Reflections, operational lessons, and practical insights from a pharmacovigilance inspection: a case example of organizational strategies for medical safety readiness.

Background: Pharmacovigilance (PV) inspections are critical regulatory assessments that evaluate the robustness and compliance of a company's drug safety system. Despite their significance, there is limited published guidance on how organizations-particularly Medical Safety functions-can prepare operationally for such inspections.

Objectives: To share practical, experience-based insights and organizational strategies for inspection readiness, execution, and follow-up, based on a recent large-scale European Medicines Agency PV inspection.

Teratogenic Risk Impact Mitigation (TRIM): Development of Explicit Criteria to Facilitate Decisions Regarding Teratogenic Risk Mitigation Strategies.

Background: Preventing fetal exposure to teratogenic medications is an important target for risk mitigation efforts. Decisions about risk mitigation efforts specific to teratogenic medications are complex.

Objectives: The Teratogenic Risk Impact and Mitigation (TRIM) tool was developed as an innovative decision support tool to facilitate prioritization of teratogenic medications for risk mitigation strategies.

Leveraging Multi-National Observational Study in Post-Marketing Safety Assessment: Challenges and Strategies.

The use of multi-national observational study in post-marketing safety assessment has been rising in recent years in parallel with the rapid development and adoption of electronic healthcare data (e.g., administrative claims, electronic health records) and novel statistical analysis methods to handle these data.

Exploring the complexities of disproportionality analysis in pharmacovigilance: reflections on the READUS-PV guideline and a call to action.

The use of disproportionality analysis (DA) in pharmacovigilance to detect signals of disproportionate reporting (SDRs) has gained popularity, resulting in a surge of publications based on aggregate analysis of spontaneously reported adverse events (AE). The recently published READUS-PV guideline, designed to standardize reporting practices of DA-based publications, is a commendable first step toward standardizing DA reporting; however, it will not overcome totally many of the inherent limitations of DA including their inability to eliminate unnecessary noise in order to identify true signals. The limitations arise from the data sources of AEs, the analytic approaches, and the interpretability of the results.

Interplay of Spontaneous Reporting and Longitudinal Healthcare Databases for Signal Management: Position Statement from the Real-World Evidence and Big Data Special Interest Group of the International Society of Pharmacovigilance.

Signal management, defined as the set of activities from signal detection to recommendations for action, is conducted using different data sources and leveraging data from spontaneous reporting databases (SRDs), which represent the cornerstone of pharmacovigilance. However, the exponentially increasing generation and availability of real-world data collected in longitudinal healthcare databases (LHDs), along with the rapid evolution of artificial intelligence-based algorithms and other advanced analytical methods, offers a wide range of opportunities to complement SRDs throughout all stages of signal management, especially signal detection. Integrating information derived from SRDs and LHDs may reduce their respective limitations, thus potentially enhancing post-marketing surveillance.

Navigating Diverging Perspectives: Reasoning, Evidence, and Decision-Making in Drug Safety.

Decision making in drug safety is a complex and iterative process that requires the integration of diverse evidence sources, scientific reasoning, and clinical judgment. Diverging opinions among stakeholders-including pharmacovigilance professionals, regulatory authorities, clinical researchers, statisticians, and epidemiologists-often stem from differences in data interpretation, methodological approaches, and thresholds for concern or action. This paper examines the key sources of these divergences and presents a structured framework to enhance alignment in drug safety decision making.

Strategic Partnerships in Pharmacovigilance: Business, Legal, and Regulatory Domains.

Pharmaceutical development is a highly regulated industry through numerous worldwide guidance, laws, and regulations. Issues related to the safety of pharmaceutical products have been the most common cause of withdrawals from the market, as well as restrictions on distribution and limitations on labeling. Collaboration (hereafter referred to as partnership) between pharmaceutical companies in drug development has been recognized as critically significant to maximize the efficiency of drug development.

How can patient preferences be used and communicated in the regulatory evaluation of medicinal products? Findings and recommendations from IMI PREFER and call to action.

Patients have unique insights and are (in-)directly affected by each decision taken throughout the life cycle of medicinal products. Patient preference studies (PPS) assess what matters most to patients, how much, and what trade-offs patients are willing to make. IMI PREFER was a six-year European public-private partnership under the Innovative Medicines Initiative that developed recommendations on how to assess and use PPS in medical product decision-making, including in the regulatory evaluation of medicinal products.

Immunologic profiles in patients with chronic limb-threatening ischemia undergoing endovascular revascularization.

Background: Inflammation and immune dysregulation have been associated with adverse outcomes in cardiovascular disease. There is limited understanding of the association of different profiles of white blood cell (WBC) subsets and red cell distribution width (RDW) in patients with chronic limb-threatening ischemia (CLTI).

Methods: Patients with CLTI undergoing endovascular revascularization in our single-center, tertiary care hospital from 2017 to 2019, who had a preceding complete blood count (CBC) with WBC differentials ( =213), were included in the analysis.

Novel intracardiac echocardiography-guided catheter-based removal of inoperable tricuspid valve vegetation.

With the ongoing intravenous drug abuse (IVDA) epidemic, the number of IVDA patients with infective endocarditis is increasing. These cases are often characterized by large vegetations complicated by valvular dysfunction, heart failure, and recurrent septic pulmonary emboli demanding surgical intervention. Latter cannot be offered in a good proportion of the patients due to challenging medical and social complexities.

Predictors and potential advantages of PERT and advanced therapy use in acute pulmonary embolism.

Objectives: We sought to examine predictors of pulmonary embolism response team (PERT) utilization and identify those who could benefit from advanced therapy.

Background: PERT and advanced therapy use remain low. Current risk stratification tools heavily weight age and comorbidities, which may not always correlate with presentation's severity.

Prospective Experience of Pulmonary Embolism Management and Outcomes.

Objective: We sought to evaluate the impact of pulmonary embolism (PE) response teams (PERTs) on all consecutive patients with PE.

Background: Multidisciplinary PERTs have been promoted for the management and treatment of (PE); however, the impact of PERTs on clinical outcomes has not been prospectively evaluated.

Methods: We prospectively studied 220 patients with computed tomography (CT)-confirmed PE between January, 2019 and August, 2019.

The utility of real-world evidence for benefit-risk assessment, communication, and evaluation of pharmaceuticals: Case studies.

Purpose: In recent years, novel types of real-world evidence (RWE) have played a role in various decision-making processes relating to medicinal products, including regulatory approval, patient access, health technology assessment, safety monitoring, clinical use, and post-approval lifecycle management. We therefore reviewed the potential utility of RWE in the cycle of medicinal product benefit-risk (BR) assessment, communication/risk minimization and evaluation ("BRACE").

Methods: A convenience sample of illustrative studies was drawn from the published literature and examined.

Impact of COVID-19 pandemic on ST-elevation myocardial infarction in a non-COVID-19 epicenter.

Objectives: We sought to study the impact of COVID-19 pandemic on the presentation delay, severity, patterns of care, and reasons for delay among patients with ST-elevation myocardial infarction (STEMI) in a non-hot-spot region.

Background: COVID-19 pandemic has significantly reduced the activations for STEMI in epicenters like Spain.

Methods: From January 1, 2020, to April 15, 2020, 143 STEMIs were identified across our integrated 18-hospital system.

Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients With Peripheral Artery Disease (STOP-PAD) Trial: Six-Month Results.

To present the 6-month results of the tromal Cell-Derived Factor-1 Plasmid reatment fr atients with eripheral rtery isease (STOP-PAD) trial. The trial was an attempt to alter the course of chronic limb-threatening ischemia (CLTI) with a biological agent vs placebo after successful arterial revascularization at or below the knee. The multicenter, randomized, double-blinded, placebo-controlled, phase 2B STOP-PAD trial ( identifier NCT02544204) randomized 109 patients (mean age 71 years; 68 men) with Rutherford category 5 or 6 CLTI and evidence of persistent impaired forefoot perfusion following recent successful revascularization to 8- (n=34) or 16-mg (n=36) intramuscular injections of a non-viral DNA plasmid-based treatment vs placebo (n=34).

Personalized benefit-risk assessments combining clinical trial and real-world data provide further insights into which patients may benefit most from therapy: Demonstration for a new oral antiplatelet therapy.

Purpose: Quantitative benefit-risk (B-R) assessments are used to characterize treatment by combining key benefits and risks into a single metric but have historically been done for the "average" patient. Our aim was to conduct an individualized assessment for the oral antiplatelet vorapaxar by combining trial and real-world data to further personalize the treatment profiles.

Methods: Using linked UK health care databases, we developed risk prediction equations for key ischemic and bleeding events using Cox proportional hazards models.

SDF-1 plasmid treatment for patients with peripheral artery disease (STOP-PAD): Randomized, double-blind, placebo-controlled clinical trial.

The efficacy of biologic therapies in critical limb ischemia (CLI) remains elusive, in part, due to limitations in trial design and patient selection. Using a novel design, we examined the impact of complementing revascularization therapy with intramuscular JVS-100 - a non-viral gene therapy that activates endogenous regenerative repair pathways. In this double-blind, placebo-controlled, Phase 2B trial, we randomized 109 patients with CLI (Rutherford class V or VI) to 8 mg or 16 mg intramuscular injections of placebo versus JVS-100.

Associations of exercise ankle-brachial index, pain-free walking distance and maximum walking distance with the Peripheral Artery Questionnaire: Finding from the PORTRAIT PAD Registry.

An exercise ankle-brachial index (ABI) test can provide further insight into the functional significance of peripheral artery disease (PAD). The variability in its use, associated patient factors and its relation to patients' symptoms are unknown. From the international PORTRAIT registry, we identified 1131 patients with PAD.

Myocarditis Associated with Immune Checkpoint Inhibitors: An Expert Consensus on Data Gaps and a Call to Action.

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for cancer. Due to the mechanism of action of ICIs, inflammatory reactions against normal tissue were an anticipated side effect of these agents; these immune-related adverse events have been documented and are typically low grade and manageable. Myocarditis has emerged as an uncommon but potentially life-threatening adverse reaction in patients treated with ICIs.