Adverse Events In Clinical Trials Research Articles

Ensuring safety and monitoring adverse events in clinical trials: Challenges and innovations

Safety and adverse events (AEs) monitoring in clinical trials are critical to ensuring participant safety and the successful development of new therapies. Effective monitoring not only protects patients but also helps identify any risks associated with the investigational product. This paper elaborates on the methodologies used to detect, categorize, and report adverse events during clinical trials, and how these processes are governed by stringent regulatory frameworks. Additionally, the discussion highlights the role of pharmacovigilance systems, the ethical obligations researchers face in AE reporting, and the technological innovations that are transforming safety monitoring. Challenges, including under-reporting, data variability, and interpretation difficulties, are examined in depth. Ultimately, advancements in real-time data collection, adaptive trial designs, and artificial intelligence (AI) are promising to improve the accuracy and timeliness of adverse event monitoring, shaping the future of clinical research and patient safety.

Managing Adverse Events in Clinical Trials with R and Shiny

Adverse events (AEs) are critical occurrences that can significantly impact patient safety and the overall success of clinical trials. Effective management of AEs is essential for ensuring regulatory compliance and safeguarding participants' well-being. This paper explores the integration of R and Shiny as innovative tools for the real-time monitoring, visualization, and analysis of AEs in clinical trials. By leveraging R’s robust statistical capabilities and Shiny’s interactive interface, researchers can enhance data management processes, facilitate informed decision- making, and foster collaboration among stakeholders. A case study is presented to illustrate the practical application of R Shiny in tracking AEs, demonstrating its effectiveness in improving trial outcomes and ensuring patient safety. The findings emphasize the need for adopting dynamic data analysis tools to optimize adverse event management in the evolving landscape of clinical research. KEYWORDS Adverse Events, Clinical Trials, R, Shiny, Data Management, Visualization, Real-Time Monitoring, Patient Safety.

High-Throughput Assay for Predicting Diarrhea Risk Using a 2D Human Intestinal Stem Cell-Derived Model.

Gastrointestinal toxicities (GITs) are the most prevalent adverse events (AE) reported in clinical trials, often resulting in dose-limitations that reduce drug efficacy and delay development and treatment optimization. Preclinical animal models do not accurately replicate human GI physiology, leaving few options for early detection of GI side effects prior to human studies. Development of an accurate model that predicts GIT earlier in drug discovery programs would better support successful clinical trial outcomes. Chemotherapeutics, which exhibit high rates of clinical GIT, frequently target mitotic cells. Therefore, we hypothesized that a model utilizing proliferative cell populations derived from human intestinal crypts would predict the occurrence of clinical GITs with high accuracy. Here, we describe the development of a multiparametric assay utilizing the RepliGut® Planar system, an intestinal stem cell-derived platform cultured in an accessible high throughput Transwell™ format. This assay addresses key physiological elements of GIT by assessing cell proliferation (EdU incorporation), cell abundance (DAPI quantification), and barrier function (TEER). Using this approach, we demonstrate that primary proliferative cell populations reproducibly respond to marketed chemotherapeutics at physiologic concentrations. To determine the ability of this model to predict clinical diarrhea risk, we evaluated a set of 30 drugs with known clinical diarrhea incidence in three human donors, comparing results to known plasma drug concentrations. This resulted in highly accurate predictions of diarrhea potential for each endpoint (balanced accuracy of 91% for DAPI, 90% for EdU, 88% for TEER) with minimal variation across human donors. In vitro toxicity screening using primary proliferative cells may enable improved safety evaluations, reducing the risk of AEs in clinical trials and ultimately lead to safer and more effective treatments for patients.

Total toxicity burden as a practical tool to quantify the overall severity of multiple adverse events in clinical trials.

3156 Background: Phase I clinical trials (CT) report adverse events (AEs) using the Common Terminology Criteria for AEs (CTCAE) version 5.0. If multiple qualitatively AEs are recorded in a trial, this results into manifold AE counts. Total toxicity burden (TTB) is defined for each patient as the sum of the highest grade of each AE divided by the number of AEs recorded [Thall, 2003]. We computed the TTBs for five groups of drugs studied in phase I trials. Methods: Pts treated from 2016 to 2022 in the phase I CT unit at MD Anderson Cancer Center were included. Clinical baseline prognostic factors [ECOG, age, Carlson comorbidity index (CCI)] were included and analyzed. AEs according to the CTCAE v5.0 were collected and simplified into 21 categories per trial and patient. Treatments were divided into: Cytotoxic agents (Chemo), Targeted Therapy (TT), Immune checkpoint inhibitors (ICI), Chimeric antigen receptor T cells (CART), or Cytokines (CYT). Using regimen-related AEs for evaluable patients, mean (SD) TTB for each treatment group was computed using each patent’s worst grade as the severity weight for each type of AE. Results: A total of 1322 evaluable pts from an initial sample of 2,350 were collected. Median age was 61 years (range, 19-92), 75.6% ECOG PS 1, median CCI was 8, and all pts were treated in a phase I/II CT. A total of 1782 AEs were treatment related and 3071 AEs were not treatment related. 715 evaluable pts (54.1%) had at least one treatment-related AE, and 902 patients (68.2%) had at least one treatment unrelated AE. A total of 265 (20.0%) grade 1 (G1) treatment-related AEs, 231 (17.5%) G2, 184 (13.9%) % G3, and 29 (2.2%) G4, and one G5 was reported. The most frequent G≥3 AEs overall were Neutropenia (N=54), Anemia (N=52), and low platelets (N=35). The most frequent G≥3 AEs per treatment group were Neutropenia (10%), Anemia (15%), and increased AST/ALT (13%) in group Chemo, Neutropenia (8%), Low platelets (9%), and Anemia (9%) in group TT, Increased AST/ALT (10%), Anemia (5%), and Pain (5%) in group ICI, Neutropenia (10%), Anemia (10%), and Low platelets (5%) in group CART, and Nausea/Vomit (3%), Pneumonitis (1%), and Infection (1%) in group CYT. Mean TTBs for the five treatment groups were 2.7 (SD=3.3) for Chemo, 2.9 (SD=3.6) for TT, 1.7 (SD=1.9) for IO, 5.9 (SD=5.1) for CART, and 0.8 (SD=1.8) for CYT. Corresponding G≥3 treatment-related AE rates were 21.7%, 21.0%, 12.2%, 52.4%, and 6.4% in the five treatment groups. It appears that CART is the most toxic treatment group based on TTBs and conventional analysis based on G>3. These results suggest that propensity score-based comparisons of mean TTB to correct for selection bias using prognostic variables are warranted. Conclusions: TTB is a useful tool to quantify the mean severity of qualitatively different types of adverse events experienced by patients in a clinical trial, and mean TTB may be compared between treatment groups.

Something Out of Nothing? The Influence of Double-Zero Studies in Meta-analysis of Adverse Events in Clinical Trials

Something Out of Nothing? The Influence of Double-Zero Studies in Meta-analysis of Adverse Events in Clinical Trials

0590 Hypoglossal Nerve Stimulation for OSA – a Systematic Review of Adverse Events in Clinical Trials & Real-world-data

0590 Hypoglossal Nerve Stimulation for OSA – a Systematic Review of Adverse Events in Clinical Trials & Real-world-data

Psychedelic Therapy: A Primer for Primary Care Clinicians-Lysergic Acid Diethylamide (LSD).

Lysergic acid diethylamide (LSD) is a hallucinogenic agent. In the mid-20th century, it was used to augment psychoanalysis and to treat alcohol use disorder. However, LSD was banned in 1970 in part because of concerns that it could bring about or exacerbate mental illness. Its therapeutic potential remains incompletely understood. While uncontrolled recreational use of LSD can, in rare instances, lead to long-term psychosis, adverse events in clinical trials of LSD, such as anxiety, headache, and nausea, have almost always been mild and transient. Serious adverse events, such as intense panic, suicidal ideation, and psychosis, were reported in either none or very few of the participants. However, patient selection criteria, optimal dosing strategy, and appropriate clinical follow-up guidelines remain to be established. Preliminary data suggest that LSD may be effective for the management of alcohol use disorder, anxiety, and depression. In trials of LSD for treating anxiety and depression associated with life-threatening illnesses, 77% of participants demonstrate durable relief at 1 year post-treatment. Top-line data from a large-scale phase IIb trial (n = 198) indicate that 50% of participants experience remission from generalized anxiety disorder after a single 100 μg dose of LSD. According to a meta-analysis of RCTs on LSD from the mid-20th century, single-dose regimens of LSD significantly improve alcohol use disorder (P < 0.0003) with an odds ratio (OR) of 1.96. Only one large-scale clinical trial (>50 participants) has been conducted on LSD in the contemporary era of psychedelic research. Further studies with large sample sizes are needed to explore potential clinical applications. Preliminary data suggest that LSD may be one of the most potent treatments for anxiety in patients both with and without a life-threatening illness. LSD may also be beneficial for treating depression and substance use disorders.

A64 HUMAN INTESINAL ORGANOIDS AS A MODEL FOR GASTROINTESTINAL FUNCTION AND TOXICITY SCREENING

Abstract Aims Drug-induced gastrointestinal (GI) toxicity is a common adverse event in clinical trials, with symptoms including diarrhea, ulceration, and inflammation resulting from impaired barrier function. Furthermore, the intestine is a key mediator of both drug absorption and metabolism. The human colon carcinoma cell line (Caco-2) is the most common model used in drug discovery, however, intestinal organoids provide a model that better recapitulates the self-renewal, cellular composition, and function of the intestinal epithelium.This study utilizes human intestinal organoids as a high-throughput model for evaluating intestinal function and toxicity in preclinical drug discovery. Methods To assess toxicity, intestinal organoids were treated with two GI-toxic drugs, gefitinib and colchicine, and post-treatment cell viability was compared to Caco-2 control cultures. To assess barrier function, organoid-derived monolayers cultured in Transwell® plates were treated with colchicine and sapitinib, and post-treatment permeability was evaluated using the fluorescent low-permeability markers, 4 kDa FITC-dextran and Lucifer yellow. Results Human intestinal organoid cultures exhibited 14-fold greater sensitivity to gefitinib (average organoid IC50 = 0.82 μM, n = 3; Caco-2 IC50 =11.4 μM, n = 2) and 2,238 times greater sensitivity to colchicine (average organoid IC50 = 0.028 μM, n = 3; Caco-2 IC50 = 62.89 μM, n = 6) compared to Caco-2 controls. This 96-well assay was reproducible, producing comparable IC50 concentrations in repeated experiments with cells from the same and different donors (n = 3 donors). Organoid-derived monolayers exhibited ampersand:003E 10-fold (n = 3) increase in permeability to both sapitinib and colchicine compared to Caco-2 cultures, which displayed minimal responses to either drug treatment. Finally, organoid-derived monolayer cultures in transwell® plates can be utilized to quantify drug transport and metabolism by the intestinal epithelium. Using ileal organoid-derived monolayers and Caco-2 cultures, we quantified the active transport of methotrexate by the efflux transporter BCRP, calculating an efflux ratio of 11.46 from the basal to apical chambers. We also quantified CYP3A4 activity of ileal monolayers relative to Caco-2 cultures. Ileal monolayers converted midazolam to hydroxymidazolam ampersand:003E 50-fold (n = 2) more than Caco-2 cultures, which displayed minimal CYP3A4 activity below the limit of detection. Together, these data demonstrate that human intestinal organoids are a valuable tool for high-throughput GI toxicity screening and for evaluating intestinal function in preclinical drug discovery. Conclusions Together, these data demonstrate that human intestinal organoids are a valuable tool for high-throughput GI toxicity screening and for evaluating intestinal function in preclinical drug discovery. Funding Agencies None

The neonatal adverse event severity scale: current status, a stakeholders' assessment, and future perspectives.

To support informed decisions on drug registration and prescription, clinical trials need tools to assess the efficacy and safety signals related to a given therapeutic intervention. Standardized assessment facilitates reproducibility of results. Furthermore, it enables weighted comparison between different interventions, instrumental to facilitate shared decisions. When focused on adverse events in clinical trials, tools are needed to assess seriousness, causality and severity. As part of such a toolbox, the international Neonatal Consortium (INC) developed a first version of the neonatal adverse event severity scale (NAESS). This version underwent subsequent validation in retro-and prospective trials to assess its applicability and impact on the inter-observer variability. Regulators, sponsors and academic researchers also reported on the use of the NAESS in regulatory documents, trial protocols and study reports. In this paper, we aim to report on the trajectory, current status and impact of the NAESS score, on how stakeholders within INC assess its relevance, and on perspectives to further develop this tool.

Identification, Monitoring and Reversibility of PARP Inhibitor Associated Clonal Haematopoiesis and Myelodysplastic Syndrome: A Case Series

Background: Poly ADP ribose polymerase inhibitors (PARPi) are widely used as maintenance treatment for ovarian cancer (OC) after response to platinum chemotherapy in the first line setting and recurrent disease. Their use has significantly improved outcomes, particularly in patients with BRCA mutations in whom first-line PARPi maintenance therapy increases progression-free survival from 13.8 to 56.0 months (Hazard Ratio, 0.33; 95% CI, 0.25-0.43). However, a recent meta-analysis of clinical trial adverse events and pharmacovigilance data showed that PARPi therapy significantly increases the risk of therapy related myeloid neoplasms (tMN), myelodysplastic syndrome (MDS) and acute myeloid leukaemia with poor outcomes. Platinum based chemotherapy is the mainstay of OC treatment and is associated with clonal haematopoiesis (CH) with mutations in DNA damage response genes. CH is recognised as a premalignant myeloid state but real world data on clonal dynamics during PARPi therapy are lacking. We present a case series of OC patients receiving PARPi-therapy referred for haematological review for beyond-expected HT or unexplained full blood count (FBC) abnormalities with serial FBC and myeloid next generation sequencing (mNGS) clonal monitoring in relation to PARPi therapy. Methods: Seven patients with stage III/IV high-grade OC were referred to haematology at the discretion of the treating oncologist between February 2017 and May 2022 (mean age (SD): 68 (7.0) years, median PARPi duration: 18 months (range: 4-86)). All patients had received prior platinum-based chemotherapy and were screened with mNGS in peripheral blood (PB) or bone marrow aspirate and trephine (BMAT) at initial assessment. Results: Reasons for referral are detailed in Table 1 and include two patients with isolated elevated nucleated red blood cell (NRBC) counts. Six patients had clonal pathology (CP), five of whom had single-nucleotide variants typical of platinum-exposure defined by the involved gene or platinum-associated mutational signatures. Clinical details including BRCA-status, haematological diagnosis and mNGS results are detailed in Table 1. PARPi-therapy was discontinued in four patients with CP, with resolution or improvement of FBC and m-NGS abnormalities (variant allele frequencies (VAFs) and/or copy number variations (CNVs)) in three patients. These findings were most marked in Patient 1, referred with grade 3 thrombocytopenia and transfusion dependence and in whom PARPi cessation resulted in transfusion independence and resolution of morphological and cytogenetic abnormalities (clinical course including BMAT results and haematological parameters illustrated in Figure 1), and Patient 3, who demonstrated selective regression of a TP53 mutated clone on PARPi cessation. Two patients with germline BRCA mutations continued PARPi therapy with 3 monthly PB mNGS monitoring after discussion at multidisciplinary team meetings. Conclusions: We show using sequential molecular and haematological monitoring before and after PARPi cessation that morphological, FBC and clonal abnormalities can be reversed on PARPi discontinuation, potentially mitigating the risk of life-threatening tMNs in some patients. We also highlight that, in addition to cytopenias, persistently elevated NRBCs may be an indicator of clinically relevant CP not well described in pharmacovigilance data based on common terminology criteria for adverse events criteria. Large scale prospective data on clonal dynamics in PARPi therapy are needed to inform mNGS screening and tMN risk stratification as scoring systems based on age associated clonal haematopoiesis of indeterminate potential may not be applicable. Until these data are available we demonstrate the value in MDT discussion and serial PB mNGS monitoring in formulating case-by-case therapeutic decisions regarding CP and PARPi therapy, particularly patients with high risk BRCA mutated OC.

Quality of reporting of adverse events in clinical trials of covid-19 drugs: systematic review

ObjectiveTo assess the quality of reporting of adverse events in clinical trials of covid-19 drugs based on the CONSORT (Consolidated Standards of Reporting Trials) harms extension and according to clinical...

Concomitant medications associated with ischemic, hypertensive, and arrhythmic events in MDMA users in FDA adverse event reporting system.

3,4-Methylenedioxymethamphetamine (MDMA) is currently being investigated as an adjunctive treatment to therapy for posttraumatic stress and other anxiety related disorders in clinical trials. Within the next few years MDMA-assisted therapy is projected for approval by regulatory authorities. MDMA's primary mechanism of action includes modulation of monoamine signaling by increasing release and inhibiting reuptake of serotonin, norepinephrine, and, to a lesser extent, dopamine. This pharmacology affects sympathomimetic physiology. In controlled trials, special attention has been given to cardiovascular adverse events (AEs), because transient increases in heart rate and blood pressure have been observed during the MDMA-assisted therapy sessions. Finding and quantifying the potential drivers of cardiac AEs in clinical trials is difficult since only a relatively small number of participants have been included in these studies, and a limited set of allowed concomitant drugs has been studied. In this study a more diverse set of reports from the FDA Adverse Event Reporting System was surveyed. We found 17 cases of cardiovascular AEs, in which the individuals had taken one or more substances in addition to MDMA. Interestingly, all of those concomitant medications and illicit substances, including opioids, stimulants, anticholinergics, and amphetamines, had been previously associated with cardiovascular AEs. Furthermore, in none of the reports MDMA was marked as the primary suspect.

Protection against toxic amyloid-beta oligomers by PMN310, a monoclonal antibody rationally designed for greater therapeutic potency in Alzheimer’s disease (P1-6.006)

<h3>Objective:</h3> Evaluate the protective activity of PMN310 against toxic amyloid-beta oligomers (AßO) in vitro and in vivo <h3>Background:</h3> Advances in the understanding of Alzheimer’s disease (AD) suggest that pathogenesis is not directly related to plaque burden, but rather to soluble toxic AßO. Therapeutic antibodies targeting Aß monomers and/or plaque have shown limited efficacy and dose-limiting adverse events in clinical trials. These findings suggest that antibodies capable of selectively neutralizing toxic AßO may achieve improved efficacy and safety. Monoclonal antibody PMN310 was raised against a conformational Aß epitope predicted by computational modeling to be exposed on toxic AßO but not monomers or fibrils. <h3>Design/Methods:</h3> The binding selectivity of PMN310 was characterized by surface plasmon resonance (SPR) and immunohistochemistry (IHC). Its ability to neutralize the propagation and toxicity of AßO was assessed in vitro in a thioflavin-T propagation assay and in cultures of primary rodent neurons, respectively. In vivo protection was tested in wild-type mice injected intracerebroventricularly (ICV) with AßO and in the APP/L transgenic mouse model of AD. <h3>Results:</h3> In SPR analysis, PMN310 showed little or no interaction with Aß monomers and, compared to other Aß-directed antibodies, was among the least impacted by excess monomer competition in binding to synthetic oligomers or naturally occurring toxic oligomers in AD brain extract. PMN310 additionally avoided interaction with plaque and vascular deposits as determined by IHC. In vitro, PMN310 inhibited AßO propagation and neuronal toxicity. In vivo, PMN310 prevented AßO-induced loss of memory formation after ICV injection, and systemic administration to APP/L transgenic mice preserved memory and learning in the water maze task. <h3>Conclusions:</h3> The antibody PMN310 was shown to selectively bind toxic AßO and protect against their pathogenic activity in vitro. In two rodent models of AD, PMN310 protected memory function, suggesting that PMN310 may offer a new therapeutic option for the treatment or prevention of AD. <b>Disclosure:</b> Dr. Kaplan has received personal compensation for serving as an employee of ProMIS Neurosciences. Dr. Kaplan has stock in ProMIS Neurosciences. Dr. Kaplan has received intellectual property interests from a discovery or technology relating to health care. Dr. Gibbs has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Promis Neuroscinces. Judith Silverman has received personal compensation for serving as an employee of Bill &amp; Melinda Gates Foundation. Beibei Zhao has received intellectual property interests from a discovery or technology relating to health care. Ms. Coutts has nothing to disclose. Xubiao Peng has nothing to disclose. Steven S. Plotkin has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for ProMIS Neurosciences. Steven S. Plotkin has stock in ProMIS Neurosciences. The institution of Steven S. Plotkin has received research support from Canadian Institutes of Health Research. The institution of Steven S. Plotkin has received research support from Digital Technology Supercluster. Steven S. Plotkin has received intellectual property interests from a discovery or technology relating to health care. Dr. Cashman has received personal compensation for serving as an employee of ProMIS Neurosciences. Dr. Cashman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Mitsubishi-Tanabe. Dr. Cashman has stock in ProMIS Neurosciences. The institution of Dr. Cashman has received research support from ProMIS Neurosciences. Dr. Cashman has received intellectual property interests from a discovery or technology relating to health care. Dr. Cashman has a non-compensated relationship as a BoD memeber with ALS Society of BC that is relevant to AAN interests or activities.

Abstract P4-07-53: Adverse events (AEs) in phase III clinical trials of patients with human epidermal growth factor receptor-2 positive (HER2+) breast cancer (BC): a meta-analysis

Abstract Background. In the last five years, several new drugs have been approved for BC in the United States, many of which target HER2, including neratinib, margetuximab, tucatinib, and trastuzumab deruxtecan. These approvals depend on a drug’s benefits outweighing its risks in clinical trials (CTs). However, limited information on safety is available from single CTs. The objective of this study is to identify recently published phase III CTs that report AEs in patients (pts) with HER2+ BC and perform a meta-analysis to estimate the frequency of the most common AEs reported in ≥2 CTs. Methods. A literature search was conducted (Ovid, ClinicalTrials.Gov) to identify phase III CTs published from 2017-2021. Search terms included BC, HER2+, phase III, CT, and others. Articles were independently screened by two researchers in two levels (title/abstract; full text) and were included if they reported AEs in pts with HER2+ BC. Meta-analysis was performed in Comprehensive Meta Analysis v3 to estimate frequency of AEs using random effects models. Results. Of 519 articles identified, 33 were included for analysis (455 excluded in level 1 screening; 31 excluded in level 2 screening). Most excluded articles were not phase III or did not include only pts with HER2+ BC. BC treatments most commonly included chemotherapy and HER2-targeted agents (e.g., trastuzumab), including antibody-drug conjugates (ADCs; e.g., trastuzumab emtansine). Most trials (N=27) included ≥1 treatment arm with pts who received chemotherapy in combination with a HER2-targeted agent. Fewer trials (N=10) included ≥1 treatment arm with pts who received only a HER2-targeted agent. Across all 33 trials, 181 unique AEs were reported. Specific chemotherapy agents used were not always reported, but included taxanes, anthracyclines, cyclophosphamide, 5-fluorouracil, capecitabine, and carboplatin. In chemotherapy treated pts (with or without reported concomitant HER2-targeted agent), the most frequent any grade AEs were hand-foot syndrome (63.8%, N=1814), alopecia (56.6%, N=9677), and diarrhea (39.9%, N=12628); the most frequent grade ≥3 AEs were neutropenia (21.7%, N=14349), hand-foot syndrome (12.2%, N=2252), and leukopenia (8.4%, N=3852). HER2-targeted agents included trastuzumab emtansine, trastuzumab, pertuzumab, lapatinib, and neratinib. In pts treated with any HER2-targeted agent (without reported concomitant chemotherapy), the most frequent any grade AEs were diarrhea (31.7%, N=5518), nausea (30.8%, N=5518), and epistaxis (24.9%, N=3622); the most frequent grade ≥3 AEs were thrombocytopenia (4.8%, N=3980), anemia (4.2%, N=3845), and aspartate aminotransferase increase (3.3%, N=3975). In the subgroup of pts treated with an ADC (trastuzumab emtansine), the most frequent any grade AEs were nausea (41.4%, N=3622), fatigue (31.6%, N=2895), and headache (28.0%, N=3622); the most frequent grade ≥3 AEs were similar to those in pts treated with any HER2-targeted agent. Significant heterogeneity was detected among trials for the outcomes reported here (Q statistic ranged from 12-2176, p&amp;lt; 0.05). No analysis was conducted in pts who received hormone therapy due to limited available information about this group in the included trials. Conclusion. When evaluating pooled data, the most commonly reported AEs in CTs of patients with HER2+ BC varied by drug classes included in treatment regimens. This meta-analysis provides a more comprehensive understanding of the most frequent AEs in this population by pooling patient data from several CTs and will contribute to better contextualize the safety of products used in this population. Future research including real-world studies can be used to better understand the safety profile of these medications. Citation Format: Mackenzie Henderson, Priyanka Yalamanchili, Eric Wang, Maribel Salas. Adverse events (AEs) in phase III clinical trials of patients with human epidermal growth factor receptor-2 positive (HER2+) breast cancer (BC): a meta-analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-53.

Hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation are underestimated, but fatal adverse events in chimeric antigen receptor T-cell therapy.

Hematotoxicity is the most common long-term adverse event (AE) after chimeric antigen receptor T-cell (CAR T) therapy. However, patients who receive CAR T therapy in pivotal clinical trials are subjected to restrictive selection criteria, and this means that rare but fatal toxicities are underestimated. Here, we systematically analyzed CAR T-associated hematologic AE using the US Food and Drug Administration Adverse Event Reporting System (FAERS) between January 2017 and December 2021. Disproportionality analyses were performed using reporting odds ratios (ROR) and information component (IC); the lower limit of the ROR and IC 95% confidence interval (CI) (ROR025 and IC025) exceeding one and zero was considered significant, respectively. Among the 105,087,611 reports in FAERS, 5,112 CAR T-related hematotoxicity reports were identified. We found 23 significant over-reporting hematologic AE (ROR025 >1) compared to the full database, of which hemophagocytic lymphohistiocytosis (HLH; n=136 [2.7%], ROR025 = 21.06), coagulopathy (n=128 [2.5%], ROR025 = 10.43), bone marrow failure (n=112 [2.2%], ROR025 = 4.88), disseminated intravascular coagulation (DIC; n=99 [1.9%], ROR025 = 9.64), and B-cell aplasia (n=98 [1.9%], ROR025 = 118.16, all IC025 > 0) were highly under-reported AE in clinical trials. Importantly, HLH and DIC led to mortality rates of 69.9% and 59.6%, respectively. Lastly, hematotoxicity-related mortality was 41.43%, and 22 death-related hematologic AE were identified using LASSO regression analysis. These findings could help clinicians in the early detection of those rarely reported but lethal hematologic AE, thus reducing the risk of severe toxicities for CAR T recipients.

Assessing adverse events in clinical trials during the era of the COVID-19 pandemic

ABSTRACT Interpretation of safety data for clinical trials that were ongoing at the onset of the COVID-19 pandemic or were started subsequent to the beginning of the pandemic may be affected in a variety of ways. Pandemic-related issues can influence the extent of study participation and introduce data collection gaps. A SARS-CoV-2 infection among study subjects as a post-randomization event may introduce a number of confounding factors that can alter the frequency of adverse events, in some cases appearing as an increase in the frequency of an adverse event associated with a study drug relative to a comparator. The authors discuss clinical challenges and statistical concerns, specifically the estimand framework, including examples for consideration, to address these challenges in safety evaluation wrought by the COVID-19 pandemic. Our aim is to shed light on the importance of starting an early dialogue among the drug development team on the evaluation of safety, critical for benefit-risk evaluation throughout the drug development process.

Correlations between preclinical BJAB assay ranking of antisense drugs and clinical trial adverse events.

This analysis sought to assess the clinical predictivity of an in vitro assay which utilized the human B-lymphoma BJAB cell line, for identification of antisense oligonucleotides (ASOs) with the potential to elicit innate immune activation in humans. Adverse events (AEs) from clinical trial data were analyzed based on prior clinical knowledge and network analysis of the clinical data to identify correlations with the BJAB assay. Clinically evaluated ASOs were ranked by the BJAB assay's mean log-fold increase in TNF expression levels. Flu-like reactions (FLRs) and injection site reactions (ISRs), were chosen as AEs of interest, along with those Medical Dictionary for Regulatory Activities preferred terms identified using AE network analysis. Fifteen different 2'-O-methoxyethyl (2'MOE) modified ASOs were ranked by the incidence of each AE group in the integrated safety data from 35 clinical trials. ISRs are considered to be local to the injection site, whereas FLRs are reflected by systemic constitutional symptoms. The correlations identified in this analysis of integrated clinical data provide evidence that the ASO sequences selected by the BJAB assay have a lower likelihood of causing systemic inflammatory AEs associated with FLRs, but not ISRs.

Reduced blood-brain barrier penetration of acne vulgaris antibiotic sarecycline compared to minocycline corresponds with lower lipophilicity.

Vestibular side effects such as dizziness and vertigo can be a limitation for some antibiotics commonly used to treat acne, rosacea, and other dermatology indications. Unlike minocycline, which is a second-generation tetracycline, sarecycline, a narrow-spectrum third-generation tetracycline-class agent approved to treat acne vulgaris, has demonstrated low rates of vestibular-related adverse events in clinical trials. In this work, we evaluate the brain-penetrative and lipophilic attributes of sarecycline in 2 non-clinical studies and discuss potential associations with vestibular adverse events. Rats received either intravenous sarecycline or minocycline (1.0 mg/kg). Blood-brain penetrance was measured at 1, 3, and 6 h postdosing. In another analysis, the lipophilicity of sarecycline, minocycline, and doxycycline was measured via octanol/water and chloroform/water distribution coefficients (logD) at pH 3.5, 5.5, and 7.4. Unlike minocycline, sarecycline was not detected in brain samples postdosing. In the octanol/water solvent system, sarecycline had a numerically lower lipophilicity profile than minocycline and doxycycline at pH 5.5 and 7.4. The reduced blood-brain penetrance and lipophilicity of sarecycline compared with other tetracyclines may explain low rates of vestibular-related adverse events seen in clinical trials.

Sequenced treatment after regorafenib and survival in metastatic colorectal cancer: a qualitative clinical review

There is limited evidence-based guidance regarding treatment sequencing and outcomes following regorafenib in patients with refractory metastatic colorectal cancer (mCRC). A targeted literature review was conducted to identify studies with clinical outcomes associated with regorafenib therapy and subsequent treatment following regorafenib therapy. The median overall survival range of the nine studies with sequenced-based survival data was 2.1–19.3 months for regorafenib prior to subsequent therapy in refractory mCRC. Safety outcomes in patients treated with regorafenib prior to other therapies in mCRC were generally comparable to reported adverse events in clinical trials for subsequent agents. Data from this review demonstrate a potential correlation between survival and the use of regorafenib prior to subsequent chemotherapy or targeted therapy in patients with refractory mCRC.

Rates of laboratory adverse events by course in paediatric leukaemia ascertained with automated electronic health record extraction: a retrospective cohort study from the Children's Oncology Group

Adverse events are often misreported in clinical trials, leading to an incomplete understanding of toxicities. We aimed to test automated laboratory adverse event ascertainment and grading (via the ExtractEHR automated package) to assess its scalability and define adverse event rates for children with acute myeloid leukaemia and acute lymphoblastic leukaemia. For this retrospective cohort study from the Children's Oncology Group (COG), we included patients aged 0-22 years treated for acute myeloid leukaemia or acute lymphoblastic leukaemia at Children's Healthcare of Atlanta (Atlanta, GA, USA) from Jan 1, 2010, to Nov 1, 2018, at the Children's Hospital of Philadelphia (Philadelphia, PA, USA) from Jan 1, 2011, to Dec 31, 2014, and at the Texas Children's Hospital (Houston, TX, USA) from Jan 1, 2011, to Dec 31, 2014. The ExtractEHR automated package acquired, cleaned, and graded laboratory data as per Common Terminology Criteria for Adverse Events (CTCAE) version 5 for 22 commonly evaluated grade 3-4 adverse events (fatal events were not evaluated) with numerically based CTCAE definitions. Descriptive statistics tabulated adverse event frequencies. Adverse events ascertained by ExtractEHR were compared to manually reported adverse events for patients enrolled in two COG trials (AAML1031, NCT01371981; AALL0932, NCT02883049). Analyses were restricted to protocol-defined chemotherapy courses (induction I, induction II, intensification I, intensification II, and intensification III for acute myeloid leukaemia; induction, consolidation, interim maintenance, delayed intensification, and maintenance for acute lymphoblastic leukaemia). Laboratory adverse event data from 1077 patients (583 from Children's Healthcare of Atlanta, 200 from the Children's Hospital of Philadelphia, and 294 from the Texas Children's Hospital) who underwent 4611 courses (549 for acute myeloid leukaemia and 4062 for acute lymphoblastic leukaemia) were extracted, processed, and graded. Of the 166 patients with acute myeloid leukaemia, 86 (52%) were female, 80 (48%) were male, 96 (58%) were White, and 132 (80%) were non-Hispanic. Of the 911 patients with acute lymphoblastic leukaemia, 406 (45%) were female, 505 (55%) were male, 596 (65%) were White, and 641 (70%) were non-Hispanic. Patients with acute myeloid leukaemia had the most adverse events during induction I and intensification II. Hypokalaemia (one [17%] of six to 75 [48%] of 156 courses) and alanine aminotransferase (ALT) increased (13 [10%] of 134 to 27 [17%] of 156 courses) were the most prevalent non-haematological adverse events in patients with acute myeloid leukaemia, as identified by ExtractEHR. Patients with acute lymphoblastic leukaemia had the greatest number of adverse events during induction and maintenance (eight adverse events with prevalence ≥10%; induction and maintenance: anaemia, platelet count decreased, white blood cell count decreased, neutrophil count decreased, lymphocyte count decreased, ALT increased, and hypocalcaemia; induction: hypokalaemia; maintenance: aspartate aminotransferase [AST] increased and blood bilirubin increased), as identified by ExtractEHR. 187 (85%) of 220 total comparisons in 22 adverse events in four AAML1031 and six AALL0923 courses were substantially higher with ExtractEHR than COG-reported adverse event rates for adverse events with a prevalence of at least 2%. ExtractEHR is scalable and accurately defines laboratory adverse event rates for paediatric acute leukaemia; moreover, ExtractEHR seems to detect higher rates of laboratory adverse events than those reported in COG trials. These rates can be used for comparisons between therapies and to counsel patients treated on or off trials about the risks of chemotherapy. ExtractEHR-based adverse event ascertainment can improve reporting of laboratory adverse events in clinical trials. US National Institutes of Health, St Baldrick's Foundation, and Alex's Lemonade Stand Foundation.