Online causal inference with application to near real-time post-market vaccine safety surveillance.

Streaming data routinely generated by social networks, mobile or web applications, e-commerce, and electronic health records present new opportunities to monitor the impact of an intervention on an outcome via causal inference methods. However, most existing causal inference methods have been focused on and applied to static data, that is, a fixed data set in which observations are pooled and stored before performing statistical analysis. There is thus a pressing need to turn static causal inference into online causal learning to support near real-time monitoring of treatment effects. In this paper, we present a framework for online estimation and inference of treatment effects that can incorporate new information as it becomes available without revisiting prior observations. We show that, under mild regularity conditions, the proposed online estimator is asymptotically equivalent to the offline oracle estimator obtained by pooling all data. Our proposal is motivated by the need for near real-time vaccine effectiveness and safety monitoring, and our proposed method is applied to a case study on COVID-19 vaccine safety surveillance.

Risk of acute pancreatitis among new users of empagliflozin compared to sulfonylureas in patients with type 2 diabetes: A post-authorization safety study.

PURPOSE: This study was undertaken to evaluate the potential risk of acute pancreatitis with empagliflozin in patients with type 2 diabetes (T2D) newly initiating empagliflozin. METHODS: Data from two large US claims databases were analyzed in an observational study of patients with T2D receiving metformin who were newly prescribed empagliflozin versus sulfonylurea (SU). Because dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists have been associated with the risk of acute pancreatitis in some studies, patients on these agents were excluded. Using pooled analyses of data from the two databases (2014-2021), patients initiating empagliflozin were matched 1:1 within database to patients initiating SU using propensity scores (PS) that incorporated relevant demographic and clinical characteristics. Prespecified sensitivity analyses were performed for design parameters. RESULTS: The analyses identified 72 661 new users of empagliflozin and 422 018 new users of SUs, with both patient groups on concurrent metformin therapy. Baseline characteristics within treatment groups appeared to be similar across the 72 621 matched pairs. After mean follow-up of ~6 months, incidence rates of acute pancreatitis in the pooled matched cohort were 10.30 (95% confidence interval [CI] 9.29-11.39) events per 1000 patient-years (PY) for empagliflozin and 11.65 (95% CI 10.59-12.77) events per 1000 PY for SUs. On a background of metformin, patients newly initiating empagliflozin did not have an increased risk of acute pancreatitis compared with those initiating an SU (pooled PS matched hazard ratio 0.88 [0.76-1.02]) across 75621.42 PY of follow-up. CONCLUSIONS: The results of this voluntary post-approval safety study provide additional evidence that the use of empagliflozin for the treatment of T2D is not associated with an increased risk of acute pancreatitis.

A Broad Safety Assessment of the 9-Valent Human Papillomavirus Vaccine.

Parents indicate that safety is their top concern about human papillomavirus (HPV) vaccination. A data-mining method not requiring prespecification of health outcome(s) or postexposure period(s) of potentially increased risk can be used to identify possible associations between an exposure and any of thousands of medically attended health outcomes; this method was applied to data on the 9-valent HPV vaccine (HPV9) to detect potential safety problems. Data on 9- to 26-year-olds who had received HPV9 vaccine between November 4, 2016, and August 5, 2018, inclusive, were extracted from the MarketScan database and analyzed for statistically significant clustering of incident diagnoses within the hierarchy of diagnoses coded using the International Classification of Diseases and temporally within the 1 year after vaccination, using the self-controlled tree-temporal scan statistic and TreeScan software. Only 56 days of postvaccination enrollment was required; subsequent follow-up was censored at disenrollment. Multiple testing was adjusted for. The analysis included 493,089 doses of HPV9. Almost all signals resulted from temporal confounding, not unexpected with a 1-year follow-up period. The only plausible signals were for nonspecific adverse events (e.g., injection-site reactions, headache) on days 1-2 after vaccination, with attributable risks as low as 1 per 100,000 vaccinees. Considering the broad scope of the evaluation and the high statistical power, the findings of no specific serious adverse events should provide reassurance about this vaccine's safety.

Risk of hypertension in erenumab-treated patients with migraine: Analyses of clinical trial and postmarketing data.

OBJECTIVE: To assess the risk of hypertension in patients with migraine who received erenumab in clinical trials and in the postmarketing setting. BACKGROUND: Erenumab is a monoclonal antibody for migraine prevention that targets the calcitonin gene-related peptide (CGRP) receptor. Hypertension is a theoretical risk for inhibitors of the CGRP pathway. Although no evidence of an association between erenumab treatment and hypertension was observed during the clinical development program, adverse events (AEs) of hypertension have been identified in the postmarketing setting. METHODS: Safety data from four phase 2 and phase 3 clinical trials were used to perform a pooled analysis of hypertension AEs in patients with migraine receiving erenumab. Postmarketing AEs of hypertension were identified from the Amgen Global Safety database from May 17, 2018, through January 31, 2020. RESULTS: In the pooled analysis of clinical trials, hypertension AEs (placebo, 9/1043 [0.9%]; erenumab 70 mg, 7/893 [0.8%]; erenumab 140 mg, 1/507 [0.2%]) and percentage of patients initiating medication to treat hypertension (12/1043 [1.2%], 7/893 [0.8%], 1/507 [0.2%], respectively) were similar across treatment groups. A total of 362 AEs of hypertension were identified from the postmarketing setting, 26.2% (95/362) of which were serious, >245,000 patient-years of exposure. The exposure-adjusted incidence of hypertension was 0.144 per 100 patient-years. CONCLUSIONS: Clinical trials did not demonstrate an increased risk of hypertension with erenumab compared with placebo, and AE rates of hypertension reported with erenumab in the postmarketing setting were generally low. Additional data are needed to fully characterize the extent to which hypertension is a risk associated with erenumab.

Unexpected beneficial effects of drugs: an analysis of cases in the Dutch spontaneous reporting system.

INTRODUCTION: Drug use is inherently related to both beneficial effects on health as well as the occurrence of risks. The beneficial effects may be related to efficacy, the treatment range of a product, or even to user-friendliness of a product. However, in addition to the occurrence of adverse drug reactions, a drug can also have an unexpected beneficial effect on a patient's health, not related to the indication for which the drug was used. The aim of this article is to characterize the reports of unexpected beneficial effects of drugs in the Dutch spontaneous reporting system. METHODS: A descriptive analysis was used to gain insight in number of reports and drug classes responsible for unexpected beneficial effects of drugs. Grouping of positive side effects into classes was done by a conventional qualitative content analysis of the cases. RESULTS: Four hundred nine reports which described unexpected beneficial effects of drugs were included, which mentioned 451 associations between suspected drugs and unexpected beneficial effects. There were 147 drug classes on the 4th ATC level involved. Content analysis of the reports gave rise to 22 categories of unexpected beneficial effects of drugs, including one "other category". DISCUSSION AND CONCLUSION: The analysis showed a diverse spectrum of reported reactions and drugs with some categories of unexpected beneficial effects of drugs mentioned multiple times for certain drug classes on the 4th ATC level. Most of these findings are consistent with the existing literature and knowledge on the pharmacological mechanism of the drugs in question. Coding harmonization would make it possible to study these effects in international databases.

Post-market utilization patterns of Alzheimer's disease treatments in South Korea: comparison with countries with universal health coverage.

PURPOSE: This study aimed to compare the utilization of Alzheimer's disease (AD) treatments, donepezil, galantamine, rivastigmine, and memantine, in Korea with Australia and other countries with universal health coverage. METHODS: Reimbursement criteria and the patent status of four AD treatments in Korea and Australia were reviewed. The monthly spending and utilization of the treatments were extracted from the national electronic database in Korea and Australia. The defined daily dose per 1000 elderly population per day (DDD/1000e/day) were calculated from July 2008 to June 2019. Annual cost trends of Norway and England were compared with Korea and Australia. RESULTS: With the highest share of the use of donepezil in both countries, the cost and utilization of AD treatments in Korea increased more rapidly and remained higher than Australia. The cost of AD treatments in Korea increased by 15.5% every year during the study period, while the spending of the same drugs in Australia decreased by 10.5% annually. The utilization in DDD/1000e/day of AD treatments in Korea increased by 18.3% annually compared with 1.4% in Australia. When compared with Norway and England, countries with similar universal health coverage (UHC) system and elderly polupation, the cost of AD treatments in Korea was still higher with the opposite trend from other countries. CONCLUSIONS: Despite the similar UHC systems, there were considerable differences in the post-market utilization of AD treatments in Korea from Australia and other countries. This results can be attributed to differences in re-assessment system, pricing and reimbursement policies, and prescribing culture. This study provides a baseline to explore more comprehensive cross-country studies on rational use of medicines.

Suitability of databases in the Asia-Pacific for collaborative monitoring of vaccine safety.

INTRODUCTION: Information regarding availability of electronic healthcare databases in the Asia-Pacific region is critical for planning vaccine safety assessments particularly, as COVID-19 vaccines are introduced. This study aimed to identify data sources in the region, potentially suitable for vaccine safety surveillance. This manuscript is endorsed by the International Society for Pharmacoepidemiology (ISPE). METHODS: Nineteen countries targeted for database reporting were identified using published country lists and review articles. Surveillance capacity was assessed using two surveys: a 9-item introductory survey and a 51-item full survey. Survey questions related to database characteristics, covariate and health outcome variables, vaccine exposure characteristics, access and governance, and dataset linkage capability. Other questions collated research/regulatory applications of the data and local publications detailing database use for research. RESULTS: Eleven databases containing vaccine-specific information were identified across 8 countries. Databases were largely national in coverage (8/11, 73%), encompassed all ages (9/11, 82%) with population size from 1.4 to 52 million persons. Vaccine exposure information varied particularly for standardized vaccine codes (5/11, 46%), brand (7/11, 64%) and manufacturer (5/11, 46%). Outcome data were integrated with vaccine data in 6 (55%) databases and available via linkage in 5 (46%) databases. Data approval processes varied, impacting on timeliness of data access. CONCLUSIONS: Variation in vaccine data availability, complexities in data access including, governance and data release approval procedures, together with requirement for data linkage for outcome information, all contribute to the challenges in building a distributed network for vaccine safety assessment in the Asia-Pacific and globally. Common data models (CDMs) may help expedite vaccine safety research across the region.

Maternal and neonatal data collection systems in low- and middle-income countries for maternal vaccines active safety surveillance systems: A scoping review.

BACKGROUND: Most post-licensure vaccine pharmacovigilance in low- and middle-income countries (LMICs) are passive reporting systems. These have limited utility for maternal immunization pharmacovigilance in LMIC settings and need to be supplemented with active surveillance. Our study's main objective was to identify existing perinatal data collection systems in LMICs that collect individual information on maternal and neonatal health outcomes and could be developed to inform active safety surveillance of novel vaccines for use during pregnancy. METHODS: A scoping review was performed following the Arksey and O'Malley six-stage approach. We included studies describing electronic or mixed paper-electronic data collection systems in LMICs, including research networks, electronic medical records, and custom software platforms for health information systems. Medline PubMed, EMBASE, Global Health, Cochrane Library, LILACS, Bibliography of Asian Studies (BAS), and CINAHL were searched through August 2019. We also searched grey literature including through Google and websites of existing relevant perinatal data collection systems, as well as contacted authors of key studies and experts in the field to validate the information and identify additional sources of relevant unpublished information. RESULTS: A total of 11,817 records were identified. The full texts of 264 records describing 96 data collection systems were assessed for eligibility. Eight perinatal data collection systems met our inclusion criteria: Global Network's Maternal Newborn Health Registry, International Network for the Demographic Evaluation of Populations and their Health; Perinatal Informatic System; Pregnancy Exposure Registry & Birth Defects Surveillance; SmartCare; Open Medical Record System; Open Smart Register Platform and District Health Information Software 2. These selected systems were qualitatively characterized according to seven different domains: governance; system design; system management; data management; data sources, outcomes and data quality. CONCLUSION: This review provides a list of active maternal and neonatal data collection systems in LMICs and their characteristics as well as their outreach, strengths, and limitations. Findings could potentially help further understand where to obtain population-based high-quality information on outcomes to inform the conduct of maternal immunization active vaccine safety surveillance activities and research in LMICs.

Estimating Baseline Incidence of Conditions Potentially Associated with Vaccine Adverse Events: a Call for Surveillance System Using the Korean National Health Insurance Claims Data.

BACKGROUND: Vaccines against coronavirus disease 2019 (COVID-19) are raising concerns about vaccine safety, particularly in the context of large-scale immunization. To address public concerns, we measured the baseline incidence rates of major conditions potentially related to vaccine-related adverse events (VAEs). We aimed to provide a basis for evaluating VAEs and verifying causality. METHODS: Conditions of interest were selected from the US Vaccine Adverse Event Reporting System Table of Reportable Events and a recent report from a European consortium on vaccine surveillance. We used the National Health Insurance Service database in Korea to identify the monthly numbers of cases with these conditions. Data from January 2006 to June 2020 were included. Prediction models were constructed from the observed incidences using an autoregressive integrated moving average. We predicted the incidences of the conditions and their respective 95% confidence intervals (CIs) for January through December 2021. In addition, subgroup analysis for the expected vaccination population was conducted. RESULTS: Mean values (95% CIs) of the predicted monthly incidence of vasovagal syncope, anaphylaxis, brachial neuritis, acute disseminated encephalomyelitis, Bell's palsy, Guillain-Barré syndrome, encephalopathy, optic neuritis, transverse myelitis, immune thrombocytopenic purpura, and systemic lupus erythematosus in 2021 were 23.89 (19.81-27.98), 4.72 (3.83-5.61), 57.62 (51.37-63.88), 0.03 (0.01-0.04), 8.58 (7.90-9.26), 0.26 (0.18-0.34), 2.13 (1.42-2.83), 1.65 (1.17-2.13), 0.19 (0.14-0.25), 0.75 (0.61-0.90), and 3.40 (2.79-4.01) cases per 100,000 respectively. The majority of the conditions showed an increasing trend with seasonal variations in their incidences. CONCLUSION: We measured the incidence of a total of 11 conditions that could potentially be associated with VAEs to predict the monthly incidence in 2021. In Korea, conditions that could potentially be related to VAEs occur on a regular basis, and an increasing trend is observed with seasonality.

Cardiovascular Adverse Reactions During Antipsychotic Treatment: Results of AMSP, A Drug Surveillance Program Between 1993 and 2013.

BACKGROUND: Cardiovascular diseases are still the leading cause of global mortality. Some antipsychotic agents can show severe cardiovascular side effects and are also associated with metabolic syndrome. METHODS: This observational study was based on data of AMSP (Arzneimittelsicherheit in der Psychiatrie), a multicenter drug surveillance program in Austria, Germany and Switzerland, that recorded severe drug reactions in psychiatric inpatients. RESULTS: A total of 404 009 inpatients were monitored between 1993 and 2013, whereas 291 510 were treated with antipsychotics either in combination or alone. There were 376 cases of severe cardiovascular adverse reactions reported in the given timespan, yielding a relative frequency of 0.13%. The study revealed that incidence rates of cardiovascular adverse reactions were highest during treatment with ziprasidone (0.35%), prothipendyl (0.32%), and clozapine (0.23%). The lowest rate of cardiovascular symptoms occurred during treatment with promethazine (0.03%) as well as with aripiprazole (0.06%). The most common clinical symptoms were orthostatic collapse and severe hypotonia, sinustachycardia, QTc prolongation, myocarditis, and different forms of arrhythmia. The dosage at the timepoint when severe cardiovascular events occurred was not higher in any of the given antipsychotics than in everyday clinical practice and was in average therapeutic ranges. In terms of subclasses of antipsychotics, no significant statistical difference was seen in the overall frequencies of adverse reactions cases, when first-generation high potency, first-generation low potency, and second-generation antipsychotics were compared. Thirty percent of adverse events among second-generation antipsychotics were induced by clozapine. CONCLUSIONS: Our findings on cardiovascular adverse reactions contribute to a better understanding of cardiovascular risk profiles of antipsychotic agents in inpatients.

Global post-marketing safety surveillance of Tumor Treating Fields (TTFields) in patients with high-grade glioma in clinical practice.

INTRODUCTION: Tumor Treating Fields (TTFields; antimitotic treatment) delivers low-intensity, intermediate-frequency, alternating electric fields through skin-applied transducer arrays. TTFields (200 kHz) was FDA-approved in glioblastoma (GBM), based on the phase 3 EF-11 (recurrent GBM, rGBM) and EF-14 (newly diagnosed GBM, ndGBM) trials. The most common TTFields-related adverse event (AE) in both trials was array-associated skin irritation. We now report on TTFields-related AEs in the real-world, clinical practice setting. METHODS: Unsolicited, post-marketing surveillance data from TTFields-treated patients (October 2011-February 2019) were retrospectively analyzed using MedDRA v21.1 preferred terms, stratified by region (US, EMEA [Europe, Middle East, Africa], Japan), diagnosis (ndGBM, rGBM, anaplastic astrocytoma/oligodendroglioma, other brain tumors), and age (< 18 [pediatric], 18-64 [adults], ≥ 65 [elderly]; years of age). RESULTS: Of 11,029 patients, 53% were diagnosed with ndGBM and 39% were diagnosed with rGBM at any line of disease recurrence. Most were adults (73%), 26% were elderly, and the male-to-female ratio was ~ 2:1 (close to published ratios of typical GBM populations). The most commonly reported TTFields-related AE was array-associated skin reaction, occurring in patients with ndGBM (38%), rGBM (29%), anaplastic astrocytoma/oligodendroglioma (38%), and other brain tumors (31%); as well as 37% of pediatric, 34% of adult, and 36% of elderly patients. Most skin AEs were mild/moderate and manageable. Other TTFields-related AEs in patients with ndGBM/rGBM included under-array heat sensation (warmth; 11%, 10%, respectively) and electric sensation (tingling; 11%, 9%, respectively), and headache (7%, 6%, respectively). CONCLUSIONS: This TTFields safety surveillance analysis in > 11,000 patients revealed no new safety concerns, with a favorable safety profile comparable with published TTFields/GBM trials. The safety profile remained consistent among subgroups, suggesting feasibility in multiple populations, including elderly patients.

Adverse drug reaction or innocent bystander? A systematic comparison of statistical discovery methods for spontaneous reporting systems.

PURPOSE: Spontaneous reporting systems (SRSs) are used to discover previously unknown relationships between drugs and adverse drug reactions (ADRs). A plethora of statistical methods have been proposed over the years to identify these drug-ADR pairs. The objective of this study is to compare a wide variety of methods in their ability to detect these signals, especially when their detection is complicated by the presence of innocent bystanders (drugs that are mistaken to be associated with the ADR, since they are prescribed together with the drug that is the ADR's actual cause). METHODS: Twelve methods, 24 measures in total, ranging from simple disproportionality measures (eg, the reporting odds ratio), hypothesis tests (eg, test of the Poisson mean), Bayesian shrinkage estimates (eg, the Bayesian confidence propagation neural network, BCPNN) to sparse regression (LASSO), are compared in their ability to detect drug-ADR pairs in a large number of simulated SRSs with varying numbers of innocent bystanders and effect sizes. The area under the precision-recall curve is used to assess the measures' performance. RESULTS: Hypothesis tests (especially the test of the Poisson mean) perform best when the associations are weak and there is little to no confounding by other drugs. When the level of confounding increases and/or the effect sizes become larger, Bayesian shrinkage methods should be preferred. The LASSO proves to be the most robust against the innocent bystander effect. CONCLUSIONS: There is no absolute "winner". Which method to use for a particular SRS depends on the effect sizes and the level of confounding present in the data.

Translational hurdles with cannabis medicines.

PURPOSE: Internationally, there has been widespread medical use of cannabis medicines before rigorous evaluations in randomised controlled trials (RCTs). Some advocates of medicinal use of cannabis argue that real-world evidence (RWE) can be a substitute for or at least supplement evidence from RCTs. We explore the utility, limitations and impact of RWE in the translation of cannabis medicines research into clinical practice using the established literature. METHODS: A literature search was performed via Embase and Medline using a diverse range of cannabinoid and RWE search terms. The review provides a snapshot of cannabis medicine RWE initiatives from around the world. RESULTS: Diverse and novel sources of real-world data and RWE include international cannabis registries, surveys, post-marketing data collection and use of electronic or digital health records. The strengths and limitations of using RWE in translational research are highlighted, along with the identification of barriers to RCTs involving cannabis medicines. CONCLUSIONS: RWE promises to play a significant role in the evaluation of cannabis medicines around the world. When used appropriately RWE may complement RCT data by providing valuable insights into cannabis medicine safety and effectiveness. TAKE HOME MESSAGES: It is important that real-world evidence (RWE) is used to complement rather than replace randomised controlled trial (RCT) evidence on cannabis medicines. Technological advances have created the opportunity to explore diverse and novel sources of cannabis medicine RWE. Although RWE may be more reflective of real-world clinical practice, it cannot provide conclusive evidence of the safety and efficacy of cannabis medicines. While acknowledging its limitations, RWE may nonetheless provide some guidance on safety and adverse events of cannabis medicines. RWE has already had a significant impact on the regulation of cannabis medicines.

Safety and effectiveness of baloxavir marboxil for the treatment of influenza in Japanese clinical practice: A postmarketing surveillance of more than 3000 patients.

Baloxavir marboxil is an oral anti-influenza drug that inhibits the cap-dependent endonuclease of the virus polymerase acidic protein. In clinical trials, baloxavir reduced the time to alleviation of influenza symptoms and time to resolution of fever in adults, adolescents, and children. The purpose of this study is to collect data on the safety and effectiveness of baloxavir when used in clinical practice. This postmarketing surveillance (clinicaltrials.jp; JapicCTI-183882), conducted at 688 Japanese hospitals or clinics (March 2018 to March 2019), enrolled patients of any age with influenza A or B infection who received a single, weight-based dose of baloxavir. Adverse drug reactions (ADRs) were seen in 11.2% of 3094 patients during the 7-day observation period; the most common ADR was diarrhea (6.1%). ADRs were more common in children aged <12 years (14.1%) than in adults (10.0%). Almost all ADRs were non-serious (98.9%) and were recovered or recovering (96.7%). Median time to alleviation of symptoms (N = 2884) was 2.5 days (overall, influenza A, and influenza B groups). Median time to resolution of fever (N = 2946) was 1.5 days (overall, influenza A, and influenza B groups). Biphasic fever (increased temperature after previous fever resolution) was seen in 6.7% of patients overall and 28.6% of patients <6 years infected with influenza B, similar to rates published elsewhere with other influenza drugs and in untreated influenza. This postmarketing surveillance of >3000 patients suggests that baloxavir is well tolerated and effective regardless of patient age or influenza virus type.

Postmarket Experience of Polymethylmethacrylate-Collagen Gel Dermal Filler.

BACKGROUND: This report synthesizes 12 years of postmarket surveillance data (PMSD) for polymethylmethacrylate (PMMA)-collagen gel dermal filler. OBJECTIVE: To present PMMA-collagen gel PMSD findings on real-world safety. METHODS: Postmarket surveillance data were collected from January 2007 to December 2018 and evaluated to determine the overall adverse event (AE) complaint rate, the nature of reported AEs, and whether the complaint included on-label, off-label, both, or unknown areas. RESULTS: In the 12 years examined, 754,229 PMMA-collagen gel syringes were distributed worldwide, and 839 product-related complaints (including those classified as unknown) resulted in an overall complaint rate of 0.11%. The 3 most frequent primary complaints in AE reports were lump/bump (309/839, 37%), nodule (152/839, 18%), and swelling (138/839, 16%). Histologically confirmed granuloma accounted for 17/839 complaints (2.0%; overall complaint rate of 0.002%), and histologically unconfirmed granuloma accounted for 66/839 complaints (8%; overall rate of 0.009%). There were 666 complaints representing AEs related to off-label injection in which the periocular area was most frequently represented. CONCLUSION: Although a limiting factor across all PMSD is voluntary reporting and resultant underrepresentation of AEs, the PMSD reported here are consistent with safety findings from US clinical studies in more than 1,500 patients with up to 5 years of follow-up.

A Bayesian approach to sequential analysis in post-licensure vaccine safety surveillance.

With rapid development of computing technology, Bayesian statistics have increasingly gained more attention in various areas of public health. However, the full potential of Bayesian sequential methods applied to vaccine safety surveillance has not yet been realized, despite acknowledged practical benefits and philosophical advantages of Bayesian statistics. In this paper, we describe how sequential analysis can be performed in a Bayesian paradigm in the field of vaccine safety. We compared the performance of the frequentist sequential method, specifically, Maximized Sequential Probability Ratio Test (MaxSPRT), and a Bayesian sequential method using simulations and a real world vaccine safety example. The performance is evaluated using three metrics: false positive rate, false negative rate, and average earliest time to signal. Depending on the background rate of adverse events, the Bayesian sequential method could significantly improve the false negative rate and decrease the earliest time to signal. We consider the proposed Bayesian sequential approach to be a promising alternative for vaccine safety surveillance.

Safety and effectiveness of high-dose methotrexate (over 8 mg/week) in 2838 Japanese patients with rheumatoid arthritis: a postmarketing surveillance report.

Objectives: To confirm the safety and effectiveness of high-dose (>8 mg/week) methotrexate (MTX) for the treatment of rheumatoid arthritis in Japan.Methods: A postmarketing surveillance program enrolled Japanese patients with rheumatoid arthritis starting on high-dose MTX followed up for 24 or 52 weeks. Analyses for safety, risk factors affecting safety, and effectiveness were conducted.Results: The safety/effectiveness analysis sets included 2838/2779 and 335/326 patients in the 24 and 52-week follow-up groups, respectively. Incidence of adverse drug reactions (ADRs) and serious ADRs was 21.42 and 1.66% in the 24-week and 35.52 and 2.69% in the 52-week groups, respectively. The Disease Activity Score in 28 Joints (DAS28) was significantly decreased as early as four weeks from the start of high-dose MTX; after 24-week (4.09-3.21) and 52-week treatment (3.91-2.80; both p < .001). In a majority of patients at baseline who had high-to-moderate disease activity, the remission rate (defined as DAS28-4ESR <2.6) increased three-fold from 10.6% (baseline) to 33.0% (24-week) compared to patients with low disease activity whose remission rate increased two-fold from 24.0% (baseline) to 53.6% (24 weeks).Conclusion: High-dose MTX was well tolerated in Japanese patients, resulted in improved disease control, and can be considered a step forward in achieving treat-to-target goals.

Post-marketing dosing changes in the label of biologicals.

AIM: The aim of this study was to evaluate post-marketing label changes in dosing information of biologicals. METHODS: Biologicals authorized between 2007 and 2014 by the European Medicines Agency (EMA) were included and followed up from marketing authorization until 31 December 2016 or date of withdrawal of the marketing authorization. The primary outcome of the study was defined as label change in dosing information for the initially approved indication. Incidence of changes, type of change and mean time to change were assessed. As a secondary outcome, label changes in dosing information for extended indications were assessed. RESULTS: A total of 71 biologicals were included. Dosing information in the label changed for the initial indication during follow-up for eight products (11%). In one of the eight products the change concerned an increase in dose. Also, a change in dosing frequency was identified in three products, for one product a recommendation was added that therapy could be initiated with or without a loading dose, and for one product the minimum dose was removed and a maximum dose was added. For the remaining product the dose was decreased due to safety issues. For 30 products (42%) the indication was extended at least once. No changes in dosing information were observed for the extended indications (n = 59) during follow-up. CONCLUSIONS: This study showed that in 11% of the biologicals, the dosing for the initial indication in the label was changed. In contrast to small molecules, the dose was rarely reduced for safety reasons.

FDA-approved drugs for multiple sclerosis have no efficacy or disability data in non-Caucasian patients.

Pharmacotherapy of multiple sclerosis (MS) is evolving rapidly. Despite impressive gains over the past 2 decades in the approval of multiple drugs for MS, lack of recruitment of minorities with MS in phase 3 clinical studies is a persistent concern and skews efficacy and disability data.

Causal inference for evaluating prescription opioid abuse using trend-in-trend design.

PURPOSE: One response to the opioid crisis in the United States has been the development of opioid analgesics with properties intended to reduce non-oral use. Previous evaluations of abuse in the community have relied on population averaged interrupted time series Poisson models with utilization offsets. However, competing interventions and secular trends complicate interpretation of time-series analyses. An alternative research design, trend-in-trend, accounts for heterogeneity in per capita opioid dispensing and unmeasured time-varying confounding, which provides a causal evaluation, provided that underlying assumptions are met. METHODS: Trend-in-trend can be modeled using a logistic regression framework. In logistic regression, exposure was any product-specific outpatient dispensing by three-digit ZIP code and calendar quarter, for 22 opioids. The outcome was any product-specific abuse case ascertained from poison centers and drug treatment programs, covering 94% of the US population, between July 2009 and December 2016. Product-specific odds ratios compared places without dispensing with places with any dispensing; the causal contrast represents the odds of product-specific abuse in the community given exposure. RESULTS: Dispensing of new and low-volume opioids varied considerably across the country, with no region showing high of all products. Of 22 opioids analyzed, the three with approved labeling as intended to deter abuse ranked near the lowest in both absolute (population-adjusted rates: 1.7, 0.9, and 8.2 per million people per quarter, respectively) and relative measures (trend-in-trend ORs: 1.96, 1.79, 1.69, respectively). CONCLUSIONS: Postmarketing studies of prescription opioid abuse may benefit by evolving from unadjusted surveillance rates to a causal inference approach.