In pharmacovigilance, disproportionality analyses based on individual case safety reports are widely used to detect safety signals. Unfortunately, publishing disproportionality analyses lacks specific guidelines, often leading to incomplete and ambiguous reporting, and carries the risk of incorrect conclusions when data are not placed in the correct context. The REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance (READUS-PV) statement was developed to address this issue by promoting transparent and comprehensive reporting of disproportionality studies. While the statement paper explains in greater detail the procedure followed to develop these guidelines, with this explanation paper we present the 14 items retained for READUS-PV guidelines, together with an in-depth explanation of their rationale and bullet points to illustrate their practical implementation. Our primary objective is to foster the adoption of the READUS-PV guidelines among authors, editors, peer reviewers, and readers of disproportionality analyses. Enhancing transparency, completeness, and accuracy of reporting, as well as proper interpretation of their results, READUS-PV guidelines will ultimately facilitate evidence-based decision making in pharmacovigilance.

Purpose: We assessed pulmonary toxicity of cyclin-dependent kinase (CDK)4/6 inhibitors by analyzing the publicly available FDA Adverse Event Reporting System (FAERS). Methods: Reports of interstitial lung disease (ILD) were characterized in terms of demographic information, including daily dose, latency, concomitant drugs known to be associated with ILD, and causality assessment (adapted WHO system). Disproportionality analyses were carried out by calculating reporting odds ratios (RORs) with 95% confidence interval (CI), accounting for major confounders, including notoriety and competition biases. Results: ILD reports (N = 161) represented 2.1% and 0.3% of all reports for abemaciclib and palbocilcib/ribociclib, respectively, with negligible proportion of concomitant pneumotoxic drugs. Increased reporting was found for CDK4/6 inhibitors when compared to other drugs (ROR = 1.50; 95%CI = 1.28–1.74), and abemaciclib vs other anticancer agents (4.70; 3.62–5.98). Sensitivity analyses confirmed a strong and consistent disproportionality for abemaciclib. Higher-than-expected reporting emerged for palbociclib (1.38; 1.07–1.77) and ribociclib (2.39; 1.34–3.92) only when removing Japan reports. ILD occurred at recommended daily doses, with median latency ranging from 50 (abemaciclib) to 253 (ribociclib) days. Causality was highly probable in 55% of abemaciclib cases, probable in 68% of palbociclib cases. Conclusions: Increased reporting of ILD with CDK4/6 inhibitors calls for further comparative population-based studies to characterize and quantify the actual risk, taking into account drug- and patient-related risk factors. These findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals through FAERS and other real-world data, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of CDK4/6 inhibitors when diagnosing a lung injury.

In recent years, the volume of data collected by spontaneous reporting systems (SRS) has steadily increased, particularly for SRS with global coverage, namely the WHO VigiBase [1] and the US FDA Adverse Event Reporting System (FAERS, which also collects serious and unexpected events from the rest of the world) [2]. The sharing of their data through public dashboards has limitations because they have undergone only partial harmonisation and deduplication and, in the case of VigiBase, only provide access to aggregated data. Public dashboards should therefore be viewed with circumspection for research purposes, although they raise awareness among healthcare professionals and the public regarding the importance of reporting adverse events. Among these systems, FAERS stands out as the sole provider of complete and unrestricted access to its raw data (access to narratives can be achieved upon request). This feature allows researchers to exercise greater control over the data, as they can implement their own choices in the cleaning and codification, perform disproportionality analysis (DA) with different strata and groups of comparisons, as well as assess individual cases for drug safety investigations. The FAERS raw data can be sourced from the FDA as ASCII or XLM files, with some differences in the available variables. Several technical issues need to be addressed prior to any analysis, including duplicated reports, incomplete information, and non-standardised terms.

We analyzed thromboembolic events, recognized (AESIs), with cyclin-dependent kinase (CDK)4/6 inhibitors, using the Food and Drug Administration adverse event reporting system. Methods: Thromboembolic events were characterized in terms of spectrum [venous and arterial thromboembolism (VTE; ATE)] and clinical features by combining the disproportionality approach [reporting odds ratio (ROR) with 95% confidence interval (CI)] with individual case assessment. Results: A total of 1722 thromboembolic events were retained. Increased VTE reporting emerged for CDK4/6 inhibitors in the exploratory analyses (n = 659; ROR = 1.51; 95% CI = 1.39–1.63), with consistent disproportionality in the consolidated analyses (e.g., deep vein thrombosis with abemaciclib: 17; 1.98; 1.22–3.19). Higher-than-expected ATE reporting was found for ribociclib, including myocardial infarction (41; 1.82; 1.33–2.48), with rapid onset (median latency 1 vs. 6 months for other CDK4/6 inhibitors). Causality was highly probable or probable in 83.2% of cases, with a negligible proportion of pre-existing drug- and patient-related risk factors except for cardiovascular comorbidities (26%). Conclusions: Although causal association cannot be firmly inferred, oncologists should proactively monitor the occurrence of VTE with CDK4/6 inhibitors. The unexpected distinctive increased ATE reporting with ribociclib deserves urgent clarification though large comparative population-based studies. We support pharmacovigilance for the post-marketing characterization of AESIs, thus promoting real-time safe prescribing in oncology.

Introduction As chimeric antigen receptor T-cell therapies are becoming increasingly available in the armamentarium of the hematologist, there is an emerging need to monitor post-marketing safety. Objective We aimed to better characterize their safety profile by focusing on cytokine release syndrome and identifying emerging signals. Methods We queried the US Food and Drug Administration Adverse Event Reporting System (October 2017–September 2020) to analyze suspected adverse drug reactions to tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel). Disproportionality analyses (reporting odds ratio) were performed by comparing chimeric antigen receptor T-cell therapies with (a) all other drugs (reference group 1) and (b) other onco-hematological drugs with a similar indication, irrespective of age (reference group 2), or (c) restricted to adults (reference group 3). Notoriety was assessed through package inserts and risk management plans. Adverse drug reaction time to onset and cytokine release syndrome features were investigated. Results Overall, 3225 reports (1793 axi-cel; 1433 tisa-cel) were identified. The reported toxicities were mainly: cytokine release syndrome (52.2%), febrile disorders (27.7%), and neurotoxicity (27.2%). Cytokine release syndrome and neurotoxicity were often co-reported and 75% of the events occurred in the first 10 days. Disproportionalities confirmed known adverse drug reactions and showed unexpected associations: for example, axi-cel with cardiomyopathies (reporting odds ratio = 2.3; 95% confidence interval 1.2–4.4) and gastrointestinal perforations (2.9; 1.2–7.3), tisa-cel with hepatotoxicity (2.5; 1.1–5.7) and pupil disorders (15.3; 6–39.1). Conclusions Our study confirms the well-known adverse drug reactions and detects potentially emerging safety issues specific for each chimeric antigen receptor T-cell therapy, also providing insights into a stronger role for tisa-cel in inducing some immunodeficiency-related events (e.g., hypogammaglobulinemia, infections) and coagulopathies, and for axi-cel in neurotoxicity.

From 2009 to 2015, the IMI PROTECT conducted rigorous studies addressing questions about optimal implementation and significance of disproportionality analyses, leading to the development of Good Signal Detection Practices. The ensuing period witnessed the independent exploration of research paths proposed by IMI PROTECT, accumulating valuable experience and insights that have yet to be seamlessly integrated. This state-of-the-art review integrates IMI PROTECT recommendations with recent acquisitions and evolving challenges. It deals with defining the object of study, disproportionality methods, subgrouping, masking, drug-drug interaction, duplication, expectedness, the debated use of disproportionality results as risk measures, integration with other types of data. Despite the ongoing skepticism regarding the usefulness of disproportionality analyses and individual case safety reports, their ability to timely detect safety signals regarding rare and unpredictable adverse reactions remains unparalleled. Moreover, recent exploration into their potential for characterizing safety signals revealed valuable insights concerning potential risk factors and the patient's perspective. To fully realize their potential beyond hypothesis generation and achieve a comprehensive evidence synthesis with other kinds of data and studies, each with their unique limitations and contributions, we need to investigate methods for more transparently communicating disproportionality results and mapping and addressing pharmacovigilance biases.