national adverse drug reaction monitoring sentinel alliance has been created to actively identify, report, and evaluate adverse reactions, with more than 1.4 million cases reported in 2017. But the quality of the reports is not optimal, with few reports from drug manufacturers, low rate of severe reports, and trend of lag reporting. Drug safety evaluation in China is transitioning from passive monitoring to a combination mode. Drug pharmacovigilance is a powerful tool for active monitoring, but participation by drug manufacturers would be essential to an effective drug safety evaluation system.

Post-marketing safety surveillance and re-evaluation of Xueshuantong injection.

BACKGROUND: Traditional Chinese medicine injections (TCMIs) have been widely used to treat severe and acute diseases due to their high bioavailability, accurate curative effect, and rapid effect. However, incidence rates of adverse drug reactions (ADRs) of TCMIs have also increased in recent years. Xueshuantong injection (XSTI) is a commonly-used TCMI comprised of Panax notoginseng total sapiens for the treatment of stroke hemiplegia, chest pain, and central retinal vein occlusion. Its safety remains uncelar. Therefore, post-marketing safety of XSTI was studied in this research. METHODS: In present study, post-marketing safety surveillance and re-evaluation of XSTI were reported. Thirty thousand eight hundred eighty-four patients in 33 hospitals from 7 provinces participated in this study. Incidence rate, most common clinical manifestations, types, severity, occurrence time, and disposal of ADRs were calculated. RESULTS: Incidence rate of ADR of XSTI was 4.14‰ and the most common clinical manifestations were skin and its appendages damage. Type A accounts for 95.49% of ADRs of XSTI and most of them (41.41%) were occurred within 24 h after receiving XSTI treatment. Severities of most ADRs of XSTI were moderate reactions (86.72%). Main disposition of ADRs of XSTI was drug withdrawal and symptomatic treatment (54.69%). CONCLUSIONS: Our data provide basis for improvement of instructions of XSTI and clinical safety of XSTI. Post-marketing surveillance of TCMIs in this study is a powerful tool to identify types and manifestations of ADRs to improve safety and effectiveness of drugs in clinical applications. TRIAL REGISTRATION: This protocol has international registration in China clinical trial registration center ( ChiCTR~OPC~ 14,005,718 ) at December 22, 2014.

Adverse Events to Food Supplements Containing Red Yeast Rice: Comparative Analysis of FAERS and CAERS Reporting Systems.

INTRODUCTION: Food supplements containing red yeast rice (RYR) are proposed as an alternative in statin-intolerant patients, although they actually contain natural statin(s) and their safety in clinical practice is still incompletely characterized. We described and compared adverse events (AEs) associated with RYR products submitted to reporting systems maintained by the Food and Drug Administration (FDA), with a focus on liver and muscular events. METHODS: We extracted RYR-related AEs from the FDA Adverse Event Reporting System (FAERS) [first quarter (Q1)-2004 to Q2-2016], a drug-based archive, and the Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS) (Q1-2004 to Q1-2017). Disproportionality via reporting odds ratio (ROR) with 95% confidence interval (CI) calculation and case-by-case inspection were performed, with a focus on muscular and hepatic AEs. RESULTS: One thousand three hundred AEs were extracted from FAERS (RYR mainly reported as a concomitant agent), whereas only 159 AEs were found in CAERS (RYR recorded mainly as a suspect agent). In FAERS, a large number of reports emerged for "general disorders and administration site conditions," whereas CAERS received also a high number of reports for "investigations" and "musculoskeletal and connective tissue disorders". Disproportionality analyses confirmed higher reporting of serious muscular and liver injuries: in FAERS, five cases of hepatic disorders (ROR = 13.71; 95% CI 5.44-34.57); in CAERS, 27 cases of rhabdomyolysis/myopathy (8.44; 5.44-13.10). CONCLUSIONS: Notwithstanding recognized limitations, these findings strengthen the importance of exploring multiple databases in safety assessment of RYR products, which should be monitored by clinicians for muscular and hepatic safety, and call for urgent review by policymakers to harmonize their regulatory status.

Adjuvanted (AS03) A/H1N1 2009 Pandemic Influenza Vaccines and Solid Organ Transplant Rejection: Systematic Signal Evaluation and Lessons Learnt.

INTRODUCTION: We investigated a signal of solid organ transplant (SOT) rejection after immunisation with (AS03) A/H1N1 2009 pandemic influenza vaccines. METHODS: Potential immunological mechanisms were reviewed and quantitative analyses were conducted. The feasibility of pharmacoepidemiological studies was explored. RESULTS: Overall results, including data from a pharmacoepidemiological study, support the safety of adjuvanted (AS03) pandemic influenza vaccination in SOT recipients. The regulatory commitment to evaluate the signal through a stepwise investigation was closed in 2014. CONCLUSION: Lessons learned highlight the importance of investigating plausible biological mechanisms between vaccines and potentially associated adverse outcomes, and the importance of selecting appropriate study settings and designs for safety signal investigations.

Protocol: changes in rates of opioid overdose and poisoning events in an integrated health system following the introduction of a formulation of OxyContin® with abuse-deterrent properties.

BACKGROUND: Addiction, overdoses and deaths resulting from prescription opioids have increased dramatically over the last decade. In response, several manufacturers have developed formulations of opioids with abuse-deterrent properties. For many of these products, the Food and Drug Administration (FDA) recognized the formulation with labeling claims and mandated post-marketing studies to assess the abuse-deterrent effects. In response, we assess differences in rates of opioid-related overdoses and poisonings prior to and following the introduction of a formulation of OxyContin® with abuse-deterrent properties. METHODS/DESIGN: To assess effects of this formulation, electronic medical record (EMR) data from Kaiser Permanente Northwest (KPNW) and Kaiser Permanente Northern California (KPNC) are linked to state death data and compared to chart audits. Overdose and poisoning events will be categorized by intentionality and number of agents involved, including illicit drugs and alcohol. Using 6-month intervals over a 10-year period, trends will be compared in rates of opioid-related overdoses and poisoning events associated with OxyContin® to rates of events associated with other oxycodone and opioid formulations. Qualitative interviews with patients and relatives of deceased patients will be conducted to capture circumstances surrounding events. DISCUSSION: This study assesses and tracks changes in opioid-related overdoses and poisoning events prior to and following the introduction of OxyContin® with abuse-deterrent properties. Public health significance is high because these medications are designed to reduce abuse-related behaviors that lead to important adverse outcomes, including overdoses and deaths.

[Post-marketing reevaluation for potential quality risk and quality control in clinical application of traditional Chinese medicines].

The effective quality control in clinical practices is an effective guarantee for the authenticity and scientificity of the findings. The post-marketing reevaluation for traditional Chinese medicines (TCM) focuses on the efficacy, adverse reaction, combined medication and effective dose of drugs in the market by expanded clinical trials, and requires a larger sample size and a wider range of patients. Therefore, this increases the difficulty of quality control in clinical practices. With the experience in quality control in clinical practices for the post-marketing reevaluation for Kangbingdu oral for cold, researchers in this study reviewed the study purpose, project, scheme design and clinical practice process from an overall point of view, analyzed the study characteristics of the post-marketing reevaluation for TCMs and the quality control risks, designed the quality control contents with quality impacting factors, defined key review contents and summarized the precautions in clinical practices, with the aim to improve the efficiency of quality control of clinical practices. This study can provide reference to clinical units and quality control-related personnel in the post-marketing reevaluation for TCMs.

Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance.

No consensus has previously been formed regarding the types and presentations of infectious pathogens to be considered as 'opportunistic infections' (OIs) within the setting of biologic therapy. We systematically reviewed published literature reporting OIs in the setting of biologic therapy for inflammatory diseases. The review sought to describe the OI definitions used within these studies and the types of OIs reported. These findings informed a consensus committee (infectious diseases and rheumatology specialists) in deliberations regarding the development of a candidate list of infections that should be considered as OIs in the setting of biologic therapy. We reviewed 368 clinical trials (randomised controlled/long-term extension), 195 observational studies and numerous case reports/series. Only 11 observational studies defined OIs within their methods; no consistent OI definition was identified across studies. Across all study formats, the most numerous OIs reported were granulomatous infections. The consensus group developed a working definition for OIs as 'indicator' infections, defined as specific pathogens or presentations of pathogens that 'indicate' the likelihood of an alteration in host immunity in the setting of biologic therapy. Using this framework, consensus was reached upon a list of OIs and case-definitions for their reporting during clinical trials and other studies. Prior studies of OIs in the setting of biologic therapy have used inconsistent definitions. The consensus committee reached agreement upon an OI definition, developed case definitions for reporting of each pathogen, and recommended these be used in future studies to facilitate comparison of infection risk between biologic therapies.