Drug Safety Data Research Articles

Knowledge, attitude, and practice of medication use among pregnant women in Riyadh City: a cross-sectional study.

Medication use during pregnancy is limited by the scarcity of safety data for many drugs. The use of certain drugs during pregnancy can be teratogenic. Overestimating teratogenic medication risk could have serious consequences from drug non-adherence. Assessing and understanding the knowledge, attitude, and practice of medication use among pregnant women is crucial to optimizing the health of pregnant women and their fetuses. An observational cross-sectional study used convenience and snowball sampling with a self-administered online questionnaire in 562 pregnant women from Riyadh City. The questionnaire used was adapted from previously published surveys. The survey included sections on sociodemographic background, awareness of medication risks, medication use during pregnancy, sources of drug information, and statements from the Beliefs about Medicines Questionnaire (BMQ), both general and pregnancy-specific. Medication use during pregnancy was reported by 44.7%. The primary source for medication information for the majority was the physician. Over 58% indicated inadequate or inconsistent information about medication from physicians. Additionally, 65.7% confirmed not receiving sufficient or inconsistent information from pharmacists during medication dispensing. The responses to the questionnaire reveal a commendable level of knowledge and positive attitude and practice. However, variations could be found in these responses. Overall, no evident relationships were observed between predictors and responses, except in specific statements that indicated a positive association between beliefs and higher levels of education and youth. The results suggest a positive knowledge, attitude, and practice level. However, there was hesitancy and a restrictive attitude towards medication during pregnancy. The study identified inadequate education provided by healthcare professionals, thus presenting an area for improvement to enhance the safety and efficacy of medication use during pregnancy.

Postmarketing Surveillance: Review of Open Sources of Drug Safety Data

INTRODUCTION. Postmarketing surveillance is the main mechanism to monitor and evaluate the safety of drugs approved for widespread clinical use. This mechanism provides up-to-date information on adverse drug reactions and facilitates the implementation of necessary measures to prevent or minimize the risks associated with pharmacotherapy. Marketing authorization holders should regularly conduct searches for and analyses of drug safety data from all available sources. The lack of practical recommendations for selecting relevant information sources complicates the development of an optimal strategy for collecting drug safety data necessary for timely detection of changes in the safety profile of a drug that may affect the benefit–risk ratio.AIM. This study aimed to select the most appropriate methods for collecting drug safety information from the open sources used to monitor the safety profiles of approved drugs and assess their benefit–risk ratios.DISCUSSION. The main sources of new information on the safety of drugs include pharmacovigilance databases, websites of regulatory authorities, publications in medical scientific journals, and real-world clinical practice. According to the analysis results, the most widely used databases are the World Health Organization (WHO) VigiBase database, the European Union (EU) EudraVigilance database, and the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). This article also discusses the capabilities and interfaces of various applications for working with safety data, as well as the conditions for accessing databases. Additionally, the article provides detailed instructions on how to search for safety information on the websites of the European Medicines Agency (EMA) and FDA, which are considered to be the most reliable sources of information. Further, the article provides an overview of reputable medical journals most likely to publish articles on adverse drug reactions. In addition, the article covers bibliographic databases and search engines, which can simplify the search for scientific publications. Systematic monitoring of these sources can help marketing authorization holders to effectively assess the safety profiles and benefit–risk ratios of approved drugs.CONCLUSIONS. The use of recommended data sources can optimize the process of safety monitoring, significantly increase the identification rate for potential risks of pharmacotherapy, and facilitate the timely development of measures to prevent these risks. This, in turn, can contribute to improving the safety of patients and the quality of medical care.

Impact of eligibility criteria discordance on clinical trial accrual in diffuse large B-cell lymphoma (DLBCL).

e13707 Background: Excessively stringent clinical trial eligibility criteria may hinder trial accrual, differentially exclude racial-ethnic minority groups, and limit generalizability. This study reviewed the association between trial accrual and concordance of eligibility criteria with known drug safety data in DLBCL clinical trials. Methods: Eligibility criteria and accrual of completed phase II/III clinical trials for DLBCL that opened in the US between 2010-2020 were abstracted from ClinicalTrials.gov. Trials missing posted results or studying cellular therapy / transplant were excluded. Concordance with known safety data was assessed by comparing study eligibility criteria for QTc, renal, hepatic, and cardiac function to FDA labels and phase I safety signals of study drugs. Excessively strict discordant criteria (ExSDC) were defined as eligibility criteria without supporting safety signals. Logistic regression +/- dispersion was used for analysis. Results: 58 trials met criteria for inclusion, accruing 6,232 participants. 88% of studies involved a non-FDA-approved agent, 74% were multicenter, 55% were industry sponsored, 66% only accrued in the US, and 86% were phase II. Eligibility criteria were highly variable (Table). Discordance of renal, hepatic, cardiac function, and QTc criteria from known safety data occurred in 31%, 26%, 41%, and 29% of studies, respectively. Race and ethnicity data were not reported in 22% and 45% of studies, respectively. Trials after 2015 were more likely to report race (p=0.04) and ethnicity (p=0.01). In a multivariable model adjusted for international study sites, greater number of ExSDC was associated with a lower proportion of black patients in the trial (OR 0.45, CI 0.29-0.71, p=0.001). ExSDC in cardiac function were most associated with reduced accrual of this minority group (OR 0.17, CI 0.05-0.58, p=0.007). 11 studies (19%) had early termination for lack of accrual (ETLA). In multivariable analysis, greater number of ExSDC was independently associated with ETLA (OR 3.53, CI 1.45-8.64, p=0.006), while multicenter status protected against ETLA (OR 0.05, CI 0.01-0.31, p=0.002). Industry sponsor and concordance of cardiac criteria protected against ETLA in univariable analysis only. Other eligibility criteria were not associated. Conclusions: Eligibility criteria in DLBCL trials varied widely and were often discordant with known safety data. Higher number of ExSDC was associated with lower accrual of black patients and higher risk of ETLA. Optimizing concordance of eligibility criteria with safety data may improve trial accrual and diversity. [Table: see text]

Alignment of Later Phase Clinical Trial Eligibility Criteria with Drug Safety in Acute Leukemia: Minimizing Unnecessary Patient Risk and Exclusion

Introduction Clinical trial eligibility criteria can unfairly exclude patients or expose patients to risk if they are not justified by drug safety. Our prior analysis of acute myeloid leukemia (AML) trials identified unjustified variability in the use of criteria and in the limits placed when criteria were used (ASCO 2023 Abstract #6525). As additional safety data are available in later phase studies, we sought to assess if criteria were more justified in phase III versus phase II trials, and we extended our analysis to include acute lymphoblastic leukemia (ALL). Methods Trials and criteria were identified using ClinicalTrials.gov. Trials were included if they treated patients in the United States, were interventional, therapeutic, phase II or III, treated previously untreated adults with AML and/or ALL, were not cellular therapy trials, and had study start dates from 1/1/2010-12/31/2019. Drug safety data from labels, trial protocols, and previous study results available as of study start dates, as identified in the ClinicalTrials.gov record, were compared to systematically coded eligibility criteria following FDA publications.Primary endpoints were differences in discordant criteria use (presence of criteria without a known, relevant drug safety signal or absence of criteria with a signal) and limits (numerical values of drug safety- or criteria-based limits) between phase II and III studies assessed via Fisher's exact, rank sum, and median absolute deviation (MAD) testing. Regression modeling assessed differences in infectious disease (ID) exclusions by phase adjusted for disease type and trial sponsor, year, size, and drug safety profiles (drug-drug interaction and association with viral reactivation). Results There were 250 eligible trials, of which 203 were phase II and 47 phase III; 190 trials were in AML and 60 ALL. Similar proportions of phase II and III trials had exclusion criteria (with specific limits when applicable) for low left ventricular ejection fraction (LVEF; 36 vs 25%), high corrected QT interval (QTc; 21 vs 27%), presence of human immunodeficiency virus (HIV; 57 vs 47%), and hepatitis B (43 vs 38%) and C (42 vs 38%). More phase II than phase III trials had renal function (70 vs 53%; p=0.04), bilirubin (73 vs 49%; p<0.01), and alanine transaminase/aspartate transaminase (AST/ALT; 26 vs 64%; p<0.01) based exclusions. Table 1 shows proportions and odds ratios (OR) of discordant criteria by trial phase. OR of discordance for renal function (1.90), AST/ALT (2.30), and bilirubin (2.45) were significantly higher for phase III studies (all p<0.05); no criteria were less discordant for phase III studies. Drug safety- and trial-based limits for renal and liver function are shown in Figure 1. Median differences between limits numerically improved from phase II to phase III (renal: 0.62 to 0.20; AST/ALT: 0.50 to 0; bilirubin: 0.20 to 0); only the change in renal function was significant (rank sum p=0.03). The dispersion of these differences was numerically smaller for renal function (phase III to III MAD ratio: 0.65) and bilirubin (0.91) and higher for AST/ALT (1.17); no changes in dispersion were significant. In multivariable regressions adjusted for other trial and drug safety factors, phase III trials were equally likely to exclude persons diagnosed with HIV and hepatitis B and C as phase II (adjusted OR 1.48, 1.37, 1.41; all p>0.05). Conclusions Despite increasing understanding of drug safety profiles in later phase trials, the use of eligibility criteria for phase III acute leukemia clinical trials were at least as discordant with known drug safety as earlier phase studies. When drug safety- and trial-based limits were present, phase III criteria were not consistently more aligned with drug safety and were equally likely to exclude persons diagnosed with HIV and hepatitis. Future phase III trials in acute leukemia should standardize and rigorously justify eligibility criteria to enhance patient representativeness and welfare.

Call to action: Harmonization of pharmacovigilance regulations for post-marketing pregnancy and breastfeeding safety studies.

Globally, more than 200 million women become pregnant each year, most of whom receive medications despite limited information on their safe use during pregnancy. The paucity of drug safety data on pregnant and breastfeeding women stems from the routine exclusion of this population from clinical trials due to scientific, ethical, regulatory and legal concerns. Consequently, at the time of initial drug approval, there may be scant safety data to inform the drug benefit-risk balance to the mother, foetus or infant. Although momentum is growing to include this underrepresented population in clinical trials, most information on drug exposure outcomes comes from data collected in the postmarketing setting. Regulatory guidance and legislation on medication use in pregnancy and breastfeeding were reviewed globally by the TransCelerate IGR PV Pregnancy and Breastfeeding Team. The International Conference of Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) standards and Council for International Organizations of Medical Sciences guidelines served as benchmarks for national safety regulations and guidance. The landscape assessment identified a lack of harmonization of global regulations on research in pregnant and breastfeeding women and a lack of specific regulations on this topic in the majority of the territories included in the assessment. This article focuses on the ambiguities and lack of harmonization in global regulations on postmarketing pregnancy and breastfeeding safety studies. There is currently no ICH standard to guide these types of safety studies and, in most regions reviewed, there are no clear regulations or guidance on when and how to conduct them. While a challenging undertaking, greater clarity and harmonization would facilitate more timely completion of postmarketing pregnancy safety studies that would ultimately generate the critical data needed to optimize benefit-risk decisions for women who may conceive, as well as pregnant and breastfeeding women.

Abstract 18525: Sex Differences in Reporting of Statin-Associated Diabetes Mellitus - A Pharmacovigilance Analysis of Us Drug Safety Data

Introduction: Limited observational and clinical trial data have suggested a higher likelihood of statin-associated diabetes mellitus (DM) in women compared with men. However, real-world evidence of sex differences in statin-associated DM generally and with specific statins are lacking. Spontaneous adverse reporting pharmacovigilance systems provide an opportunity to assess these potential sex differences. Hypothesis: Statin-associated DM is reported to the FDA disproportionately more in women than in men. Methods: : Adverse event reports from the FDA Adverse Event Reporting System between 1960 and 2021 were obtained. Cases that included lovastatin, fluvastatin, pravastatin, simvastatin, atorvastatin, and rosuvastatin were analyzed together and individually with respect to reporting of DM vs. all other reactions starting at FDA approval of each. Signals of disproportionate reporting (SDR) were identified using the proportional reporting ratio (PRR) with a threshold of 2, and X2 of 4 with > 3 cases of reaction if interest. Differences between SDR in men vs. women were identified using a lower bound of the 95% confidence interval of the Reporting Odds Ratio (ROR) > 1 in > 3 events. Results: In both men and women, DM was associated with a significantly elevated PRR for all statins combined and individually for atorvastatin, lovastatin, rosuvastatin, fluvastatin, simvastatin, and nominally for pitavastatin. Pravastatin was disproportionately reported in women only (M=1.80, W=2.32). Using ROR, statin-induced DM was reported significantly more frequently for atorvastatin, simvastatin, pravastatin, and rosuvastatin but not for pitavastatin, fluvastatin, or lovastatin. Conclusions: Statin-associated DM is disproportionately reported to the FDA in both men and women for most agents compared with other adverse events. Importantly, statin-associated DM is reported significantly more in women than men for the statins most commonly used in current practice.

Controversies regarding lithium-associated weight gain: case–control study of real-world drug safety data

BackgroundThe impact of long-term lithium treatment on weight gain has been a controversial topic with conflicting evidence. We aim to assess reporting of weight gain associated with lithium and other mood stabilizers compared to lamotrigine which is considered free of metabolic adverse drug reactions (ADRs).MethodsWe conducted a case/non-case pharmacovigilance study using data from the AMSP project (German: “Arzneimittelsicherheit in der Psychiatrie”; i.e., Drug Safety in Psychiatry), which collects data on ADRs from patients treated in psychiatric hospitals in Germany, Austria, and Switzerland. We performed a disproportionality analysis of reports of weight gain (> 10% of baseline body weight) calculating reporting odds ratio (ROR). We compared aripiprazole, carbamazepine, lithium, olanzapine, quetiapine, risperidone, and valproate to lamotrigine. Additional analyses related to different mood stabilizers as reference medication were performed. We also assessed sex and age distributions of weight-gain reports.ResultsWe identified a total of 527 cases of severe drug-induced weight gain representing 7.4% of all severe ADRs. The ROR for lithium was 2.1 (95%CI 0.9–5.1, p > 0.05), which did not reach statistical significance. Statistically significant disproportionate reporting of weight gain was reported for olanzapine (ROR: 11.5, 95%CI 4.7–28.3, p < 0.001), quetiapine (ROR: 3.4, 95%CI 1.3–8.4, p < 0.01), and valproate (ROR: 2.4, 95%CI 1.1–5.0, p = 0.03) compared to lamotrigine. Severe weight gain was more prevalent in non-elderly (< 65 years) than in elderly patients, with an ROR of 7.6 (p < 0.01) in those treated with lithium, and an ROR of 14.7 (p < 0.01) in those not treated with lithium.ConclusionsOur findings suggest that lithium is associated with more reports of severe weight gain than lamotrigine, although this difference did not reach statistical significance. However, lithium use led to fewer reports of severe weight gain than some alternative drugs for long-term medication (olanzapine, quetiapine, and valproate), which is consistent with recent studies. Monitoring of weight gain and metabolic parameters remains essential with lithium and its alternatives.

Post-Transplant Cyclophosphamide for the Prevention of Graft-vs.-Host Disease in Allogeneic Hematopoietic Cell Transplantation: A Guide to Management for the Advanced Practitioner.

Cyclophosphamide remains a critical component to haploidentical transplant conditioning regimens. Post-transplant cyclophosphamide (PTCy) emerged as an effective component of graft-vs.-host disease (GVHD) prophylaxis in the nonmyeloablative haploidentical bone marrow transplant setting. The relative ease of administration compared with ex vivo manipulations and efficacy in reducing GVHD has led to increasing PTCy use in transplant centers around the world. The role of PTCy has expanded to haploidentical transplantation with myeloablative conditioning regimens and peripheral blood progenitor cells as the donor source. Moreover, encouraging results in GVHD management have been shown with the use of PTCy alone or in combination with other immunosuppressives in the human leukocyte antigen-matched donor setting. The toxicity profile of cyclophosphamide varies extensively depending on dose, duration, overall drug exposure, and, potentially, pharmacogenetics. This review highlights the pharmacology, pharmacokinetics, and toxic effects of cyclophosphamide and offers practical guidance for clinical application in the post-transplant setting. We summarize data on the management of high-dose cyclophosphamide toxicities and provide insights into the pharmacogenetic implications on drug efficacy and safety data.

Drug repurposing: A futuristic approach in drug discovery

Drug repurposing (DR), also known as drug repositioning, is a strategy aimed at identifying new therapeutic uses for existing drugs. It offers an effective approach to discovering or developing drug molecules with novel pharmacological or therapeutic indications. In recent years, pharmaceutical companies have increasingly embraced the drug repurposing strategy in their drug discovery and development programs, leading to the identification of new biological targets. This strategy is highly efficient, time-saving, cost-effective, and carries a lower risk of failure compared to traditional drug discovery methods. By maximizing the therapeutic value of existing drugs, drug repurposing increases the likelihood of success. It serves as a valuable alternative to the lengthy, expensive, and resource-intensive process of finding new molecular entities (NMEs) through traditional or de novo drug discovery approaches. Drug repurposing combines activity-based or experimental methods with in silico-based or computational approaches to rationally develop or identify new uses for drug molecules. It leverages the existing safety data of drugs tested in humans and redirects their application based on valid target molecules. This approach holds great promise, particularly in addressing rare, difficult-to-treat diseases, and neglected diseases. By utilizing the wealth of knowledge and resources available, drug repurposing presents an emerging strategy for optimizing the therapeutic potential of existing medicines. It offers a pathway to rapidly identify effective treatments and repurpose approved drugs for new indications, benefiting patients and healthcare systems alike.

Drug Retention Rates and the Safety of Janus Kinase Inhibitors in Elderly Patients with Rheumatoid Arthritis.

We examined the real-world drug retention rate and safety data of Janus kinase inhibitors (JAKis) in elderly patients with rheumatoid arthritis (RA). This study enrolled 133 RA patients (≥65 years) with sufficient clinical data who were initiated with JAKis during the study period. These patients were divided into two groups: the very elderly group (≥ 75 years) and the elderly group (65 ≤ years < 75). The drug retention rates of JAKis were compared using Kaplan-Meier curves. The discontinuation rates of JAKis were as follows: lack of effectiveness 27 (20.3%), adverse events (AEs) 29 (21.8%), and remission 2 (1.5%). There was no significant difference in the overall drug retention rate between the very elderly group (≥75 years) and the elderly group. Furthermore, the overall drug retention rates of JAKis were not affected by gender, methotrexate use, and anti-citrullinated protein/peptide antibody (ACPA) status. The discontinuation rates of JAKis due to AEs were comparable both in the very elderly group (≥75 years) and the elderly group (65 ≤ years < 75). Whereas chronic lung disease and hypoalbuminemia were independently associated with discontinuation rates due to AEs, the overall drug retention rates were significantly lower in patients treated with the approved dose of JAKis than in those treated with a reduced or tapered dose. Our results suggest that the overall drug retention rate of JAKis in very elderly patients (≥75 years) was comparable with that in elderly patients (65 ≤ years < 75). The discontinuation rates of JAKis due to AEs were also comparable both in very elderly group patients and elderly patients.

OP10 Safety Monitoring of Orphan Drugs Project: SFDA Experience

Orphan drugs are developed to treat rare diseases. Some regulatory bodies established orphan drug designation with incentives to help pharmaceutical companies to develop orphan drugs. However, there is a lack of pre-marketing safety data for orphan drugs because limited number of patients involved, due to the rarity of the diseases. Considering that post-marketing long-term safety of orphan drugs still uncertain and the low utilization profile which make it challenging to monitor the safety of orphan drugs.The Saudi Food and Drug Authority (SFDA) initiated a project to monitor the safety of orphan drugs registered.

Assessment of the scope, completeness, and consistency of various drug information resources related to COVID-19 medications in pregnancy and lactation

BackgroundDrug use in pregnancy and lactation is challenging. It becomes more challenging in pregnant and lactating women with certain critical clinical conditions such as COVID-19, because of inconsistent drug safety data. Therefore, we aimed to evaluate the various drug information resources for the scope, completeness, and consistency of the information related to COVID-19 medications in pregnancy and lactation.MethodsData related to COVID-19 medications from various drug information resources such as text references, subscription databases, and free online tools were used for the comparison. The congregated data were analyzed for scope, completeness, and consistency.ResultsScope scores were highest for Portable Electronic Physician Information Database (PEPID), Up-to-date, and drugs.com compared to other resources. The overall completeness scores were higher for Micromedex and drugs.com (p < 0.05 compared to all other resources). The inter-reliability analysis for overall components by Fleiss kappa among all the resources was found to be 'slight' (k < 0.20, p < 0.0001). The information related to the older drugs in most of the resources, provides in-depth details on various components such as pregnancy safety, clinical data related to lactation, the effect of the drug distribution into breast milk, reproductive potential/infertility risk and the pregnancy category/recommendations. However, the information related to these components for newer drugs was superficial and incomplete, with insufficient data and inconclusive evidence, which is a statistically significant observation. The strength of observer agreement for the various COVID-19 medications ranged from poor to fair and moderate for the various recommendation categories studied.ConclusionThis study reports discrepancies in the information related to pregnancy, lactation, drug level, reproductive risk, and pregnancy recommendations among the resources directing to refer to more than one resource for information about the safe and quality use of medications in this special population.The present study also emphasizes the need for development of comprehensive, evidence-based, and precise information guide that can promote safe and effective drug use in this special population.

Real-life Data of Glecaprevir/Pibrentasvir in Chronic Hepatitis C Patients: A Single-center Study

Background: Glecaprevir/pibrentasvir (G/P) is a pangenotypic direct-acting antiviral (DAA) drug with a high resistance barrier. It has been used in patients with chronic hepatitis C in Turkey since March 2019. This drug's efficacy and safety data in Turkey are very limited, and there are not enough studies on real-life data. Objectives: In this study, we aim to present real-life data, efficacy, and safety for our patients. Methods: In this retrospective, observational, single-center study, 116 patients who were started on G/P (100mg/40mg) oral therapy at the infectious diseases clinic between March 2019 and December 2021 due to HCV were included. Of the 116 patients included in the study, 92 were analyzed. Demographic data of the patients, previous treatment experience, drug use, viral load (HCV RNA levels at the 4th week of treatment and 12th week after treatment), and viral genotype data were obtained retrospectively from the automation system. Statistical analysis IBM SPSS version 21.0 statistical package program was used. Results: Seventy-one (77.2%) of the patients were male, and 21 (22.8%) were female, with a mean age of 47.4 (18 - 89). Genotype distribution of patients 8.7% (n = 8) type 1a, 31.5% (n = 29) type 1b, 26.1% (n = 24) type 2, 22.9% (n = 21) type 3, 10.9% (n = 10) were type 4, 8.7% (n = 8) of the patients were treatment-experienced. In our study, there were no patients with cirrhosis. SVR-12 could not be obtained from a patient infected with only genotype 1a. In addition, this patient was co-infected with Hepatitis B. No side effects were observed in any of the patients that required treatment discontinuation. The SVR-12 rate was 98.6% with patients per protocol analysis (PP), but the SVR-12 rate was 77.2% with intention to treat analysis (ITT). Conclusions: In conclusion, this study suggested that G/P therapy in Turkey is used in real life with very high efficacy and tolerability. In addition, a significant change was observed in the genotype distribution previously reported in Turkey in the patient group we treated.

The Struggle to End a Millennia-Long Pandemic: Novel Candidate and Repurposed Drugs for the Treatment of Tuberculosis.

This article provides an encompassing review of the current pipeline of putative and developed treatments for tuberculosis, including multidrug-resistant strains. The review has organized each compound according to its site of activity. To provide context, mention of drugs within current recommended treatment regimens is made, thereafter followed by discussion on recently developed and upcoming molecules at established and novel targets. The review is designed to provide a clinically applicable understanding of the compounds that are deemed most currently relevant, including those already under clinical study and those that have shown promising pre-clinical results. An extensive review of the efficacy and safety data for key contemporary drugs already incorporated into treatment regimens, such as bedaquiline, pretomanid, and linezolid, is provided. The three levels of the bacterial cell wall (mycolic acid, arabinogalactan, and peptidoglycan layers) are highlighted and important compounds designed to target each layer are delineated. Amongst others, the highly optimistic and potent anti-mycobacterial activity of agents such as BTZ-043, PBTZ 169, and OPC-167832 are emphasized. The evolving spectrum of oxazolidinones, such as sutezolid, delpazolid, and TBI-223, all aiming to exceed the efficacy achieved with linezolid yet offer a safer alternative to the potential toxicity, are reviewed. New and exciting prospective agents with novel mechanisms of impact against TB, including 3-aminomethyl benzoxaboroles and telacebec, are underscored. We describe new diaryloquinolines in development, striving to build on the immense success of bedaquiline. Finally, we discuss some of these compounds that have shown encouraging additive or synergistic benefit when used in combination, providing some promise for the future in treating this ancient scourge.

Barriers and Facilitators Influencing Real-time and Digital-Based Reporting of Adverse Drug Reactions by Community Pharmacists: Qualitative Study Using the Task-Technology Fit Framework.

BackgroundMedication use can result in adverse drug reactions (ADRs) that cause increased morbidity and health care consumption for patients and could potentially be fatal. Timely reporting of ADRs to regulators may contribute to patient safety by facilitating information gathering on drug safety data. Currently, little is known about how community pharmacists (CPs) monitor, handle, and report ADRs in Australia.ObjectiveThis study aimed to identify perceived barriers to and facilitators of ADR reporting by CPs in Australia and suggest digital interventions.MethodsA qualitative study with individual interviews was conducted with CPs working across Victoria, Australia, between April 2022 and May 2022. A semistructured interview guide was used to identify perceived barriers to and facilitators of ADR reporting among CPs. The data were analyzed using thematic analysis. We constructed themes from the CP-reported barriers and facilitators. The themes were subsequently aligned with the Task-Technology Fit framework.ResultsA total of 12 CPs were interviewed. Identified barriers were lack of knowledge of both the ADR reporting process and ADR reporting systems, time constraints, lack of financial incentives, lack of organizational support for ADR reporting, inadequate IT systems, and preference to refer consumers to physicians. The proposed facilitators of ADR reporting included enhancing CPs knowledge and awareness of ADRs, financial incentives for ADR reporting, workflow-integrated ADR reporting technology systems, feedback provision to CPs on the reported ADRs, and promoting consumer ADR reporting.ConclusionsBarriers to and facilitators of ADR reporting spanned both the task and technology aspects of the Task-Technology Fit model. Addressing the identified barriers to ADR reporting and providing workplace technologies that support ADR reporting may improve ADR reporting by CPs. Further investigations to observe ADR handling and reporting within community pharmacies can enhance patient safety by increasing ADR reporting by CPs.

A Detailed Insight onto the Molecular and Cellular Mechanism of Action of the Antifungal Drugs Used in the Treatment of Superficial Fungal Infections

Background: Dermatomycosis is a type of fungal infection that can infect human skin, hair, and nails; an increasing growth of fungal infections ranging from superficial to systemic infection is alarming. Common causative agents are Candida, Cryptococcus, Aspergillus, and Pneumocystis species. A wide range of antifungal drugs is used for the treatment of mycotic infections. These antifungal drugs can be oral or topical. The topical therapy ensures reduced side effects. Some act as fungistatic, while others act as fungicidal. These drugs work by a different mechanism of action to prevent and cure fungal infections. Objective: The effective treatment of the fungal infection includ the use of proper antifungal drug therapy. Antifungal drugs are classified into various classes. This paper focuses on understanding and interpreting the detailed molecular and cellular mechanism of action of various classes of anti-fungal drugs with their important characteristics along with the safety and efficacy data of individual drugs of the particular class. Methods: The data selection for carrying out the respective study has been made by studying the combination of review articles and research papers from different databases, like ResearchGate, PubMed, MDPI, Elsevier, ScienceDirect, and MedCrave, ranging from the year 1972 to 2019, by using the keywords like “anti-fungal agents”, “dermatophytes”, “cutaneous candidiasis”, “superficial fungal infections”, “oral candidiasis”, “amphotericin”, “echinocandins”, “azoles”, “polyenes” “ketoconazole”, “terbinafine”, “griseofulvin”, “azoles”. Result: Based on interpretation, it is concluded that the different classes of antifungal drugs follow the different mechanisms of action and target the fungal cell membrane, and are efficient in reducing fungal disease by their respective mechanism. Conclusion: The prevention and cure of fungal infections can be done by oral or topical antifungal drugs aimed to destroy the fungal cell membrane. These drugs show action by their respective pathways that are either preventing the formation of ergosterol or squalene or act by inhibiting the β-1,3- glucan synthase enzyme. All the drugs are found to be effective in treating fungal infections.

Methods used to generate safety-related evidence in real-world oncology settings: A systematic literature review.

e18769 Background: With the increasing availability of real-world data (RWD) as a valuable healthcare data source, there have been large shifts in how a drug’s properties can be evaluated over its life cycle. RWD can be used for many evidence generation purposes, including the evaluation of a drug’s safety in real-world settings outside of clinical trials. Traditional methods (e.g., cohort and case-control studies) are often used to analyze RWD, but novel methods have emerged as the field advances with access to more diverse data sources. The extent to which these newer methods are being used is unclear. The aim of this systematic review is to identify methods that have been used in recent years to generate safety-related evidence in real-world oncology settings. Methods: A search of literature published between 1/1/2016-8/10/2021 (Embase, Ovid) was performed to identify studies describing methods used to generate evidence related to the real-world safety of oncology products. Each article was independently screened by two researchers in two levels (title/abstract and full text screening). Data extracted included, but was not limited to, study design, cancer type, data source, and statistical methods. Results: Out of 845 publications identified, 44 were included for review (742 excluded after level 1 screening; 59 excluded after level 2 screening). The most common method used was the retrospective cohort study (n = 26), followed by prospective cohort study (n = 8), literature review (n = 4), cross-sectional study (n = 3), artificial intelligence (AI) methods (n = 3), data mining analysis (n = 2), case-series, and case-control study (n = 1 each). Some publications used multiple methods. While traditional methods (e.g., cohort study, literature review) were the most common throughout the search period, newer methods (e.g., AI methods) were identified in the latter part of the search period (2019-2020). The majority of studies that used traditional methods relied on medical records or claims data (e.g., Optum), which often provided structured RWD to evaluate physician-documented drug safety data. In contrast, articles that used newer methods like AI analyzed large amounts of patient-reported data (e.g., chatbot conversations; social networks), which allowed researchers to evaluate patients’ own experiences with drug safety. Conclusions: The most common evidence generation methods identified involved traditional methods, but novel methods were also identified, especially in recent years. This indicates a trend towards increased use of innovative methods like AI that allow for the analysis of data in ways not possible before. Taken together with more traditional methods and data sources, these findings can provide clinicians with a more comprehensive and patient-focused understanding of drug safety, which will ultimately improve patient care.

Barriers and facilitators for systematically registering adverse drug reactions in electronic health records: a qualitative study with Dutch healthcare professionals

Background Systematically registering ADRs in electronic health records (EHRs) likely contribute to patient safety as it enables the exchange of drug safety data. Currently, ADRs registrations by healthcare professionals (HCPs) is suboptimal. This study aimed to identify barriers and facilitators perceived by HCPs to register ADRs systematically in EHRs. Research design and methods A qualitative study with individual interviews was conducted among specialist physicians and hospital pharmacists from 10 different Dutch hospitals. A semi-structured interview guide was used to identify experienced barriers and facilitators for systematically registering ADRs. Data was analysed following thematic analysis. Themes within barriers and facilitators were aligned with the Capability–Opportunity-Motivation–Behaviour (COM-B) framework. Results In total, 16 HCPs were interviewed. Identified barriers were: lack of knowledge to recognize ADRs, time constraints, inadequate IT system, lack of support, stuck in routine, and not recognizing the importance of registering ADRs. Identified facilitators were: enhanced knowledge and awareness of ADRs, functional IT systems, expanding accountability for registration, and motivation towards registering. Conclusions Barriers and facilitators for registering spanned all aspects of the COM-B model and occurred in individual, social and environmental domains. Addressing these aspects could improve the registration of ADRs and may contribute to patient safety.

Reporting of clinical trial safety results in ClinicalTrials.gov for FDA-approved drugs: A cross-sectional analysis.

Adverse events identified during clinical trials can be important early indicators of drug safety, but complete and timely data on safety results have historically been difficult to access. The aim was to compare the availability, completeness, and concordance of safety results reported in ClinicalTrials.gov and peer-reviewed publications. We analyzed clinical trials used in the Food and Drug Administration safety assessment of new drugs approved between 1 July 2018 and 30 June 2019. The key safety outcomes examined were all-cause mortality, serious adverse events, adverse events, and withdrawals due to adverse events. Availability of safety results was measured by the presence and timing of a record of trial-level results in ClinicalTrials.gov and a corresponding peer-reviewed publication. For the subset of trials with available results, completeness was defined as the reporting of safety results for all participants and compared between ClinicalTrials.gov and publications. To assess concordance, we compared the numeric results for safety outcomes reported in ClinicalTrials.gov and publications to results in Food and Drug Administration trial reports. Among 156 trials studying 52 drugs, 91 (58.3%) trials reported safety results in ClinicalTrials.gov and 106 (67.9%) in peer-reviewed publications (risk difference = -9.6%, 95% confidence interval = -20.3 to 1.0). All-cause mortality was reported sooner in published articles compared with ClinicalTrials.gov (log-rank test, p = 0.01). There was no difference in time to reporting for serious adverse events (p = 0.05), adverse events (p = 0.09), or withdrawals due to adverse events (p = 0.20). Complete reporting of all-cause mortality was similar in ClinicalTrials.gov and publications (74.7% vs 78.3%, respectively; risk difference = -3.6%, 95% confidence interval = -15.5 to 8.3) and higher in ClinicalTrials.gov for serious adverse events (100% vs 79.2%; risk difference = 20.8%, 95% confidence interval = 13.0 to 28.5) and adverse events (100% vs 86.8%; risk difference = 13.2%, 95% confidence interval = 6.8 to 19.7). Withdrawals due to adverse events were less often completely reported in ClinicalTrials.gov (62.6% vs 92.5%; risk difference = -29.8%, 95% confidence interval = -40.1 to -18.7). No difference was found in concordance of results between ClinicalTrials.gov and publications for all-cause mortality, serious adverse events, or withdrawals due to adverse events. Safety results were available in ClinicalTrials.gov at a similar rate as in peer-reviewed publications, with more complete reporting of certain safety outcomes in ClinicalTrials.gov. Future efforts should consider adverse event reporting in ClinicalTrials.gov as an accessible data source for post-marketing surveillance and other evidence synthesis tasks.

Financial conflicts of interest during meetings of the cardiovascular and renal drugs advisory committee.

The Cardiovascular and Renal Drugs Advisory Committee (CRDAC) of the Food and Drug Administration (FDA) reviews safety and efficacy data for cardiovascular and renal drugs, ultimately making recommendations to the Commissioner of Food and Drugs for approval. The Open Public Hearing segment of these meetings allows for patients, advocates, healthcare professionals, clinical trialists, and members of the public to provide testimony, which often results in expressing their preference for, or against, drug approval. Prior to providing testimony, the public speakers are highly encouraged to disclose any financial conflicts of interest (FCOIs) with the sponsor or other groups. Given the potential influence of these speakers on drug approval recommendations, we investigated the industry associations disclosed by public speakers in the Open Public Hearing section of the CRDAC meetings. Previous studies, such as one done by Lurie etal. indicated that positive testimony is tied to a higher likelihood of drug approval, and because drug companies provide financial compensation for speakers to provide testimony in general, we wanted to determine the likelihood with which speakers who have an FCOI provided a positive testimony vs. those without any FCOI. The purpose is to evaluate whether public speakers with an FCOI are more likely to provide positive testimony regarding the drug in question during the CRDAC of the FDA between February 2009 and December 2019 through the use of publicly available transcripts. Independent researchers investigated public transcripts and minutes of the CRDAC meetings with public speakers (n=20). We identified all speakers, along with characteristics such as an FCOI, and classified statements utilizing a pilot-tested Google form. The data collected were analyzed utilizing Stata. The speaker's testimony was then compared with their FCOI. An ordered logistic regression was performed utilizing the speaker's testimony regarding the drug as the dependent variable. Of the 88 speakers represented in our sample, 35 (35/88, 39.8%) disclosed an FCOI, most commonly regarding travel cost. Among speakers with an FCOI, 30 (30/35, 85.7%) spoke positively. Speakers with an FCOI were 4.96 times more likely to provide positive testimony (OR=4.96, 95% CI 1.67-14.78). Speakers with the disease were also more likely to provide positive testimony (OR=13.05, 95% CI 2.84-59.93). Public speakers often play a role during meetings, and they may also have an FCOI, most commonly related to travel expenses. Our study shows that speakers with an FCOI are more likely to provide positive testimony. Stipulations, such as requiring disclosure of FCOI and randomizing the selection process of speakers, can help ensure the integrity of the drug approval process.