Purpose: There is a need to develop hybrid trial methodology combining the best parts of traditional randomized controlled trials (RCTs) and observational study designs to produce real-world evidence (RWE) that provides adequate scientific evidence for regulatory decision-making. Methods: This review explores how hybrid study designs that include features of RCTs and studies with real-world data (RWD) can combine the advantages of both to generate RWE that is fit for regulatory purposes. Results: Some hybrid designs include randomization and use pragmatic outcomes; other designs use single-arm trial data supplemented with external comparators derived from RWD or leverage novel data collection approaches to capture longterm outcomes in a real-world setting. Some of these approaches have already been successfully used in regulatory decisions, raising the possibility that studies using RWD could increasingly be used to augment or replace traditional RCTs for the demonstration of drug effectiveness in certain contexts. These changes come against a background of long reliance on RCTs for regulatory decision-making, which are labor-intensive, costly, and produce data that can have limited applicability in real-world clinical practice. Conclusions: While RWE from observational studies is well accepted for satisfying postapproval safety monitoring requirements, it has not commonly been used to demonstrate drug effectiveness for regulatory purposes. However, this position is changing as regulatory opinions, guidance frameworks, and RWD methodologies are evolving, with growing recognition of the value of using RWE that is acceptable for regulatory decision-making.
Automation of pharmaceutical safety case processing represents a significant opportunity to affect the strongest cost driver for a company's overall pharmacovigilance budget. A pilot was undertaken to test the feasibility of using artificial intelligence and robotic process automation to automate processing of adverse event reports. The pilot paradigm was used to simultaneously test proposed solutions of three commercial vendors. The result confirmed the feasibility of using artificial intelligence–based technology to support extraction from adverse event source documents and evaluation of case validity. In addition, the pilot demonstrated viability of the use of safety database data fields as a surrogate for otherwise time‐consuming and costly direct annotation of source documents. Finally, the evaluation and scoring method used in the pilot was able to differentiate vendor capabilities and identify the best candidate to move into the discovery phase.
Objective To investigate the effects of maternal dexamethasone administration on umbilical and fetal Design Cross-sectional study.Setting Department of Obstetrics and Gynaecology, Robert Ballanger Hospital, Aulnay-sous-Bois, Sample Twenty-six pregnant women with singleton pregnancies considered at risk for preterm delivery.At baseline, all pregnancies had normal fetoplacental vascular resistance.Methods These women were given weekly six intravenous doses of 4 mg of dexamethasone eight hours apart.Main outcome measures Doppler studies were performed from both umbilical artery (UA) and fetal middle cerebral artery (MCA) before (day 0), during (day 2), immediately after (day 4) and shortly after (day 7) every steroid course.Results No significant variation was noted in both umbilical artery pulsatility index (PI) and fetal heart rate through dexamethasone therapy. Compared with mean initial values, we found on day 4 a significant decrease in MCA PI of 0.28 (F = 7.17, P c 0.001) and a significant increase in UA:MCA PI ratio of 0.08 (F = 3.85, P = 0.013); in contrast no significant change was documented on days 2 and 7 in both MCA pulsatility index and UA:MCA PI ratio. After multiple regression analysis, only the decrease in fetal middle cerebral artery pulsatility index on day 4 remained significant Conclusions The current study finds in healthy fetuses a transient, significant and unexplained decrease in fetal middle cerebral artery impedance on the fourth day following maternal dexamethasone administration. Further basic research and clinical studies including larger sample sizes or pregnancerebral artery flow velocity waveforms.France.(F=5.84, P = 0.001).cies with fetoplacental dysfunction are needed. that betamethasone and dexamethasone were associated with an increase in long term and short term variability and decreased fetal movements on the first day after steroid administration followed by a decline in fetal heart rate variability on the second day. Similarly, the trial of Mulder et aL6 reported a transient decrease in fetal heart rate variability and in fetal body and breathing movements after betamethasone; conversely, a rise in fetal heart rate variability was noted on the first day after dexamethasone. These effects are more obvious with betamethasone than dexamethas~ne~,~.'~. Evaluation of fetal wellbeing with Doppler waveform studies after maternal corticosteroid administration is therefore important. Knowledge of fetal haemodynamic effects of exogenous corticosteroids is limited. Little is known about the impact of antenatal 0 RCOG 2000 British Journal of Obstetrics and Gynaecology INTRODUCTION
Introduction Evidence-based clinical data on coronavirus disease 2019 (COVID-19) pharmacotherapies are scarce . Objective This study documented and characterized COVID-19 cases reported in individuals receiving treatment with Pfizer pharmaceutical products and cases that reported use of Pfizer pharmaceutical products for COVID-19 treatment. Methods This retrospective observational review leveraged the Pfizer safety database containing adverse event data collected in association with use of Pfizer products between 1 October, 2019, and 25 June, 2020; the database includes worldwide adverse event data from various sources. Selected Medical Dictionary for Drug Regulatory Activities (MedDRA ® ) Preferred Terms and subsequent clinical review were used to characterize COVID-19 cases. Results Over 1500 relevant cases were identified over an 8-month period. In cases that reported COVID-19, immunosuppressant/immunomodulating agents, followed by anticoagulant/antithrombic agents and corticosteroids, were the most frequently reported agents. The frequent reporting of immunosuppressant/immunomodulating agents among cases of COVID-19 suggests increased vulnerability to infection among treated patients, either because of immunosuppressive effects of certain agents or the nature of the underlying treated condition. In cases involving off-label pharmacotherapy use for the treatment of COVID-19-related conditions, the most frequently reported therapeutic classes included antibiotics, antimalarial agents, antivirals/antiretroviral agents, immunosuppressant/immunomodulating agents, corticosteroids, anticoagulants, and immunoglobulin/interferons. The most frequently reported pharmacotherapeutic agents were azithromycin and chloroquine/hydroxychloroquine, followed by lopinavir-ritonavir, ceftriaxone, and tofacitinib. The most frequently reported clinical adverse events associated with azithromycin (as sole therapy or combined with chloroquine/hydroxychloroquine) include electrocardiogram QT prolonged, drug interaction, hepatitis, diarrhea, and hepatitis acute. Regarding cardiac-related events, 19% (120/645) of azithromycin cases reported events associated with QT prolongation/torsade de pointes (which included seven fatal cardiac events). The most frequently reported clinical adverse events associated with other commonly used agents are also presented. Conclusions This pharmacovigilance surveillance study provides a unique characterization of cases in which a broad range of pharmaceutical products was reported in relation to COVID-19.
Future research is needed to find better refinements of query data and/or the metrics to improve the specificity of these web query log algorithms.
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