Dictionary For Regulatory Activities Terms Research Articles

COVID-19 Vaccine Adverse Event Detection Based on Multi-Label Classification With Various Label Selection Strategies.

Analyzing massive VAERS reports without medical context may lead to incorrect conclusions about vaccine adverse events (VAE). Facilitating VAE detection promotes continual safety improvement for new vaccines. This study proposes a multi-label classification method with various term-and topic-based label selection strategies to improve the accuracy and efficiency of VAE detection. Topic modeling methods are first used to generate rule-based label dependencies from Medical Dictionary for Regulatory Activities terms in VAE reports with two hyper-parameters. Multiple label selection strategies, namely one-vs-rest (OvsR), problem transformation (PT), algorithm adaption (AA), and deep learning (DL) methods, are used in multi-label classification to examine the model performance, respectively. Experimental results indicated that the topic-based PT methods improve the accuracy by up to 33.69% using a COVID-19 VAE reporting data set, which improves the robustness and interpretability of our models. In addition, the topic-based OvsR methods achieve an optimal accuracy of up to 98.88%. The accuracy of the AA methods with topic-based labels increased by up to 87.36%. By contrast, the state-of-art LSTM- and BERT-based DL methods have relatively poor performance with accuracy rates of 71.89% and 64.63%, respectively. Our findings reveal that the proposed method effectively improves the model accuracy and strengthens VAE interpretability by using different label selection strategies and domain knowledge in multi-label classification for VAE detection.

Cardiovascular Effects of GnRH Antagonists Compared With Agonists in Prostate Cancer: A Systematic Review

BackgroundAndrogen deprivation therapy is the cornerstone of treatment for patients with advanced prostate cancer. Meta-analysis of small, oncology-focused trials suggest gonadotropin-releasing hormone (GnRH) antagonists may be associated with fewer adverse cardiovascular outcomes compared with GnRH agonists. ObjectivesThis study sought to determine whether GnRH antagonists were associated with fewer major adverse cardiovascular events compared with GnRH agonists. MethodsElectronic databases were searched for all prospective, randomized trials comparing GnRH antagonists with agonists. The primary outcome was a major adverse cardiovascular event as defined by the following standardized Medical Dictionary for Regulatory Activities terms: “myocardial infarction,” “central nervous system hemorrhages and cerebrovascular conditions,” and all-cause mortality. Bayesian meta-analysis models with random effects were fitted. ResultsA total of 11 eligible studies of a maximum duration of 3 to 36 months (median = 12 months) enrolling 4,248 participants were included. Only 1 trial used a blinded, adjudicated event process, whereas potential bias persisted in all trials given their open-label design. A total of 152 patients with primary outcome events were observed, 76 of 2,655 (2.9%) in GnRH antagonist-treated participants and 76 of 1,593 (4.8%) in agonist-treated individuals. Compared with GnRH agonists, the pooled OR of GnRH antagonists for the primary endpoint was 0.57 (95% credible interval: 0.37-0.86) and 0.58 (95% credible interval: 0.32-1.08) for all-cause death. ConclusionsDespite the addition of the largest, dedicated cardiovascular outcome trial, the volume and quality of available data to definitively answer this question remain suboptimal. Notwithstanding these limitations, the available data suggest that GnRH antagonists are associated with fewer cardiovascular events, and possibly mortality, compared with GnRH agonists.

Assessment of Reported Adverse Events After Interchanging Between TNF-α Inhibitor Biosimilars in the WHO Pharmacovigilance Database.

Observational studies have shown that a significant proportion of patients interchanging between tumor necrosis factor-α inhibitor biosimilars withdraws from the new treatment because of adverse effects. We aim to analyze adverse events related to interchanging from tumor necrosis factor-α (TNF-α) inhibitor reference products to biosimilars and between biosimilars reported in the World Health Organization pharmacovigilance database. We extracted all cases reporting the Medical Dictionary for Regulatory Activities term "Product substitution issue (PT)" for TNF-α inhibitors. Then, we analyzed and categorized all adverse events reported in more than 1% of cases. We compared the adverse events reported according to reporter qualification, type of switch, and type of TNF-α inhibitor using Chi2 tests. We conducted a network analysis coupled with a clustering approach to identify syndromes of co-reported adverse events. In the World Health Organization pharmacovigilance database, 2543 cases and 6807 adverse events related to TNF-α inhibitor interchangeability have been reported up to October 2022. Injection-site reactions were the most reported adverse events with 940 cases (37.0%), followed by modifications in drug effect in 607 cases (23.9%). Musculoskeletal, cutaneous, and gastrointestinal disorders linked to the underlying disease were reported in 505 (20.0%), 145 (5.7%), and 207 (8.1%) cases, respectively. Adverse events non-related to the underlying disease were nonspecific (n = 458, 18.0%), neurologic (n = 224, 8.8%), respiratory (n = 132, 5.2%), and psychological disorders (n = 64, 2.5%). Injection-site reactions and infection-related symptoms (e.g., nasopharyngitis, urinary tract infection, lower respiratory tract infection) were more reported by non-healthcare professionals while adverse events related to reduced clinical efficacy (e.g., drug ineffective, arthralgia, psoriasis) were more reported by healthcare professionals. The proportions of injection-site reactions were higher when switching between biosimilars of the same reference product, but the proportions of adverse events related to reduced clinical efficacy (e.g., psoriasis, arthritis, psoriatic arthropathy) were more reported when switching from a reference product. The main differences in the proportions of reported cases between adalimumab, infliximab, and etanercept were driven by symptoms related to the underlying targeted diseases, except for a higher reporting rate of injection-site pain with adalimumab. Adverse events evocative of hypersensitivity reactions were reported in 192 (7.6%) cases. Most of the network clusters concerned non-specific adverse events or were related to reduced clinical efficacy. This analysis highlights the burden of patient-reported adverse events when interchanging between TNF-α inhibitor biosimilars, notably injection-site reactions, non-specific adverse events, and symptoms related to reduced clinical efficacy. Our study also highlights differences in reporting patterns between patients and healthcare professionals and depending on the type of switch. The results are limited by missing data, the lack of precision of the coded Medical Dictionary for Regulatory Activities terms, and by the variability of reporting rate of adverse events. Thus, incidence rates of adverse events cannot be inferred from these results.

1056-P: Reported Pregnancy Outcomes with Insulin Glargine 100 U/mL (Gla-100) and 300 U/mL (Gla-300) : Post-Marketing Survey of Pharmacovigilance Data

Background: Good metabolic control during pregnancy is crucial for people with diabetes to prevent adverse events associated with hyperglycemia. Gla-300, a long-acting basal insulin (BI) analog, provides similar glycemic control and less hypoglycemia versus the first-generation BI Gla-100. We examined real-life safety of insulin glargine use in pregnancy. Methods: Cumulative searches of the Sanofi global pharmacovigilance database for Gla-100/Gla-300 exposures in pregnancy were performed using Medical Dictionary for Regulatory Activities terms, from database initiation to March 9, 2021. Results: Searches found 4936 (2370 solicited, 2566 unsolicited; 71 countries) exposures to Gla-100 and 246 (66 solicited, 180 unsolicited; 44 countries) for Gla-300 (Table) . Cumulative exposure was 89 million and 7.9 million person-years for Gla-100 and Gla-300, respectively. Congenital, familial, and genetic anomalies were rare (2.6% Gla-100; 2.0% Gla-300) , in line with general population rates (3-5%) . Spontaneous abortion rates were low (3.0% Gla-100; 2.8% Gla-300) , which is also in line with the general population (˜10%) . Conclusion: Rates of congenital anomalies and spontaneous abortions for Gla-100 and Gla-300 were consistent with the general population. The results indicate no safety issues with insulin glargine use during pregnancy. Disclosure J.Westerbacka: Employee; Sanofi, Stock/Shareholder; Sanofi. C.Bassole: Employee; Sanofi. M.Duverne: Employee; Sanofi. Z.Doder: None. H.Schoepper: None. Funding Sanofi

New Associations between Drug-Induced Adverse Events in Animal Models and Humans Reveal Novel Candidate Safety Targets.

To improve our ability to extrapolate preclinical toxicity to humans, there is a need to understand and quantify the concordance of adverse events (AEs) between animal models and clinical studies. In the present work, we discovered 3011 statistically significant associations between preclinical and clinical AEs caused by drugs reported in the PharmaPendium database of which 2952 were new associations between toxicities encoded by different Medical Dictionary for Regulatory Activities terms across species. To find plausible and testable candidate off-target drug activities for the derived associations, we investigated the genetic overlap between the genes linked to both a preclinical and a clinical AE and the protein targets found to interact with one or more drugs causing both AEs. We discuss three associations from the analysis in more detail for which novel candidate off-target drug activities could be identified, namely, the association of preclinical mutagenicity readouts with clinical teratospermia and ovarian failure, the association of preclinical reflexes abnormal with clinical poor-quality sleep, and the association of preclinical psychomotor hyperactivity with clinical drug withdrawal syndrome. Our analysis successfully identified a total of 77% of known safety targets currently tested in in vitro screening panels plus an additional 431 genes which were proposed for investigation as future safety targets for different clinical toxicities. This work provides new translational toxicity relationships beyond AE term-matching, the results of which can be used for risk profiling of future new chemical entities for clinical studies and for the development of future in vitro safety panels.

Adjudication of cardiovascular events in patients with chronic obstructive pulmonary disease: SUMMIT trial.

Background:Adjudicated cause-specific mortality has been used in major trials of chronic obstructive pulmonary disease. However, there is less experience with adjudicated major adverse cardiovascular events as a key efficacy outcome in chronic obstructive pulmonary disease trials. The Study to Understand Mortality and Morbidity in chronic obstructive pulmonary disease trial required a Clinical Endpoint Committee to adjudicate the outcomes of modified major adverse cardiovascular events and cause-specific mortality.Methods and results:A six-member Clinical Endpoint Committee reviewed adverse event and serious adverse event reports included in a list of 204 Medical Dictionary for Regulatory Activities terms. Adverse events were triaged by one Clinical Endpoint Committee member, and then reviewed by three reviewers (round 1). If these three disagreed on the adjudication, the event was discussed by the full committee to reach a consensus (round 2). Among 16,485 participants, 48,105 adverse events were reported, among which 3314 were reviewed by the Clinical Endpoint Committee. After triage, 1827 were adjudicated in round 1; 338 required committee consensus in round 2, yielding 450 myocardial infarctions, strokes, unstable anginas or transient ischaemic attacks. Only 20/1627 (1%) non-serious adverse events were adjudicated as cardiovascular events. Only 45/204 Medical Dictionary for Regulatory Activities terms reviewed yielded cardiovascular events. A total of 430 deaths were adjudicated in round 1 and 631 in round 2, yielding 459 cardiovascular deaths. Adjudication of chest pain and sudden death often required additional information from site investigators. Site assessment of cardiovascular death was moderately specific (501/602 = 83%) but not sensitive (256/459 = 56%).Conclusion:A Clinical Endpoint Committee is useful for adjudication of major adverse cardiovascular events in chronic obstructive pulmonary disease trials but requires considerable resources and effort by investigators. This process can be streamlined by reviewing only serious adverse events and filtering by selected Medical Dictionary for Regulatory Activities terms.

Real-World Data Approaches for Early Detection of Potential Safety and Effectiveness Signals for Generic Substitution: A Metoprolol Extended-Release Case Study.

Real-world spontaneous adverse event reports and administrative health care data were utilized as one part of a multipronged approach to verify surveillance signals related to generic drug formulations. This study used metoprolol succinate extended release as a historic case example from which to develop an analytic framework. The US Food and Drug Administration Adverse Event Reporting System was utilized for disproportionality analyses and to identify outcomes of interest. Claims data were analyzed for generic uptake, proportion of prescriptions with "dispense as written" orders, time to discontinuation or switching, and relative rates of clinical events. Adverse Event Reporting System data showed that the Medical Dictionary for Regulatory Activities terms for product quality were higher for generic metoprolol cases and that a number of clinical events were increased that could be side effects of high or low variability in drug levels. Compared to amlodipine-benazepril, which also had a first-approved generic at the same time, market share data showed that metoprolol succinate had lower utilization and more prescriptions written as dispense as written. Switching and discontinuation were generally higher for metoprolol users compared to amlodipine-benazepril users. Finally, clinical event rates were generally higher for generic versus brand metoprolol but lower for the same comparison for amlodipine-benazepril users. In the claims-based analyses, the 90-day period immediately after generic entry provided stronger signal capture than using the entire study period. This analytic framework can be implemented to actively monitor new generic formulations for potential bioequivalence failures. Signals from these analyses require confirmation (eg, via pharmacometric analyses) to be informative for regulatory action.

Long-Term Safety Experience with Bendamustine for Injection in a Real-World Setting

Introduction: Bendamustine hydrochloride injection (Treanda®) was approved in 2008 by the US Food and Drug Administration (FDA) for the treatment of patients with chronic lymphocytic leukemia (CLL) and relapsed/refractory indolent B-cell non-Hodgkin’s lymphoma (NHL). Postmarketing pharmacovigilance (PV) is required for products approved by the FDA to meet regulatory and contractual requirements. Here we report on the real-world safety profile of bendamustine to better understand its long-term safety. PV data spanning a 9-year period were reviewed, with an emphasis on safety signals that led to product label revisions since initial FDA approval.Methods: A total of 12 quarterly postmarketing periodic adverse drug experience reports (PADERs) spanning March 20, 2008, to March 31, 2011, and three subsequent annual PADERs for the period ending March 31, 2015, were included. PV data were collected from foreign and domestic Teva-sponsored clinical studies, special drug-access programs, surveys, other systems in which patients are requested to provide adverse event (AE) information, spontaneous reports, and the scientific literature.The PV data collected were housed in the Teva Pharmaceuticals safety database. AEs were coded according to Medical Dictionary for Regulatory Activities terms and classified as serious or nonserious and expected or unexpected (ie, AEs not included in the product label at the time of the report or those that occurred at a higher incidence than previously reported).Results: As of January 6, 2015, 252,229 patients have been treated with bendamustine worldwide. Of the 3679 patients (1.5%) who experienced AEs over the entire postmarket monitoring period, 2441 individuals (1%) experienced serious and unexpected AEs. There were 364 cases classified as serious and expected, and 874 classified as nonserious. The most frequently reported serious AEs are summarized in the table. Serious AEs that resulted in label updates included Stevens-Johnson syndrome (n=33), toxic epidermal necrolysis (n=12), extravasation (n=7), and secondary neoplasm (n=272). A recent safety review was conducted to evaluate the potential relationship between bendamustine administration and drug reactions with eosinophilia and systemic symptoms (DRESS). Nine reports of DRESS have been received since 2008. No clear causal relationship could be established between bendamustine and the development of DRESS because of concomitant medications known to be associated with DRESS in all cases. Information about preventive measures for tumor lysis syndrome (TLS) was revised during the PV period; 51 instances of serious TLS were reported during the monitoring period.Conclusions: This overview of AE reports collected from over 250,000 patients over 9 years suggests that the overall safety profile of bendamustine is consistent with known toxicities, with the majority of serious AEs associated with myelosuppression and infections. Although this review may be limited by voluntary reporting, the AEs reported for bendamustine in a large, heterogeneous population provide a much broader understanding of its safety profile. Based on this observational data, bendamustine appears to have a favorable risk-benefit profile and remains a useful option when considering a management strategy in patients with CLL and indolent B-cell NHL.Sponsor: Teva Branded Pharmaceutical Products R&D [Display omitted] DisclosuresMartin:Acerta: Consultancy; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Gilead: Consultancy, Other: travel, accommodations, expenses; Novartis: Consultancy; Celgene: Consultancy, Honoraria; Teva: Research Funding. Kahl:Infinity: Consultancy; Gilead: Consultancy; Juno: Consultancy; Pharmacyclics: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy. Pathak:Teva Pharmaceuticals: Employment, Equity Ownership.

578 Interplay of Gender, Age and Drug Properties in Drug-Induced Liver Injury: Analysis of Adverse Event Reporting at Who Vigibase™

[Background] Clinical hepatotoxicity is highly associated with specific drug properties (e.g., lipophilicity, transport, and metabolism) and daily dose (>100mg). However, how these drug properties interact with age and gender in drug-induced liver injury (DILI) remains unclear. [Aim] To generate hypotheses on drug-patient interactions in DILI, we performed a data-mining analysis using the WHO VigiBaseTM to 1) identify drugs with genderand age-biased reporting frequency (RF) of liver events and 2) explore the association between the groups of identified drugs and drug properties relevant to hepatotoxicity. [Methods] Empirical Bayes Geometric Mean of relative reporting ratio of liver events (EBGM) with 90% confidence interval (CI) was calculated for 375 drugs with established clinical DILI potential (Suzuki, Drug safety 2010; Chen, Drug Discovery Today 2011), partitioning all reported cases into 4 groups by gender and age 50 yrs. Drugs with gender-biased indications were manually excluded from the analysis. Combining Medical Dictionary for Regulatory Activities terms (Hunt, Regul Tox Pharm, 2014), customized liver event terms were created for hepatocellular injury, cholestatic injury, acute liver failure, and overall liver events. Comparing EBGM and 90% CI of overall liver events among the 4 groups, drugs with significant differences in genderand age-specific RF were identified. The groups of identified drugs were then associated with distinct drug properties in the Liver Toxicity Knowledge Base (Chen, Clin Pharm & Ther, 2013). [Results] Overall liver events were 13-20% more frequently reported in women compared tomen. Compared to age-matched men, women<50 yrs exhibited a 40% increased RF of acute liver failure. Across all ages, we identified 43 drugs with an increased RF among women, which were significantly associated with transporter inhibition, mitochondrial liability, and reactive metabolite formation, compared to 186 drugs with no gender difference in RF. Fourteen drugs with an increased RF among men tended to have a higher proportion causing cholestatic injury, while 57 drugs with an increased RF among women only before age 50 yrs were associated with a higher proportion causing hepatocellular injury. Regardless of gender, seventeen drugs with an increased RF in age ≥ 50 yrs were associated with transporter inhibition, lipophilicity, high daily dose (≥100mg), and higher Cmax and plasma protein binding, yet shorter plasma elimination T1/2. [Conclusions] This data-mining analysis identified specific drug properties associated with genderand age-related RF of liver events, suggesting a potential physiologic interplay between these drug properties, gender and age. The discovered associations of gender and age-related DILI and the specific drug properties should be further evaluated for drug-patient interaction in DILI susceptibility.

Premedication and incidence of infusion-related reactions in patients with metastatic colorectal cancer treated with cetuximab plus irinotecan-based chemotherapy.

3561 Background: The randomized phase III CRYSTAL study (n=1,202) and the large phase II MABEL study (n=1,147) confirmed the benefit of adding cetuximab respectively to infusional 5-fluorouracil, folinic acid, and irinotecan (FOLFIRI) or irinotecan alone in the first- or subsequent-line treatment of patients (pts) with metastatic colorectal cancer (mCRC). Methods: A post hoc analysis of the pooled population of pts receiving cetuximab was performed to investigate the effect of adding corticosteroid to antihistamine prophylactic premedication on the incidence of infusion-related reactions (IRRs) occurring following the first cetuximab infusion. Results: The incidence of grade 3/4 IRRs based on a broad selection of medical conditions (preferred Medical Dictionary for Regulatory Activities terms) was 1.0% in pts who received antihistamine plus corticosteroid as prophylactic premedication compared with 2.7% in those who received antihistamine alone. A comparable trend was seen for any grade IRRs (8.3% vs. 21.0%, respectively). In pts with a known or suspected or without predisposition to allergic reactions, a lower incidence of grade 3/4 and any grade IRRs occurred in each case for pts receiving antihistamine plus corticosteroid compared with antihistamine alone. Conclusions: These retrospective results indicate that the incidence of cetuximab-related grade 3/4 IRRs was reduced to 1.0% by a combined prophylaxis consisting of an antihistamine and a corticosteroid. N IRR incidence, N (%) Grade 3/4 Grade 4 Any grade Pooled population 1,747 Prophylactic pretreatment Antihistamine alone 596 125 (21.0) 16 (2.7) 7 (1.2) Antihistamine plus corticosteroid 1,061 88 (8.3) 11 (1.0) 2 (0.2) Other 90 Patients without predisposition to allergies 1,507 Prophylactic pretreatment Antihistamine alone 531 106 (20.0) 13 (2.4) 6 (1.1) Antihistamine plus corticosteroid 899 70 (7.8) 8 (0.9) 2 (0.2) Other 77 Patients with known or suspected* predisposition to allergies 240 Prophylactic pretreatment Antihistamine alone 65 19 (29.2) 3 (4.6) 1 (1.5) Antihistamine plus corticosteroid 162 18 (11.1) 3 (1.9) 0 Other 13 * For example, asthma, dermatitis (if not clearly of allergic origin). Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck KGaA, Merck Serono Amgen, AstraZeneca, Celgene, Fresenius Biotech, Merck Serono, Roche Amgen, Bristol-Myers Squibb, Merck Serono, Pfizer, Roche, sanofi-aventis Merck Serono

Pooled cardiac safety analysis of patients with HER2-positive metastatic breast cancer receiving trastuzumab.

Abstract Abstract #6136 Background: The outlook for women with human epidermal growth factor receptor 2 (HER2)-positive early and advanced breast cancer has been significantly improved by the incorporation of trastuzumab (Herceptin®; H) into therapeutic regimens. H has a proven safety profile observed over 10 years of clinical experience in &amp;gt;500,000 patients (pts); however some concerns remain over cardiac dysfunction. This retrospective study reports detailed new analyses of pooled cardiac safety data from 6 metastatic breast cancer (MBC) trials.&amp;#x2028; Methods: Reports of selected adverse events of symptomatic congestive heart failure (CHF) and cardiac rhythm disturbances (CRDs) as well as left ventricular ejection fraction (LVEF) declines were analysed. As definitions of CHF differed between trials, a detailed manual review of original data was performed, including serious adverse event reports. CRDs were identified based on Medical Dictionary for Regulatory Activities terms. LVEF declines were defined as decreases of ≥15 percentage points (pp) from baseline (BL) or ≥10 pp from BL to an LVEF of ≤50%.&amp;#x2028; Results: In total, 882 MBC pts from 6 trials were evaluable for the pooled analysis: in 2 of the trials H was given as monotherapy (WO16229, MO16982) and in others H was combined with paclitaxel (BO15935), docetaxel (M77001), docetaxel and capecitabine (MO16419), and anastrozole (BO16216). There were 683 pts in the H group and 199 in the control group. Pt characteristics were well balanced between treatment groups. Symptomatic CHF was identified in 11 pts (1.6%) in the H group (including 1 death) and none in the control group. Of the 11 pts with CHF, 9 had received prior anthracyclines. Fifty-five CRDs (6.6%) were reported in 45 pts in the H group, with tachycardia (3.2%), palpitations (2.6%) and arrhythmias (0.6%) being the most frequent. With the exception of a single grade 3 event in each group, all CRDs were grade 1 or 2. Nearly all CRDs resolved with no sequelae (50/55 events; 91%). In the control group 2 pts (0.1%) experienced a CRD. The total number of pts evaluable for LVEF decline was 673 in the H group and 194 in the control group; 74 (11.0%) and 7 pts (3.6%), respectively, experienced a drop of ≥10 pp from BL to ≤50%. Eighty-nine (13.2%) and 9 pts (4.6%), respectively, had an LVEF decline of ≥15 pp from BL.&amp;#x2028; Discussion: This pooled analysis of pts from 6 MBC trials demonstrates that H-based treatment in MBC is associated with a low incidence of symptomatic CHF (1.6%) and LVEF declines (11-13% of pts). Although CRDs were observed with H, the majority were of limited clinical significance. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6136.