From Food And Drug Administration Research Articles

The Amblyopia Quality of Life (AmbQoL): Development and Content Validation of a Novel Health-Related Quality of Life Instrument for Use in Adult and Pediatric Amblyopia Populations.

Amblyopia is a neurodevelopmental vision disorder, characterized by poor vision in one or both eyes. Given the lack of existing clinical outcome assessments (COA) considered fit-for-purpose for amblyopia clinical trials, this study developed new COAs to assess amblyopia symptoms and health-related quality of life (HRQoL) impacts in adult and pediatric amblyopia populations that conform with best practice standards and regulatory guidelines. Findings from a targeted qualitative literature review informed the development of three versions of the new Amblyopia Quality of Life Questionnaire (AmbQoL): a patient-reported outcome measure (PRO) for individuals aged 13years and older, a PRO for children aged 9-12years, and an observer-reported outcome measure (ObsRO) for caregivers of children aged 4-8years. Qualitative interviews were conducted with the target populations, and with ophthalmologists experienced in treating amblyopia patients to evaluate the content validity for further development of the AmbQoL. A translatability assessment was conducted to ensure cultural appropriateness and usability across multiple languages. Feedback from Food and Drug Administration (FDA) was also sought on the instruments, and clinical experts provided input at key stages. Interviews were conducted with 112 patients/caregivers and ten ophthalmologists from the USA, France, and Germany. The instructions, items, and response options were well understood across all AmbQoL versions. Feedback from the patients, caregivers, ophthalmologists, the translatability assessment, the FDA, and the expert clinicians informed minor wording modifications to enhance clarity and translatability. Some items were removed due to low relevance. The study resulted in a 23-item adult/adolescent PRO, 24-item child PRO, and 12-item ObsRO, each employing a 7-day recall period. Each AmbQoL version has documented support for its face and content validity for use in amblyopia populations aged ≥ 4years. Further research is necessary to evaluate the psychometric measurement properties of the AmbQoL instruments to enable their use in amblyopia treatment trials.

Detecting Tweets Containing Cannabidiol-Related COVID-19 Misinformation Using Transformer Language Models and Warning Letters From Food and Drug Administration: Content Analysis and Identification.

COVID-19 has introduced yet another opportunity to web-based sellers of loosely regulated substances, such as cannabidiol (CBD), to promote sales under false pretenses of curing the disease. Therefore, it has become necessary to innovate ways to identify such instances of misinformation. We sought to identify COVID-19 misinformation as it relates to the sales or promotion of CBD and used transformer-based language models to identify tweets semantically similar to quotes taken from known instances of misinformation. In this case, the known misinformation was the publicly available Warning Letters from Food and Drug Administration (FDA). We collected tweets using CBD- and COVID-19-related terms. Using a previously trained model, we extracted the tweets indicating commercialization and sales of CBD and annotated those containing COVID-19 misinformation according to the FDA definitions. We encoded the collection of tweets and misinformation quotes into sentence vectors and then calculated the cosine similarity between each quote and each tweet. This allowed us to establish a threshold to identify tweets that were making false claims regarding CBD and COVID-19 while minimizing the instances of false positives. We demonstrated that by using quotes taken from Warning Letters issued by FDA to perpetrators of similar misinformation, we can identify semantically similar tweets that also contain misinformation. This was accomplished by identifying a cosine distance threshold between the sentence vectors of the Warning Letters and tweets. This research shows that commercial CBD or COVID-19 misinformation can potentially be identified and curbed using transformer-based language models and known prior instances of misinformation. Our approach functions without the need for labeled data, potentially reducing the time at which misinformation can be identified. Our approach shows promise in that it is easily adapted to identify other forms of misinformation related to loosely regulated substances.

Identification of potential inhibitors, conformational dynamics, and mechanistic insights into mutant Kirsten rat sarcoma virus (G13D) driven cancers.

The mutations at the hotspot region of K-Ras result in the progression of cancer types. Our study aimed to explore the small molecule inhibitors against the G13D mutant K-Ras model with anti-cancerous activity fromfood and drug administration (FDA)-approved drug compounds. We implemented several computational strategies such as pharmacophore-based virtual screening, molecular docking, absorption, distribution, metabolism and excretion features, and molecular simulation to ensure the identified hit compounds have potential efficacy against G13D K-Ras. We found that the FDA-approved compounds, namely, azelastine, dihydrocodeine, paroxetine, and tramadol, are potential candidates to inhibit the action of G13D mutant K-Ras. All four compounds exhibited similar binding patterns of sotorasib, and a structural binding mechanism with significant hydrophobic contacts. The descriptor features from the QikProp of all four compounds are within allowable limits compared to sotorasib drug. Consequently, a molecular simulation result emphasized that the dihydrocodeine and tramadol exhibited less fluctuation, minimal basin, significant h-bonds, and potent inhibition against G13D K-Ras. As a result, the current research identifies prospective K-Ras inhibitors that could be further improved with biochemical analysis for precision medicine against K-Ras-driven cancers.

Ileus in patients treated with immune checkpoint inhibitors: A retrospective, pharmacovigilance study using Food and Drug Administration Adverse Event Reporting System database.

Immune checkpoint inhibitors (ICIs) have been widely used in cancer treatment; however, some case reports suggested that ICIs treatment might result in ileus. This study aims to comprehensively reveal the relationship between ileus and ICIs treatment in real-world cases from Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Reports from January 1, 2011 to December 31, 2020 were extracted from the FAERS. ICIs-related adverse events in patients were defined as related to use of anti-programmed cell death protein 1 antibodies (PD-1, nivolumab and pembrolizumab), anti-programmed cell death-ligand 1 inhibitors (PD-L1, atezolizumab, durvalumab, avelumab, and cemiplimab), and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, ipilimumab and tremelimumab). ICIs-related ileus cases were identified to characterize their clinical features. Reporting odds ratios (ROR) and information component (IC) were used to assess the relationship between ICIs and ileus. Among the 105 001 cases related to ICIs, 245 were reported with ICI-related ileus. The affected patients were mainly elderly (median age, 64.5 years) and male (58%, n=143). The median onset for all cases was 36 (range 0-880) days, and no statistical difference was observed between monotherapy and combination therapy (PD-1 or PD-L1 plus CTLA-4) (p=0.21). Most patients required drug withdrawal treatment (n=113, 74%) and can achieve a recovered-resolved state (n=72, 46%). All ICIs were significantly associated with ileus (ROR=4.27, 95%Cl: 3.75-4.85; IC=2.04, 95%Cl: 1.79-2.31). Ileus events were most commonly reported in PD-1 treatment (n=164, ROR=3.83, 95%Cl: 3.28-4.48; IC=1.90, 95%Cl: 1.62-2.21). This pharmacovigilance database analysis suggested that ICIs are related to ileus. However, combination therapy may not speed up the onset of ileus.

Discrepancies between FDA documents and ClinicalTrials.gov for Orphan Drug-related clinical trial data.

Clinical trial registries such as ClinicalTrials.gov (CTG) hold large amounts of data regarding trials. Drugs for rare diseases are known as orphan drugs (ODs), and it is particularly important that trials for ODs are registered, and the data in the trial record are accurate. However, there may be discrepancies between trial-related data that were the basis for the approval of a drug, as available from Food and Drug Administration (FDA) documents such as the Medical Review, and the data in CTG. We performed an audit of FDA-approved ODs, comparing trial-related data on phase, enrollment, and enrollment attribute (anticipated or actual) in such FDA documents and in CTG. The Medical Reviews of 63 ODs listed 422 trials. We used study identifiers in the Medical Reviews to find matches with the trial ID number, 'Other ID' or 'Acronyms' in CTG, and identified 202 trials that were registered with CTG. In comparing the phase data from the 'Table of Clinical Studies' of the Medical Review, with the data in CTG, there were exact matches in only 75% of the cases. The enrollment matched only in 70% of the cases, and the enrollment attribute in 91% of the cases. A similar trend was found for the sub-set of pivotal trials. Going forward, for all trials listed in a registry, it is important to provide the trial ID in the Medical Review. This will ensure that all trials that are the basis of a drug approval can be swiftly and unambiguously identified in CTG. Also, there continue to be discrepancies in trial data between FDA documents and CTG. Data in the trial records in CTG need to be updated when relevant.

Comparator product issues for biowaiver implementation: the case of Fluconazole

The aim of this work was to assess if the commercially available Fluconazole drug products (Reference, Generic and Similar) would meet the biowaiver criteria from Food and Drug Administration (FDA) and Brazilian Agency for Health Surveillance (ANVISA) agencies. All formulations were evaluated considering the dissolution profile carried out in Simulated Gastric Fluid (SGF) pH 1.2, Acetate Buffer (AB) pH 4.5 and Simulated Intestinal Fluid (SIF) pH 6.8. The results demonstrated that all formulations fulfilled the 85% of drug dissolved at 30 min criterion in SGF pH 1.2. However, in AB pH 4.5 and SIF pH 6.8, some formulations, including the comparator, did not achieve this dissolution percentage. The discrepant dissolution profiles also failed the ƒ2 similarity factor analysis, since none of the formulations showed values between 50 and 100 in the three dissolution media. Comparative dissolution profiles were not similar, considering that the main issues concerning the dissolution were evidenced for the comparator product. Hence, a revision in the regulatory norms in order to establish criteria to switch the comparator could result in an increased application of drugs based on biowaiver criteria.

Enzymatic non-covalent synthesis of supramolecular assemblies as a general platform for bioorthogonal prodrugs activation to combat drug resistance

Multi-drug resistance (MDR) is one of the leading causes of the anticancer failures. Besides the blockage of the MDR pathways, the development of more potent drugs is with urgent needs, but has been postponed mainly due to an imbalance between safety and efficacy. The recent development of the bioorthogonal prodrug activation strategy has shown immense potential to balance safety and efficacy, while recent studies only focused on few drug entities such as doxorubicin and monomethyl auristatin E, leaving the vast collection of toxins undetermined. Here we have enumerated typical molecular entities ranging from food and drug administration (FDA) approved drugs to a heated antibody drug conjugates (ADC) warhead and a trichothecene toxin to demonstrate that the bioorthogonal caging and specific activation could serve as a general design to increase the therapeutic index of bioactive molecules. These prodrugs can be efficiently activated on-demand by the bioorthogonal activators whose distribution was regulated by the cancer cell specific enzymatic non-covalent synthesis of supramolecular self-assemblies. The prodrug activation not only enhanced the synergistic therapeutic effect within a broad range of dose ratios but also allowed the convenient switching of drug identities to successfully combat MDR tumor in vivo. In general, this strategy might serve as a general platform, which can be readily applicable to enlarge the therapeutic window for various bioactive molecules. We envision that the spatiotemporal controlled bioorthogonal prodrug activation would facilitate the discovery of anticancer drugs.

A fully automated assay to detect the expression of pan-cytokeratins and of EML4-ALK fusion protein in circulating tumour cells (CTCs) predicts outcome of non-small cell lung cancer (NSCLC) patients

BackgroundIn advanced non-small cell lung cancer (NSCLC) a recent meta-analysis confirms circulating tumour cells (CTCs) as an independent prognostic indicator of progression-free survival (PFS) and overall survival (OS). However, further investigations are necessary to predict and dynamically monitor the therapy in NSCLC patients using CTCs. To this aim, we combined the classical standard assay (SA) with an expanded cytokeratins profile (EA) and quantified the expression of EML4-ALK fusion protein in CTCs.MethodsThe CellSearch (CS) platform—first marked in vitro diagnostic use (IVD) from Food and Drug Administration (FDA), and “gold standard” for quantifying CTCs - detects EpCAM and cytokeratins (CKs) 8, 18, and 19. Since NSCLC shows different CKs profile, we customized the SA, to recognize CK 4, 5, 6, 7, 8, 10, 13, 14, 18, and 19 (EA). Using both assays we designed a prospective, multi-center study, primarily aimed to enumerate CTCs in advanced NSCLC. Secondarily, we developed an integration of the EA to quantify the expression of EML4-ALK fusion protein in CTCs, and correlated them with PFS and OS.ResultsEA identified a significantly much more number of CTC-positive patients (115 out of 180) than SA (103 out of 192; Chi-square =4.0179, with 1 degrees of freedom, P=0.04502). Similar to SA, EA levels were still associated with patient’ outcomes. Furthermore, the expression of EML4-ALK on CTCs allowed stratifying NSCLC patients according to a statistically significant difference in PFS.ConclusionsWe proposed here two novel automated tests, to characterize the expression of specific molecules on CTCs. We demonstrated that these integrated assays are robust and actionable in prospective clinical studies, and in the future could allow clinicians to improve both choice and length of treatment in individual NSCLC patient.

Thermal inactivation and nucleic acid amplification-based testing for SARS-CoV-2.

Recently, Pang and colleagues reported that thermal inactivation of clinical samples at +56 °C adversely affected the efficiency of RT-PCR for SARS-CoV-2 detection, likely by disrupting the integrity of the SARS-CoV-2 RNA with subsequent risk of false negative results [1]. However, the impact of heat inactivation on nucleic acid amplification-based testing results remains controversial. Thus, Chen and colleagues reported that the inactivation by incubating sample at +56 °C for 30 min had no significant effect on the detection of SARS-CoV-2 by real-time RT-PCR [2]. In April 2020, Abbott Molecular (Des Plaines, IL, USA) received emergency use authorization (EUA) approval from Food and Drug Administration (FAD), USA, for real-time RT-PCR test to detect SARS-CoV-2 RNA in clinical specimens from suspected COVID-19 patients [3]. The RealTime SARS-CoV-2 assay (Abbott Molecular) amplifies target regions of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and nucleocapsid (N) genes. The assay is run on the automated Abbott m2000 SP/rt platform currently in use internationally by reference laboratories and university hospitals. The RealTime SARS-CoV-2 assay has been validated for clinical use, and with the high-throughput, fully automated Abbott m2000 SP/rt system, this assay will accelerate the pace of SARS-CoV-2 testing [4]. The instructions for use of the RealTime SARS-CoV-2 assay (Abbott Molecular; reference 09N77-095) do not give details on pre-analytical processing of samples, and only claims that all human sourced materials should be considered infectious and be handled using appropriate laboratory biosafety practices [3]. Iorder to provide protection of our laboratory staff, and in the absence of instruction for clinical specimen inactivation from the manufacturer, we investigated herein whether thermal inactivation could affect the results of viral detection using RealTime SARS-CoV-2 assay (Abbott Molecular).

Reliability of Conclusions from Early Analyses of Real-World Data for Newly Approved Drugs in Advanced Gastric Cancer in the United States.

BackgroundAs real-world data resources expand and improve, there will increasingly be opportunities to study the effectiveness of interventions. There is a need to ensure that study designs explore potential sources of bias and either acknowledge or mitigate them, in order to improve the accuracy of findings. The objective of this study was to understand newly approved drug utilization patterns in real-world clinical settings over time.MethodsThis retrospective study included three sources of real-world data (claims, electronic health records, and recoded data from a quality care program) collected from patients diagnosed with gastric cancer who initiated therapy with either trastuzumab or ramucirumab. Linear regression was used to investigate trends in the use of these drugs for the care of patients with gastric cancer over time from Food and Drug Administration (FDA) approval.ResultsEligible patients (n=1700) had consistent demographic and clinical characteristics over time. After regulatory approval, trastuzumab was used in later lines of therapy and then shifted to earlier lines (p=0.002), while ramucirumab utilization remained consistent over time after FDA approval (p=0.49). Ramucirumab augmentation, defined as the addition of the drug after initiation of a line of therapy, decreased over time (p=0.03), and trastuzumab augmentation remained consistent over time (p=0.58).ConclusionSince treatment effectiveness may change across lines of treatment, bias may arise if there are changes in the use of the drug (such as line migration) during the time period of analysis using real-world data.

Need and Recommendations for Universal Guidelines on Regulatory Status and Quality Control/Safety of Probiotic Products

Background: In today’s era, various health boosting products viz. probiotics, functional foods, dietary supplements and nutraceuticals are gaining great commercial interest. Although probiotics have traditional history of their use, their regulatory approval regimes across the globe are complicated and incoherent. Objective: The present article has been compiled to give an overview of the existing approval guidelines for the probiotic products across the globe along with their associated ambiguities. Furthermore, suggestive consolidations for harmonized approval process to be implemented in future are proposed on the basis of their intended use. Methods: The study was carried out by using secondary sources through literature survey from journals, market reports, proceedings, books and web pages of relevant regulatory authorities and a critical comparative study was conducted with respect to approval process of probiotics. Results: As per the comparative account of the current regulatory guidelines, it has been evidenced that different countries have adopted diverse approval process for probiotics and; lack of uniformity is of great concern. But due to rapid emergence of probiotics as drugs, a harmonized approval process similar to other drugs covering all aspects of Investigational New Drug Application (INDA) and New Drug Application (NDA) has been proposed in which organisms falling under Generally Recognized As Safe (GRAS) category are exempted from INDA submission whereas non GRAS, GRAE or new organisms are not exempted. After submission of NDA and getting approval from Food and Drug Administration (FDA), product should be manufactured and marketed. Conclusion: Regulatory bodies across the globe must ensure that probiotics based products should be regulated by lawful approval process in such a manner which will lead to maximal health benefits and minimal health risk for consumers.

Classification of medicines using naive bayes classifier

In data mining there is a function called classification that assigns items into groups based on their similarities. These classification techniques are used in many real time applications to classify the data. In pharmaceutical industries all the new medicines need to get approval from Food and Drug administration (FDA) before bringing them into the market. FDA is completely depended on its manual operation and leads to more amount of time for the approval of new medicines. By using classification technique the FDA can automate the procedure with which the time required for approval of new medicine can be reduced. For classification of unknown medicines six chemical properties are used such as relative molecular mass, Number of hydrogen bond donor, Number of hydrogen bond acceptor, Polar surface Area , Hydrophobic constant and number of flexible rotation keys. Drug category and these six properties are collected from U.S National Library of Medicine for creating a new database. By applying Naive Bayes algorithm on the collected data, target class of unknown medicines can be accurately predicted. The fundamental purpose of this paper is to provide a comprehensive analysis of classification methods for predicting unknown medicines. And even discusses the computation procedure of binary classification system for fever and typhoid medicines.

Transparent Assessment of the Supervision Information in China’s Food Safety: A Fuzzy-ANP Comprehensive Evaluation Method

Improving transparency of food safety supervision information can reduce the occurrence of information asymmetry, decrease food safety incidents, and promote socially joint regulation for food safety. In this study, an index system of food safety supervision information transparency (FSSIT) is constructed using the fuzzy-ANP comprehensive evaluation model. Using this system, the FSSIT in China is evaluated. A total of 1651 questionnaires containing 139525 data are collected from food and drug administration (FDA), consumer association (CA), and media at the central, provincial, prefectural, and county levels. Empirical results indicate that the FSSIT achieves a qualified level; however, the works of FDA, CA, and media still present deficiencies. The information transparency in the entirety presents deficiencies and gradually declines when that in the administrative level decreases. The economic development level indirectly determines the transparency level, and the transparency level does not conform to China’s current economic development level.

Bias in the reporting of harms in clinical trials of second-generation antidepressants for depression and anxiety: A meta-analysis

Previous research has shown that reporting bias has inflated the apparent efficacy of antidepressants. We investigated whether apparent safety was also affected. We included 133 trials, involving 31,296 patients, of second-generation antidepressants for the treatment of major depressive disorder (MDD) or anxiety disorders, obtained from Food and Drug Administration (FDA) reviews. We extracted data on overall discontinuation, discontinuation due to adverse events, and serious adverse events (SAEs). Meta-analysis was used to compare discontinuation rates between FDA reviews and matching journal articles, while SAEs were compared qualitatively. The odds ratio for overall discontinuation, comparing drug to placebo, was 1.0 for both sources, while that for discontinuation due to adverse events was 2.4 for both sources. Seventy-seven of 97 (79%) journal articles provided incomplete information on SAEs; sixty-one (63%) articles made no mention of SAEs at all. Of 21 articles which could be compared to the FDA, only 6 (29%) had full reporting without discrepancies. Nine (43%) articles reported a discrepant number of SAEs. Descriptions were absent or discrepant in 6 (29%) additional articles, even for important SAEs such as suicide attempts. In conclusion, reporting bias has not affected average discontinuation rates over trials. However, SAE reporting is not only very poor, with over half of articles failing to discuss SAEs altogether, but discrepancies between the FDA and articles were common and often led to a more favorable drug-placebo comparison. These findings suggest that journal articles are an unreliable source of data on SAEs in antidepressant trials.

Frequency and Severity of Neutropenia Associated with Food and Drug Administration Approved and Compounded Formulations of Lomustine in Dogs with Cancer.

BackgroundCompounded lomustine is used commonly in veterinary patients. However, the potential variability in these formulations is unknown and concern exists that compounded formulations of drugs may differ in potency from Food and Drug Administration (FDA)‐approved products.Hypothesis/ObjectivesThe initial objective of this study was to evaluate the frequency and severity of neutropenia in dogs treated with compounded or FDA‐approved formulations of lomustine. Subsequent analyses aimed to determine the potency of lomustine obtained from several compounding pharmacies.AnimalsThirty‐seven dogs treated with FDA‐approved or compounded lomustine.MethodsDogs that received compounded or FDA‐approved lomustine and had pretreatment and nadir CBCs performed were eligible for inclusion. Variables assessed included lomustine dose, neutrophil counts, and severity of neutropenia. Lomustine 5 mg capsules from 5 compounding sources were tested for potency using high‐pressure liquid chromatography (HPLC) with ultraviolet (UV) detection.ResultsTwenty‐one dogs received FDA‐approved lomustine and 16 dogs were treated with lomustine prescribed from a single compounding pharmacy. All dogs treated with FDA‐approved lomustine were neutropenic after treatment; 15 dogs (71%) developed grade 3 or higher neutropenia. Four dogs (25%) given compounded lomustine became neutropenic, with 2 dogs (12.5%) developing grade 3 neutropenia. The potency of lomustine from 5 compounding pharmacies ranged from 50 to 115% of the labeled concentration, with 1 sample within ±10% of the labeled concentration.Conclusions and Clinical ImportanceThese data support broader investigation into the potency and consistency of compounded chemotherapy drugs and highlight the potential need for greater oversight of these products.

Therapeutic Proteins: A to Z

In recent years, therapeutic proteins have become an important growing class of drugs in the pharmaceutics industry. The development of recombinant DNA technology has caused to appreciation of therapeutic value of many proteins and peptides in medicine. Currently, approximately 100 therapeutic proteins obtained approval from Food and Drug Administration (FDA) and they are widely used in the treatment of various diseases such as cancer, diabetes, anemia and infections. This paper will summarize the production processes, pharmaceuticals and physicochemical properties and important classes of therapeutic proteins with their potential use in clinical applications.

Project risk evaluation with design of experiment: A case of developing a generic drug analytic method development project

Generic drugs are equivalent to branded drugs but at a cheaper price. The generic drug market is highly competitive and the drug companies tend to improve their market position by being first in the market when the patent on an original drug elapses. It is because if a company gets the first approval from Food and Drug Administration (FDA), 6 months of marketing exclusivity will be granted and the company can take the granted period to grab the lion's share of the drug's market. Thus, the time-to-market of new products is crucial to their comparative advantages. FDA requires drug companies to submit Abbreviated New Drug Application (ANDA) which contains all the information that would have been in a pioneer drug application except for safety and effectiveness. Thus a robust and efficient analytical testing method for ANDA project is essential. This study proposes a method development scheme which integrates project risk evaluation with a design of experiment to efficiently carry out the critical project under ANDA programme in order to get the revenue early on. A case is implemented to demonstrate the efficiency of this integration.

Determining the predictive value of Read/OXMIS codes to identify incident acute myocardial infarction in the General Practice Research Database

To determine (1) the positive predictive value (PPV) of multiple Read/OXMIS codes to identify incident acute myocardial infarction (AMI) cases in General Practice Research Database (GPRD); (2) the ability to capture the correct timing of the clinical event. A random sample of 238 records (from 155 general practitioner (GP) practices) with AMI codes, between 1 January 1997 and 31 December 2004, was selected from GPRD. Questionnaires were sent to the GPs to verify the diagnosis and timing of code-identified incident AMI events and collect supporting information. We calculated the PPV of the AMI codes as the proportion of code-identified AMIs that the GPs confirmed as AMI cases. Two physicians from Food and Drug administration (FDA), blinded to the GP response, reviewed the supporting hospital records returned by GPs for 98 AMI cases. A total of 217 questionnaires were completed (91% response rate). The PPV of the AMI codes was 93% (201/217). Thirty one (15%) cases had a different event date than the one recorded in the electronic medical records (EMR); 28 (90%) of the dates were within 15 days. One GP indicated that a patient had a previous AMI, 110 days before the codes that captured the AMI diagnosis. A total of 159 (79%) AMI cases were hospitalized; hospital records were provided for 98 patients. Physician review of the hospital records found that 96% of these records had enough information for classification, but not independent diagnosis, of AMI. Information in GPRD is sufficient to identify incident AMI cases and determine the event date with reasonable accuracy.

Mixed‐effects Poisson regression analysis of adverse event reports: The relationship between antidepressants and suicide

A new statistical methodology is developed for the analysis of spontaneous adverse event (AE) reports from post-marketing drug surveillance data. The method involves both empirical Bayes (EB) and fully Bayes estimation of rate multipliers for each drug within a class of drugs, for a particular AE, based on a mixed-effects Poisson regression model. Both parametric and semiparametric models for the random-effect distribution are examined. The method is applied to data from Food and Drug Administration (FDA)'s Adverse Event Reporting System (AERS) on the relationship between antidepressants and suicide. We obtain point estimates and 95 per cent confidence (posterior) intervals for the rate multiplier for each drug (e.g. antidepressants), which can be used to determine whether a particular drug has an increased risk of association with a particular AE (e.g. suicide). Confidence (posterior) intervals that do not include 1.0 provide evidence for either significant protective or harmful associations of the drug and the adverse effect. We also examine EB, parametric Bayes, and semiparametric Bayes estimators of the rate multipliers and associated confidence (posterior) intervals. Results of our analysis of the FDA AERS data revealed that newer antidepressants are associated with lower rates of suicide adverse event reports compared with older antidepressants. We recommend improvements to the existing AERS system, which are likely to improve its public health value as an early warning system.

Abstract 3138: Impact of “Off Label” Utilization of Drug-Eluting Stents on Clinical Outcomes in Patients Undergoing Percutaneous Coronary Intervention

Background: The utilization of drug-eluting stents (DES) in “real world” practice has deviated substantially from Food and Drug Administration (FDA) approved indications. The outcomes of patients undergoing intracoronary DES implantation (versus BMS) for non-FDA approved indications has not been determined. Methods : The clinical outcomes of 546 patients undergoing DES implantation for ≥1 non-FDA approved (“Off label”) indication after device approval were assessed. This group was then compared to 546 propensity-matched patients receiving BMS prior to DES approval for the same indications. The primary endpoint was major adverse cardiac events [MACE; death-all cause, non-fatal Q-wave MI and target vessel revascularization (TVR)] at 12 months. Results: Baseline clinical and procedural characteristics were well matched. Patients in the BMS group were more likely to be treated with larger diameter and shorter stents. Though both in-hospital and 30-day all-cause mortality was greater in the DES group, there was no significant difference in cardiac death at both time points. At 30 days all other clinical outcomes were comparable. At 12 months MACE was significantly reduced in the DES group (27.8% vs. 21.4% p=0.014) driven by reductions in repeat revascularization [target lesion revascularization (TLR): 16.4% vs. 7.8% p<0.001, TVR: 20.2% vs.13.1% p<0.003]. There was no significant increase in death and non-fatal Q-wave MI with DES. Conclusions: The utilization of DES for non-FDA approved indications proved to be efficacious and safe when compared to a propensity-matched BMS cohort. These findings support broadening the current FDA indications for DES use.