Post-marketing Monitoring Research Articles

Knowledge and Perception of Iraqi Pharmacists Towards Biosimilar Medicines

Abstract
 Biosimilars are non-innovative copy versions of biologic medicines which are proven to be clinically equivalent to, as effective and as safe as their reference biologics. Biosimilars creates opportunities for cost savings for payers, governments, and patients compared with the reference products. Pharmacist plays an essential role in developing biosimilar medicines from manufacturing to post-marketing pharmacovigilance monitoring. The aim of the current study was to explore the level of knowledge, behaviors and practices of a sample of Iraqi pharmacists towards biosimilar medicines. The current study was a cross sectional, carried out during May 2020. A total of 264 pharmacists )143 male, 121 female) were involved in this study. A web-based self-administered questionnaire was used for data collection . Regarding pharmacists’ knowledge of biosimilar medicines, the results showed that two questions received the highest percentages of adequate answers: biosimilar medicine requires preclinical and clinical studies (58.0%) and biosimilar medicines require more comprehensive data compared to generic drugs (56.1%). In contrast, marketing authorization of biosimilar medicines is granted on the sole investigation of pharmacokinetic bioequivalence received the lowest percentage of adequate answers (21.6%). In addition, the current study showed that more experience years and male gender associated with better knowledge. With respect to perceptions of pharmacists about biosimilar medicines, two statements received the highest percentage of pharmacist agreements: biosimilar medicines are tested in terms of efficacy and safety (64.4%) and biosimilar prescription allows for reducing costs (64.4%). At the same time, 40.2% of the participating pharmacists agreed with pharmacist replacing a reference biologic medicines with its biosimilar product. In conclusion, the majority of the surveyed pharmacists had insufficient knowledge towards biosimilar medicines. The study highlighted that Iraqi pharmacists needed more accurate comprehensive information concerning biosimilar medicines.

Evaluation of Covid-19 vaccines: Pharmacoepidemiological aspects

The marketing authorization granted to SARS-Cov-2 vaccines was accompanied by reinforced safety monitoring plans. These plans’ implementation was part of the usual logic of post-marketing surveillance of new and innovative health products. It was especially adapted to the context of post-marketing monitoring of drugs developed according to the usual scientific quality standards but in an accelerated schedule. In Europe, the reinforced surveillance system relies on the complementary strengths of pharmacovigilance and pharmacoepidemiology. If the performances of pharmacovigilance monitoring are incomparable for the detection of safety signals relating to rare events of atypical presentation, it needs to be completed with pharmacoepidemiology activities for more common events, either multifactorial or frequently classified as idiopathic. The pharmacoepidemiological monitoring developed in Europe was elaborated before the first SARS-Cov-2 vaccines where marketed, taking into account the lessons learned from the vaccination campaign against 2009 A (H1N1) influenza. It includes numerous academic studies as well as studies performed within vaccines risk management plans. In terms of safety, those defined a priori mostly concerns a list of pre-established health events of specific interest. Aside of these planned activities, ad-hoc studies will be latter developed on purpose to investigate safety signals or potential signals that could be identified as the result of pharmacovigilance activities. Aside of these regulated activities, as for today, very few studies have been published regarding SARS-Cov-2 vaccines; most of the existing consist in preprints that should be considered with caution. Pharmacoepidemiology of vaccines is thought to allow near-real time monitoring that needs sufficient time to provide with valid results. In the constant urge for information that accompanies COVID-related science, it is important not to make haste the enemy of speed and to let pharmacoepidemiology provides with what it is expected to do: rock-solid scientific information contributing to evidence-based decision-making.

A novel data mining application to detect safety signals for newly approved medications in routine care of patients with diabetes.

ABSTRACTBackgroundClinical trials are often underpowered to detect serious but rare adverse events of a new medication. We applied a novel data mining tool to detect potential adverse events of canagliflozin, the first sodium glucose co‐transporter 2 (SGLT2 inhibitor) in the United States, using real‐world data from shortly after its market entry and before public awareness of its potential safety concerns.MethodsIn a U. S. commercial claims dataset (29 March 2013–30 Sept 2015), two pairwise cohorts of patients over 18 years of age with type 2 diabetes (T2D) who were newly dispensed canagliflozin or an active comparator, that is a dipeptidyl peptidase 4 inhibitor (DPP4) or a glucagon‐like peptide 1 receptor agonist (GLP1), were identified and propensity score‐matched. We used variable ratio matching with up to four people receiving a DPP4 or GLP1 for each person receiving canagliflozin. We identified potential safety signals using a hierarchical tree‐based scan statistic data mining method with the hierarchical outcome tree constructed based on international classification of disease coding. We screened for incident adverse events where there were more outcomes observed among canagliflozin vs. comparator initiators than expected by chance, after adjusting for multiple testing.ResultsWe identified two pairwise propensity score variable ratio matched cohorts of 44,733 canagliflozin vs. 99,458 DPP4 initiators, and 55,974 canagliflozin vs. 74,727 GLP1 initiators. When we screened inpatient and emergency room diagnoses, diabetic ketoacidosis was the only severe adverse event associated with canagliflozin initiation with p < .05 in both cohorts. When outpatient diagnoses were also considered, signals for female and male genital infections emerged in both cohorts (p < .05).Conclusions and relevanceIn a large population‐based study, we identified known but no other adverse events associated with canagliflozin, providing reassurance on its safety among adult patients with T2D and suggesting the tree‐based scan statistic method is a useful post‐marketing safety monitoring tool for newly approved medications.

Using Medicare Data to Assess the Proarrhythmic Risk of Non-Cardiac Treatment Drugs that Prolong the QT Interval in Older Adults: An Observational Cohort Study.

IntroductionSerious cardiac arrhythmias caused by QT-prolonging drugs are difficult to predict based on physiological measurement and pre-approval clinical trials. Post-marketing surveillance and monitoring are important to generate safety data.ObjectivesTo assess whether an observational study using Medicare claims data can detect the arrhythmogenic risk of QT-prolonging drugs.MethodsWe identified 17 QT-prolonging drugs with known risk of torsades des pointes (TdP) that were not used to treat cardiac arrhythmias. Amoxicillin and four serotonin-norepinephrine reuptake inhibitors (SNRIs) were used as controls. De-identified claims data of 1.2 million Medicare beneficiaries were accessed. Two separate Cox regressions were done for short-term and chronic-use drugs. The primary outcome was a composite of ventricular arrhythmias and/or sudden death, identified by ICD diagnostic codes. We explored the independent effect of each study drug on the outcomes. Other covariates included patient demographics, comorbidities, and known risk factors for drug-induced cardiac arrhythmia.ResultsWe were able to detect increased risk in 14 of 17 study drugs (82.3%), and none of the control drugs. Among the fluoroquinolones, ciprofloxacin was the safest. Azithromycin and clarithromycin were relatively safe compared to erythromycin. Compared to SNRIs, both citalopram and escitalopram had increased risk, more so with escitalopram than citalopram. Comorbidities associated with increased risk included ischemic heart disease, electrolyte imbalance, bradycardia, acute myocardial infarction, heart failure, and chronic kidney and liver disease.ConclusionMedicare data can be utilized for post-marketing surveillance and monitoring of the proarrhythmic risk of QT-prolonging drugs in older adults.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40801-021-00230-1.

Development and implementation of a system for medical devices monitoring in Morocco

Given the importance of medical devices in improving health, a system of monitoring their use is necessary to ensure an acceptable benefit/risk ratio. The present study focuses on the post-marketing monitoring system, of which the aimis to develop, a national strategy for the establishment of a multidimensional vigilance system to monitor medical devices in Morocco. Methods : The study is based on a systemic review selected by the PRISMA method for the period between [2011-2021] and on the Scopus, Pubmed, Science direct and Web of science databases. Results: A preliminary analysis of the data identified some challenges such as under-reporting and lack of standardization of adverse reaction coding, standard nomenclature problem for international trade, lack of clarity of requirements for manufacturers, and insufficient regulation and significant incentives for the use of unique device identifiers. Recommendations for a more effective national system are put for ward which address the regulation and computerization of the system for the development of medical devices monitoring mechanisms.

Assessing the Safety of COVID-19 Vaccines: A Primer.

Vaccines against COVID-19 are being developed at speeds not previously achieved. With this unprecedented effort comes challenges for post-marketing safety monitoring and challenges for vaccine safety communication. To deploy these new vaccines fast across diverse populations, it is vital that robust pharmacovigilance and active surveillance systems are in place. Not all countries have the capability or resources to undertake adequate surveillance and will rely on data from those who can. The tools exist to assess COVID-19 vaccines as they are deployed such as surveillance systems, administrative data and case definitions for adverse events of special interest. However, stitching these all together and using them effectively requires investment and collaboration. This paper provides a high-level overview of some of the facets of modern vaccine safety assessment and how they are, or can be, applied to COVID-19 vaccines.

IN VITRO RELEASE PERFORMANCE OF METFORMIN HYDROCHLORIDE FORMULATIONS USING THE FLOW-THROUGH CELL METHOD

Objective: The objective of this work was to evaluate the in vitro release performance of metformin hydrochloride formulations (500-mg tablets) using the hydrodynamic environment of the flow-through cell method. Results were compared with those generated by the official dissolution test (USP basket apparatus).&#x0D; Methods: The reference drug product and three generic formulations were tested with phosphate buffer pH 6.8 as dissolution medium. Dissolution profiles were carried out with an automated flow-through cell apparatus using laminar flow at 16 ml/min. Drug was quantified at 233 nm during 45 min. Dissolution profiles were compared with the calculation of f2 similarity factor, mean dissolution time, dissolution efficiency, t50% and t63.2%. Dissolution data were adjusted to several mathematical models such as Makoid-Banakar, Peppas-Sahlin, Weibull and Logistic.&#x0D; Results: With the flow-through cell method and at 45 min less than 60% of metformin hydrochloride dissolved was found, while with the USP basket apparatus, less than 75% of the drug was found. Some generic formulations showed f2&gt;50 with both USP apparatuses, but statistical comparisons of parameters indicated significant differences between their dissolution profiles and reference. Due to variability obtained no dissolution profiles were compared by model-dependent approach.&#x0D; Conclusion: To demonstrate safe interchangeability between metformin hydrochloride generic formulations and reference bioequivalence studies should be performed. It is important post-marketing monitoring of the commercial formulations because health regulatory agencies of each country must ensure drug products with quality, safety, and efficacy at the lowest possible cost.

A Framework for Effective Bt Maize IRM Programs: Incorporation of Lessons Learned From Busseola fusca Resistance Development.

Bt maize is genetically engineered to express insecticidal proteins from the bacterium Bacillus thuringiensis. Bt maize is used extensively by South African farmers to reduce yield losses caused by lepidopteran larvae. Starting in the 2004/2005 season, severe Busseola fusca-associated damage to Cry1Ab-expressing Bt maize was noted by South African farmers. The unsatisfactory pest control was eventually attributed to the development of insect resistance to the Cry1Ab protein in the Bt maize hybrids. An assessment of the historical events surrounding the development of resistance by B. fusca showed that there was room for improvement both in the insect resistance management (IRM) strategy selected and the implementation of the strategy. With the recent arrival of fall armyworm (Spodoptera frugiperda) in Africa, it is important to have IRM programs that are appropriate for all of the pests that constitute the maize lepidopteran pest complex. After the identification of shortcomings in the IRM programs implemented in South Africa, a framework is proposed for effective Bt maize IRM programs. The IRM framework integrates pre-marketing research, post-marketing monitoring, and two-level remedial action plans (RAPs). The core of the framework is a regulator-approved IRM strategy that is based on comprehensive pre-marketing research and serves to guide stakeholders during the post-marketing phase. The framework will assist technology developers and regulators, especially those with nascent regulatory systems, to select and implement IRM strategies that facilitate sustainable pest management.

Vigilance System Requirements Across US and EU for Medical Device

Medical device vigilance is concerned about device problems (incidents) their analysis and mitigation to ensure that device performance is good and that patient safety are maintained. The main aim of this is to outline the criteria of the medical device vigilance program and to highlight the requirements that still remain in the state laws of regulated markets (US and EU) and to increase access to safe, reliable and therapeutic benefits. The severity of the Subject, risk assessment should carried out by the manufacturer prior to marketing. In US, Medical Device surveillance deals with post-marketing monitoring where the manufacturer or importer is required submit reports to regulatory authorities; same as in the EU. US medical device tracking system involved with different sections to update adverse event. The user or manufacturer has to report incidents to member states where necessary actions are to be taken as early as possible to protect or reduce hazard of casualty or severe decline in terms of safety and quality by implementing the CAPA for risk analysis.

Putative Abscopal Effect in Three Patients Treated by Combined Radiotherapy and Modulated Electrohyperthermia.

Purpose: True abscopal responses from radiation therapy are extremely rare; the combination of immune checkpoint inhibitors with radiation therapy has led to more reports of the abscopal effect, but even in this setting, the genuine magnitude remains unknown and is still considered generally uncommon. We report the occurrence of what appears to be putative, durable abscopal tumor responses with associated auto-immune systemic reactions resulting from the combination of local radiotherapy (RT) and modulated electrohyperthermia (mEHT).Materials and Methods: Data from advanced cancer patients treated palliatively with RT and mEHT between January and December 2017 were collected as part of a post-marketing safety monitoring program of mEHT therapy. We specified a minimum RT dose of 30 Gy and at least four mEHT treatments for reporting toxicities, which was the primary aim of the larger study.Results: Thirty-three patients treated with RT and mEHT, both applied to the same lesion, were included. The median RT dose was 45.5 Gy in 20 fractions (fxs) and the median number of mEHT treatments was 12 (range, 4–20). Most patients had subsequent systemic therapy after one course of RT and mEHT. Three patients (9.1%) developed autoimmune toxicities. Case number 1 received RT and mEHT only; case number 2 had two cycles of concurrent low dose chemotherapy during RT; and case number 3 received concurrent immune checkpoint inhibitors. None of the three patients received any further systemic treatment due to obvious treatment-related autoimmune reactions which occurred rapidly after RT; one had autoimmune hepatitis, one had dermatitis herpetiformis and the third developed severe myasthenia gravis. Interestingly, what we surmise to be long-lasting abscopal responses outside the irradiated area, were noted in all three patients.Conclusion: RT combined with mEHT could putatively result in enhancing immune responsiveness. These preliminary observational findings lead to the generation of a hypothesis that this combination induces both an in-situ, tumor-specific immune reaction and an anti-self-autoimmune reaction, in at least a small proportion of patients, and of those who experience the auto-immune response, tumor response is a concomitant finding. Mechanisms underlying this phenomenon need to be investigated further.

Poisoning and associated factors to death from pesticides: case-control study, Brazil, 2017.

Pesticide poisoning causes high morbidity and mortality. Surveillance is required for post-marketing monitoring of these products. To assess poisonings and associated factors with lethality by pesticides. This is a case-control study based on the cases of pesticide poisoning assisted in 2017 by Brazilian Poison Control Centers. Patients who died were the cases and the survivors, the control. The odds ratio (OR) of death and 95% confidence interval (CI) were calculated. From the regression model, a predictive model of death was developed, stratified by age, gender and occupational context to investigate the risk of agricultural workers poisoned by extremely hazardous agents. 3,826 patients poisoned by pesticides were identified, of which 146 died. Older people (OR = 4.94; 95%CI 2.49 - 9.80), males (OR = 1.68; 95%CI 1.15 - 2.46), agricultural workers (OR = 2.20; 95%CI 1.15 - 4.24), suicide attempts (OR = 13.27; 95%CI 6.48 - 27.19) and exposure to extremely hazardous products (OR = 2.77; 95%CI 1.84 - 4.16) odds of death from pesticide poisoning. Out of 100 pesticides poisoning, four died. Elderly, males, working in the agricultural sector, suicide attempts and extremely hazardous products had a higher risk of death.

Defining Improvement in Nonalcoholic Steatohepatitis for Treatment Trial Endpoints: Recommendations From the Liver Forum.

Identifying effective therapies for nonalcoholic steatohepatitis (NASH) with fibrosis is a pressing challenge, with 1%-2% of the population in developed nations at risk of developing NASH cirrhosis and its complications. The design of NASH clinical therapeutic trials is hampered by the long period of minimally symptomatic disease that typically precedes the development of decompensated cirrhosis and the accompanying uncertainties regarding the best precirrhotic trial endpoints that reliably reflect a subsequent reduction in liver-related morbidity and mortality. The Liver Forum is a multistakeholder organization comprised of academic, industry, and regulatory experts working from a regulatory science perspective to identify barriers, prioritize research, and identify solutions to accelerate therapeutic development for NASH. Past work of The Liver Forum has focused on recommendations for disease definitions and baseline parameters to be implemented in clinical trials that are designed to assess disease status and prevent progression to cirrhosis, liver transplantation, hepatocellular carcinoma, and death. The purpose of this summary is to review currently available clinical data to identify parameters that change in parallel with liver histology and are likely to reflect clinically meaningful reductions in the risk of developing cirrhosis and its complications. We review available data on exploratory histological, blood-based, and imaging pharmacodynamic biomarkers that may reflect meaningful treatment responses and provide recommendations regarding measurements to be considered in phase 2 and 3 trials as well as during postmarketing monitoring trials.

A rational usage of combined using of herbal medicines and synthetic medicines: A time interval window research

The combined use of herbal and traditional medicine with synthetic drugs is a common clinical issue in China, as well as in other countries around the world. The improper combination of Traditional Chinese Medicine (TCM) with synthetic drugs may increase the risk of severe adverse drug reactions (ADRs). In China, the combination of Shuanghuanglian (SHL) and Ribavirin injections (RB) is one such example that has led to a higher risk of pseudo-allergic ADRs, observed during post-marketing safety monitoring. Such combination-related ADRs may be associated with concurrent drug exposure concentrations in vivo . Thus, it is important to administer both formulations at acceptable intervals to prevent ADRs. In this study, we propose an appropriate time interval of administration to reduce ADR risk in combination drug use. SHL and RB combination was then tested in rats. This combination was tested at different administration intervals. Ear weight was chosen as the quantitative index to indicate tissue edema and intensity of pseudo-allergic reactions. Compared to the control group, rats that were simultaneously administered with SHL and RB intravenously, showed different behaviors and symptoms such as ear edema and increase in weight, swelling of limbs and huddling, which were similar to those seen in pseudo-allergic reactions. By contrast, rats administered solely with either RB or SHL did not exhibit obvious pseudo-allergic reactions. With respect to the combination groups at different administration intervals, there were two different types of responses. One of them was similar to the concurrent administration of drug pairs, which occurred in groups at intervals of 0, 1.5, 2, 3.5 and 4 h. The other type was similar to the sole use of RB or SHL, which occurred in groups with intervals of 6, 8, 12 and 24 h. We also determined serum concentrations of complement C5 (C5) and thrombomodulin (THBD), proteins that mediate the complement system and coagulation cascade-depended pseudo-allergic reactions. Results showed that there was significant increase in these two indices in combination groups, with intervals below or equal to 4 h and non-significant increase in combination groups with intervals above or equal to 6 h. These results indicate that a “safe window” of administration interval exists when using the drug pair: SHL and RB, thus reducing the risk of pseudo-allergic reactions. Moreover, we tested serum metabolomic profiles of each group. The principal component analysis revealed that there was an obvious distinction between the rat groups, of both clusters: One cluster included the normal control group where either SHL or RB group was administered and the combination groups that were administered both SHL and RB at intervals of over or equal to 6 h. The other cluster involved combination groups that were administered both drugs at intervals below or equal to 4 h. Thus, the metabolomic results also elucidated a “safe window” administration interval, when using such drug pairs. We then screened out metabolites that might be used to distinguish these two clusters of rat groups. The results of ROC curves showed that compounds of m / z 154.0592, m / z 433.2357, and m / z 331.0528 could distinguish rats where SHL was used after and before 6 h. These metabolites were identified as L-2-Amino-3-(1-pyrazolyl) propanoic acid, [2-hydroxy-1-(6-hydroxy-1-oxo-1H-isochromen-3-yl) butoxy] sulfonic acid and LysoPA (0:0/18:2 (9Z, 12Z)) according to their MS/MS spectrum, respectively. This study verified the hypothesis of the “safe window” of administration interval in combination drug use, including TCM and synthetic drugs. Administered at appropriate intervals, it can reduce ADR risk and prevent safety-related issues from occurring. This study thus provides a new perspective for improving safety, when using Chinese herbal medicines in combination with synthetic medicine.

Drug Safety Evaluation in China.

This review aimed to introduce the regulations management and current situations of drug safety evaluation in China. The nationwide implementation of good laboratory practice and good clinical practice guarantees the quality of pre-marketing drug safety evaluation. In recent years, post-marketing drug safety monitoring is changing from passive mode to the combination of active and passive monitoring. A national adverse drug reaction monitoring sentinel alliance has been created to actively identify, report, and evaluate adverse reactions, with more than 1.4 million cases reported in 2017. But the quality of the reports is not optimal, with few reports from drug manufacturers, low rate of severe reports, and trend of lag reporting. Drug safety evaluation in China is transitioning from passive monitoring to a combination mode. Drug pharmacovigilance is a powerful tool for active monitoring, but participation by drug manufacturers would be essential to an effective drug safety evaluation system.

Technical specifications for hospital-based intensive monitoring of post-marketing Chinese patent medicine

In 2013,China pharmaceutical regulatory department issued guiduance on postmarketing drug safety monitoring for industry. It aimed to encourage industry to carry out postmarketing drug safety monitoring including hospital-based intensive monitoring of postmarketing Chinese patent medicine. Subsequently,more and more such kind of studies have been performed all over China. However,in view of the current situation in this field,the development of hospital-based intensive monitoring of postmarketing Chinese patent medicine lacks standardization,such as unreasonable design,omission of reports about adverse drug reactions,inadequate process of quality control,non-standardized interpretation of adverse reactions,etc. Therefore,it is necessary to formulate relevant technical specifications to guide this area. The developing of this technical specification refered to the international post-marketing safety monitoring model and advanced design concepts and methods. We developed it under the guidance of relevant laws,regulations and technical documents in China. Meanwhile the characteristics of Chinese patent medicines and the real situation in this area were considered. The aim of this technical specification is to obtain the incidence,type,degree and clinical manifestation of adverse drug reactions of Chinese patent medicines,to find new risk signals of adverse reactions,to identify risk factors,and to provide a basis for the formulation of risk management and control plans. This specification has been approved by China association of Chinese medicine which is numbered T/CACM011-2016.

Overcoming the Trans Fat Problem in Thailand

ABSTRACTBackgroundOwing to the clear impact of trans fatty acids (TFAs) on cardiovascular disease, Thailand urgently needs to evaluate the problem and formulate appropriate policies in order to protect the health of its own people and to benefit exportation. Since 9 January, 2019, Thailand's FDA has not allowed the use of partially hydrogenated oils (PHOs) in foods.ObjectiveThe aim of this study was to evaluate the situation and potential health risk from TFAs in foods available in Thailand, changes in fatty acid profiles upon replacement of PHOs, as well as to propose control measures for TFAs in the country.MethodsA total of 176 food samples representing potential sources of TFAs were analyzed for fatty acid profiles, which were later used to evaluate potential health risk based on Thailand's Food Consumption Survey data and the FAO/WHO Guideline on Diet, Nutrition and the Prevention of Chronic Diseases (FAO/WHO guideline). Criteria for postmarketing monitoring of TFAs in food products were also proposed.ResultsTFAs were naturally highest in butter (5%) but lower than the limit in the FAO/WHO guideline regarding consumption pattern. TFAs in refined cooking oils were 0.4–0.8%, which was below the European Union (EU) legislative limit. Bakery products, i.e., puffs, pies, and deep-fried donuts, that used PHOs contained 3–5% TFAs and were the main sources of TFAs in Thailand. The postmarketing monitoring process should be based on the FAO/WHO guideline and EU legislative limit for TFAs. The PHOs in bakery products could be replaced with blended oils, although saturated fatty acids might increase.ConclusionsThailand's TFA problem was mainly due to the use of PHOs in bakery products. It is feasible to replace PHOs with blended oils. The international TFA limits should be used for the postmarketing monitoring of TFAs in foods on the market.

1459-P: Comparative Cardiovascular Safety and Effectiveness of Linagliptin in Routine Care: Final Results from a 5-Year Post-Marketing Monitoring Program

Real world data on the cardiovascular (CV) safety and effectiveness of linagliptin (LINA) complement trial data from CARMELINA, which showed CV safety, and CAROLINA (results pending). As part of a 5-year (05/2011-12/2016) post-marketing monitoring program, using 2 large insurance claims databases, we assessed the risk of a composite CV (cCV) outcome (hospitalization for myocardial infarction, stroke, unstable angina, or coronary revascularization). We identified three 1:1 propensity score (PS)-matched cohorts of type 2 diabetes mellitus patients who initiated linagliptin or a comparator [other DPP-4is (n=39,834 pairs), pioglitazone (PIO; n=29,646 pairs), or sulfonylureas (SU; n=25,285 pairs). We estimated pooled HR and 95% CI controlling for over 180 baseline characteristics. After PS-matching, patient characteristics were similar (Table 1) and mean follow-up was 0.8 years. LINA had a similar risk of the cCV outcome compared to other DPP-4is [HR (95% CI) = 0.90 (0.80-1.02)] and PIO [HR (95% CI) = 0.99 (0.86-1.13)], but was associated with a reduced risk compared to SU [HR (95% CI) = 0.77 (0.66-0.90)] (Table 1). Results were robust across numerous sensitivity analyses. These real-world data show that LINA has reassuring effectiveness and safety on a cCV outcome compared to other DPP-4is and PIO, and is associated with a decreased risk compared to SU. Disclosure E. Patorno: Research Support; Self; National Institute on Aging. Other Relationship; Self; Boehringer Ingelheim International GmbH. C. Gopalakrishnan: None. M. Mahesri: None. K.G. Brodovicz: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. D. Bartels: Employee; Self; BI X GmbH, Boehringer Ingelheim International GmbH. A. Meyers: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. J. Barberio: None. J. Liu: None. S. Schneeweiss: Consultant; Self; Aetion, WHISCON, LLC. Funding Boehringer Ingelheim

Classifying adverse drug reactions from imbalanced twitter data

BackgroundNowadays, social media are often being used by general public to create and share public messages related to their health. With the global increase in social media usage, there is a trend of posting information related to adverse drug reactions (ADR). Mining the social media data for this type of information will be helpful for pharmacological post-marketing surveillance and monitoring. Although the concept of using social media to facilitate pharmacovigilance is convincing, construction of automatic ADR detection systems remains a challenge because the corpora compiled from social media tend to be highly imbalanced, posing a major obstacle to the development of classifiers with reliable performance. MethodsSeveral methods have been proposed to address the challenge of imbalanced corpora. However, we are not aware of any studies that investigated the effectiveness of the strategies of dealing with the problem of imbalanced data in the context of ADR detection from social media. In light of this, we evaluated a variety of imbalanced techniques and proposed a novel word embedding-based synthetic minority over-sampling technique (WESMOTE), which synthesizes new training examples from the sentence representation based on word embeddings. We compared the performance of all methods on two large imbalanced datasets released for the purpose of detecting ADR posts. ResultsIn comparison with the state-of-the-art approaches, the classifiers that incorporated imbalanced classification techniques achieved comparable or better F-scores. All of our best performing configurations combined random under-sampling with techniques including the proposed WESMOTE, boosting and ensemble, implying that an integration of these approaches with under-sampling provides a reliable solution for large imbalanced social media datasets. Furthermore, ensemble-based methods like vote-based under-sampling (VUE) and random under-sampling boosting can be alternatives for the hybrid synthetic methods because both methods increase the diversity of the created weak classifiers, leading to better recall and overall F-scores for the minority classes. ConclusionsData collected from the social media are usually very large and highly imbalanced. In order to maximize the performance of a classifier trained on such data, applications of imbalanced strategies are required. We considered several practical methods for handling imbalanced Twitter data along with their performance on the binary classification task with respect to ADRs. In conclusion, the following practical insights are gained: 1) When dealing with text classification, the proposed word embedding-based synthetic minority over-sampling technique is more effective than traditional synthetic-based over-sampling methods. 2) In cases where large amounts of training data are available, the imbalanced strategies combined with under-sampling techniques are preferred. 3) Finally, employment of advanced methods does not guarantee better performance than simpler ones such as VUE, which achieved high performance with advantages like faster building time and ease of development.

Dietary Phytochemicals and Endrocrine-related Activities: An Update.

Phytochemicals are non-nutrient bioactive compounds occurring in plants and food, which possess the capacity to modulate one or more metabolic processes or pathways in the body, resulting to health benefits and promotion of well-being. The interest of the scientific community continues to grow, powered by progressive research efforts to identify properties and potential applications of bioactive substances, and coupled with public interest and consumer demand. However, the natural derivation of these compounds is not a feature of harmlessness, over that of therapeutic efficacy, to which is also added the absence of post-marketing monitoring which does not allow to evaluate the occurrence of adverse effects related to the use of their related products. The literature is particularly rich of studies concerning phytochemicals as environmental estrogens, which result in infertility, reproductive abnormalities, and tumors but also in some endocrine-related health effects. Nevertheless, further studies have been performed to better understand the bioavailability, pharmacokinetics and mode of action of these compounds which seems to go beyond their ability to bind to oestrogen receptors and either stimulate or inhibit the activity of endogenous oestrogens, highlighting new interesting target molecules and signaling pathways. The present review summarizes the latest developments and knowledge concerning the assessment of endocrine activities of dietary phytochemicals focusing on pharmacological aspects.

Review of the Methods to Obtain Paediatric Drug Safety Information: Spontaneous Reporting and Healthcare Databases, Active Surveillance Programmes, Systematic Reviews and Meta-analyses.

Knowledge of drugs safety collected during the pre-marketing phase is inevitably limited because the randomized clinical trials (RCTs) are rarely designed to evaluate safety. The small and selective groups of enrolled individuals and the limited duration of trials may hamper the ability to characterize fully the safety profiles of drugs. Additionally, information about rare adverse drug reactions (ADRs) in special groups is often incomplete or not available for most of the drugs commonly used in the daily clinical practice. In the paediatric setting several highimpact safety issues have emerged. Hence, in recent years, there has been a call for improved post-marketing pharmacoepidemiological studies, in which cohorts of patients are monitored for sufficient time in order to determine the precise risk-benefit ratio. In this review, we discuss the current available strategies enhancing the post-marketing monitoring activities of the drugs in the paediatric setting and define criteria whereby they can provide valuable information to improve the management of therapy in daily clinical practice including both safety and efficacy aspects. The strategies we cover include the signal detection using international pharmacovigilance and/or healthcare databases, the promotion of active surveillance initiatives which can generate complete, informative data sets for the signal detection and systematic review/meta-analysis. Together, these methods provide a comprehensive picture of causality and risk improving the management of therapy in a paediatric setting and they should be considered as a unique tool to be integrated with post-marketing activities.