Use of quantitative bias analysis to evaluate single-arm trials with real-world data external controls.

PURPOSE: Use of real-world data (RWD) for external controls added to single-arm trials (SAT) is increasingly prevalent in regulatory submissions. Due to inherent differences in the data-generating mechanisms, biases can arise. This paper aims to illustrate how to use quantitative bias analysis (QBA). METHODS: Advanced non-small cell lung cancer (NSCLC) serves as an example, where many small subsets of patients with molecular tumor subtypes exist. First, some sources of bias that may occur in oncology when comparing RWD to SAT are described. Second, using a hypothetical immunotherapy agent, a dataset is simulated based on expert input for survival analysis of advanced NSCLC. Finally, we illustrate the impact of three biases: missing confounder, misclassification of exposure, and outcome evaluation. RESULTS: For each simulated scenario, bias was induced by removing or adding data; hazard ratios (HRs) were estimated applying conventional analyses. Estimating the bias-adjusted treatment effect and uncertainty required carefully selecting the bias model and bias factors. Although the magnitude of each biased and bias-adjusted HR appeared moderate in all three hypothetical scenarios, the direction of bias was variable. CONCLUSION: These findings suggest that QBA can provide an intuitive framework for bias analysis, providing a key means of challenging assumptions about the evidence. However, the accuracy of bias analysis is itself dependent on correct specification of the bias model and bias factors. Ultimately, study design should reduce bias, but QBA allows us to evaluate the impact of unavoidable bias to assess the quality of the evidence.

Updated core competencies in pharmacoepidemiology to inform contemporary curricula and training for academia, government, and industry.

PURPOSE: The first paper to specify the core content of pharmacoepidemiology as a profession was published by an ISPE (International Society for Pharmacoepidemiology) workgroup in 2012 (Jones JK et al. PDS 2012; 21[7]:677-689). Due to the broader and evolving scope of pharmacoepidemiology, ISPE considers it important to proactively identify, update and expand the list of core competencies to inform curricula of education programs; thus, better positioning pharmacoepidemiologists across academic, government (including regulatory), and industry positions. The aim of this project was to update the list of core competencies in pharmacoepidemiology. METHODS: To ensure applicability of findings to multiple areas, a working group was established consisting of ISPE members with positions in academia, industry, government, and other settings. All competencies outlined by Jones et al. were extracted from the initial manuscript and presented to the working group for review. Expert-based judgments were collated and used to identify consensus. It was noted that some competencies could contribute to multiple groups and could be directly or indirectly related to a group. RESULTS: Five core domains were proposed: (1) Epidemiology, (2) Clinical Pharmacology, (3) Regulatory Science, (4) Statistics and data science, and (5) Communication and other professional skills. In total, 55 individual competencies were proposed, of which 25 were new competencies. No competencies from the original work were dropped but aggregation or amendments were made where considered necessary. CONCLUSIONS: While many core competencies in pharmacoepidemiology have remained the same over the past 10 years, there have also been several updates to reflect new and emerging concepts in the field.

Overview of the European post-authorisation study register post-authorization studies performed in Europe from September 2010 to December 2018.

BACKGROUND: The European post-authorisation study (EU PAS) register is a repository launched in 2010 by the European Medicines Agency (EMA). All EMA-requested PAS, commonly observational studies, must be recorded in this register. Multi-database studies (MDS) leveraging secondary data have become an important strategy to conduct PAS in recent years, as reflected by the type of studies registered in the EU PAS register. OBJECTIVES: To analyse and describe PAS in the EU PAS register, with focus on MDS. METHODS: Studies in the EU PAS register from inception to 31st December 2018 were described concerning transparency, regulatory obligations, scope, study type (e.g., observational study, clinical trial, survey, systematic review/meta-analysis), study design, type of data collection and target population. MDS were defined as studies conducted through secondary use of >1 data source not linked at patient-level. Data extraction was carried out independently by 14 centres with expertise in pharmacoepidemiology, using publicly available information in the EU PAS register including study protocol, whenever available, using a standardised data collection form. For validation purposes, a second revision of key fields for a 15% random sample of studies was carried out by a different centre. The inter-rater reliability (IRR) was then calculated. Finally, to identify predictors of primary data collection-based studies/versus those based on secondary use of healthcare databases) or MDS (vs. non-MDS), odds ratios (OR) and 95% confidence intervals (CI) were calculated fitting univariate logistic regression models. RESULTS: Overall, 1426 studies were identified. Clinical trials (N = 30; 2%), systematic reviews/meta-analyses (N = 16; 1%) and miscellaneous study designs (N = 46; 3%) were much less common than observational studies (N = 1227; 86%). The protocol was available for 63% (N = 360) of 572 observational studies requested by a competent authority. Overall, 36% (N = 446) of observational studies were based fully or partially on primary data collection. Of 757 observational studies based on secondary use of data alone, 282 (37%) were MDS. Drug utilisation was significantly more common as a study scope in MDS compared to non-MDS studies. The overall percentage agreement among collaborating centres that collected the data concerning study variables was highest for study type (93.5%) and lowest for type of secondary data (67.8%). CONCLUSIONS: Observational studies were the most common type of studies in the EU PAS register, but 30% used primary data, which is more resource-intensive. Almost half of observational studies using secondary data were MDS. Data recording in the EU PAS register may be improved further, including more widespread availability of study protocols to improve transparency.

Identification of cardiotoxicity related to non-small cell lung cancer (NSCLC) treatments: A systematic review.

Introduction: In the last few decades, there has been a rapid development in cancer therapies and improved detection strategies, hence the death rates caused by cancer have decreased. However, it has been reported that cardiovascular disease has become the second leading cause of long-term morbidity and fatality among cancer survivors. Cardiotoxicity from anticancer drugs affects the heart's function and structure and can occur during any stage of the cancer treatments, which leads to the development of cardiovascular disease. Objectives: To investigate the association between anticancer drugs for non-small cell lung cancer (NSCLC) and cardiotoxicity as to whether: different classes of anticancer drugs demonstrate different cardiotoxicity potentials; different dosages of the same drug in initial treatment affect the degree of cardiotoxicity; and accumulated dosage and/or duration of treatments affect the degree of cardiotoxicity. Methods: This systematic review included studies involving patients over 18 years old with NSCLC and excluded studies in which patients' treatments involve radiotherapy only. Electronic databases and registers including Cochrane Library, National Cancer Institute (NCI) Database, PubMed, Scopus, Web of Science, ClinicalTrials.gov and the European Union Clinical Trials Register were systematically searched from the earliest available date up until November 2020. A full version protocol of this systematic review (CRD42020191760) had been published on PROSPERO. Results: A total of 1785 records were identified using specific search terms through the databases and registers; 74 eligible studies were included for data extraction. Based on data extracted from the included studies, anticancer drugs for NSCLC that are associated with cardiovascular events include bevacizumab, carboplatin, cisplatin, crizotinib, docetaxel, erlotinib, gemcitabine and paclitaxel. Hypertension was the most reported cardiotoxicity as 30 studies documented this cardiovascular adverse event. Other reported treatment-related cardiotoxicities include arrhythmias, atrial fibrillation, bradycardia, cardiac arrest, cardiac failure, coronary artery disease, heart failure, ischemia, left ventricular dysfunction, myocardial infarction, palpitations, and tachycardia. Conclusion: The findings of this systematic review have provided a better understanding of the possible association between cardiotoxicities and anticancer drugs for NSCLC. Whilst variation is observed across different drug classes, the lack of information available on cardiac monitoring can result in underestimation of this association. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020191760, identifier PROSPERO CRD42020191760.

Impact of European Union Label Changes for Fluoroquinolone-Containing Medicinal Products for Systemic and Inhalation Use: Post-Referral Prescribing Trends.

INTRODUCTION: Concerns of the persistence and severity of the adverse effects of fluoroquinolones, mainly involving the nervous system, muscles and joints, resulted in the 2018 referral procedure led by the European Medicines Agency (EMA). They advised to stop prescribing fluoroquinolones for infections of mild severity or of a presumed self-limiting course and for prevention of infections, plus to restrict prescriptions in cases of milder infections where other treatment options are available, and restrict in at-risk populations. We aimed to examine whether the impact of EMA regulatory interventions implemented throughout 2018-2019 had an impact on fluoroquinolone prescribing rates. METHODS: A retrospective population-based cohort study was conducted using electronic health care records from six European countries between 2016 and 2021. We analysed monthly incident fluoroquinolone use rates overall and for each fluoroquinolone active substance through flexible modelling via segmented regression to detect time points of trend changes, in monthly percentage change (MPC). RESULTS: The incidence of fluoroquinolone use ranged from 0.7 to 8.0/1000 persons per month over all calendar years. While changes in fluoroquinolone prescriptions were observed over time across countries, these were inconsistent and did not seem to be temporally related to EMA interventions (e.g., Belgium: February/May 2018, MPC - 33.3%, 95% confidence interval [CI] - 35.9 to - 30.7; Germany: February/May 2019, MPC - 12.6%, 95% CI - 13.7 to - 11.6]; UK: January/April 2016, MPC - 4.9%, 95% CI - 6.2 to - 3.6). CONCLUSION: The regulatory action associated with the 2018 referral did not seem to have relevant effects on fluoroquinolone prescribing in primary care.

Influenza H1N1 (swine flu) vaccination: a safety surveillance feasibility study using self-reporting of serious adverse events and pregnancy outcomes.

AIMS: During the global H1N1 influenza A (swine flu) pandemic 2009-2010, swine flu vaccines were expeditiously licensed and a mass vaccination programme for high risk groups, including pregnant women, was introduced in the UK. This pilot active safety surveillance study was performed to establish the feasibility of rapidly monitoring the new swine flu vaccines in large patient numbers receiving or offered the vaccination under normal conditions of use within a short time frame. METHODS: A cohort design with safety data capture through modern technologies was carried out in Scotland, UK during the winter swine flu vaccination programme 2009-2010 in individuals receiving or offered the swine flu vaccination. The main outcome measures were self-reported serious adverse events (SAEs) and pregnancy outcomes. RESULTS: The cohort comprised 4066 people; 3754 vaccinated and 312 offered the vaccination but not vaccinated. There were 939 self-reported events (838 different events), 53 judged to fit SAE criteria by the investigators, with nine judged as possibly, probably or definitely vaccine related. None of the seven deaths (six in vaccinees) were judged as vaccine related. One hundred and twenty-eight women reported 130 pregnancies during the study with 117 pregnant at study start. There were reports of four miscarriages in three women and six possible congenital abnormalities in live births. CONCLUSIONS: Overall, no significant safety issues were identified. The methodology and use of modern technologies to collect safety data from large numbers of patients was successful and could be used again in similar safety studies.

A Landscape Analysis of Post-Marketing Studies Registered in the EU PAS Register and ClinicalTrials.gov Focusing on Pregnancy Outcomes or Breastfeeding Effects: A Contribution from the ConcePTION Project.

INTRODUCTION: A large proportion of medicine product labels lack information on safety in pregnancy and breastfeeding. To address this gap, pharmaceutical companies are requested to develop post-approval studies regarding the use of drugs by pregnant and breastfeeding women. OBJECTIVE: Our study aims to review key features of observational studies in pregnancy and breastfeeding and their impact on the respective medicine product labels. METHODS: Observational studies focusing on the safety evaluation of medicines used during pregnancy and breastfeeding were selected from the European Union Register of Post-Authorization Studies (EU PAS register) and ClinicalTrials.gov. We extracted information on the variables of interest and performed an impact assessment on the respective label. RESULTS: A total of 141 observational studies were eligible. Of these, 63 studies (45%) were based on primary data collection and 55 studies (39%) on secondary use of health data. A small number of studies (8%) aimed to evaluate drug safety during breastfeeding. Studies using secondary data collection lasted around 2.9 years as opposed to 7.5 years' duration for studies using primary data collection. Only two product labels were updated based on the study results. CONCLUSION: The duration is significantly longer for studies based on primary data collection, and these are also smaller in size (less power), whereas outcomes of interest are similar. For completed studies, the impact on the label was very low. Given the gap in adequate pregnancy information on product labels, the current process of generating evidence in pregnancy and breastfeeding seems neither efficient nor impactful. To support evidence-based decision making by prescribers, this current process might be redesigned.

Safety profile of oxcarbazepine: results from a prescription-event monitoring study.

PURPOSE: To monitor safety of oxcarbazepine, prescribed in primary care in England, using prescription-event monitoring (PEM). METHODS: Postmarketing surveillance using observational cohort technique of PEM. Exposure data were obtained from dispensed British National Health Service prescriptions issued by general practitioners (GPs) March 2000-July 2003. Demographic, drug utilization, and clinical event data were collected from questionnaires posted to GPs at least 6 months after first prescription date for each patient. Incidence densities (IDs) (number of first reports per 1,000 patient-months of treatment) were calculated and differences for events reported in month 1 (ID(1)) and months 2-6 (ID(2-6)) (99% confidence intervals) were examined for changes in event rates. Follow-up and causality assessment of medically significant events were undertaken. RESULTS: The cohort comprised 2,243 patients [mean age 40.4 years; range 2-99 years; standard deviation (SD) 18.8; 46.3% (n = 1,038) male]. Most frequently reported primary indications were epilepsy, convulsion (n = 1,111; 49.5%, n = 209; 9.3%, respectively). GPs recorded 932 reasons for stopping medication in 698 (31.1%) patients; most frequent clinical reason "drowsiness/sedation" (n = 57; 2.5% of cohort). Clinical events (excluding indication) associated with starting treatment (lower 99% CI > 0) included: "drowsiness/sedation" (ID(1)-ID(2-6) = 14.2), "nausea/vomiting" (ID(1)-ID(2-6) = 13.0), and dizziness (ID(1)-ID(2-6) = 11.6). Events followed up and assessed as probably related to oxcarbazepine use included rash (7 of 11) and hyponatremia (15 of 38). DISCUSSION: There were no serious adverse drug reactions reported during this study. Results of the study should be taken in context with other epidemiologic studies.

A Framework for Methodological Choice and Evidence Assessment for Studies Using External Comparators from Real-World Data.

Several approaches have been proposed recently to accelerate the pathway from drug discovery to patient access. These include novel designs such as using controls external to the clinical trial where standard randomised controls are not feasible. In parallel, there has been rapid growth in the application of routinely collected healthcare 'real-world' data for post-market safety and effectiveness studies. Thus, using real-world data to establish an external comparator arm in clinical trials is a natural next step. Regulatory authorities have begun to endorse the use of external comparators in certain circumstances, with some positive outcomes for new drug approvals. Given the potential to introduce bias associated with observational studies, there is a need for recommendations on how external comparators should be best used. In this article, we propose an evaluation framework for real-world data external comparator studies that enables full assessment of available evidence and related bias. We define the principle of exchangeability and discuss the applicability of criteria described by Pocock for consideration of the exchangeability of the external and trial populations. We explore how trial designs using real-world data external comparators fit within the evidence hierarchy and propose a four-step process for good conduct of external comparator studies. This process is intended to maximise the quality of evidence based on careful study design and the combination of covariate balancing, bias analysis and combining outcomes.

Examining the tolerability of the non-sedating antihistamine desloratadine: a prescription-event monitoring study in England.

BACKGROUND: Desloratadine is a non-sedating, long-acting histamine H(1) receptor antagonist indicated for the symptomatic relief of allergic rhinitis (AR) and chronic idiopathic urticaria in patients aged>12 years. OBJECTIVE: To monitor the safety of desloratadine as prescribed in England, using the observational cohort technique of prescription event monitoring (PEM). METHODS: Exposure data were derived from dispensed prescriptions written by primary care physicians (general practitioners [GPs]) for desloratadine (March-May 2001); patient demographics, indication, pattern of use and outcome (event) data were obtained via simple questionnaires returned by GPs. Incidence density observation rates (IDobs) were calculated to compare the difference in event rates between months 1 and 2 (m1/m2) and were compared for the whole cohort and by groups defined by indication and pattern of use. RESULTS: The cohort comprised 11 828 patients (median age 37 years [interquartile range 22, 54]; 59.9% were female). The most frequent indication was AR (n=8001; 67.6%). After 2 months, 36.8% (n=2464) of patients were still taking desloratadine. 'Condition improved' was the most common event and reason for stopping. Headache/migraine was uncommon but associated with starting treatment (IDobs(m1/m2) ratio 3.99 [95% CI 1.70, 10.83]). Cardiovascular events occurred rarely or very rarely, as did central and peripheral nervous system events. No serious adverse drug reactions (ADRs) were reported. Events related to effectiveness were more frequent in month 1 than month 2 for all patient subgroups. CONCLUSIONS: This postmarketing surveillance study shows that desloratadine is well tolerated when used in general practice in England. No previously unrecognized ADRs were detected. This study highlights how modifications to PEM are contributing to the evaluation of drug utilization factors in relation to risks.

Evaluation of risk profiles for gastrointestinal and cardiovascular adverse effects in nonselective NSAID and COX-2 inhibitor users: a cohort study using pharmacy dispensing data in The Netherlands.

BACKGROUND: Newly approved drugs, in comparison with older drugs, are more often prescribed to patients who have not responded satisfactorily to established related drugs or as first-line therapy to patients with a high baseline risk for adverse outcomes (i.e. channelling). However, these patients are less likely to benefit from the prescribed drug and/or are more prone to adverse drug reactions. Therefore, it is difficult to unravel whether observed risks or increases in risk of new drugs are real, i.e. related to the pharmacology, or whether these are related to selective prescribing to patients who are more susceptible to adverse events because of some underlying risk factor(s). The channelling paradox may exist for cyclo-oxygenase (COX)-2 selective inhibitors ('coxibs') instead of traditional nonselective NSAIDs in relation to both gastrointestinal (GI) and cardiovascular (CV) safety. OBJECTIVE: To evaluate the risk profiles for GI and CV adverse effects in nonselective NSAID and coxib new-user populations over time, in terms of a quantitative measure since the introduction of coxibs. METHODS: This was a population-based cohort study using the Dutch pharmaceutical claims database (Foundation for Pharmaceutical Statistics). Eligible patients (>/=18 years) were those where the date of their first prescription (index date) of an NSAID (first-line [e.g. ibuprofen] or second-line [e.g. piroxicam] nonselective NSAID, COX-2 preferential NSAID or coxib) was between January 1999 and December 2003. For each patient, GI and CV risk profiles at index date were defined by a cumulative score derived from dispensing data (patient age, sex and history of medication use within 6 months of index date). Risk scores were categorized as low (score = 0), medium (1) or high (2+). Patients were recorded as switchers based on other NSAID use prior to the index date. Other information collected included the Chronic Disease Score (CDS). Crude odds ratios (ORs) were calculated for risk factors for each NSAID group versus first-line nonselective NSAID users as the reference cohort. The effect of calendar time was examined by plotting mean CV or GI risk score by quarter-year. Correlation between GI and CV scores was examined using the Pearson correlation coefficient (R). Data were stratified by patients' history of switching. RESULTS: The four cohorts comprised patients using: first-line nonselective NSAIDs (n = 42 750); second-line nonselective NSAIDs (n = 1771); COX-2 preferential NSAIDs (n = 3661) and coxibs (n = 4861) patients. New coxib users were most likely to have high GI and CV risk scores (OR 5.3 [95% CI 5.0, 5.6] and OR 2.2 [95% CI 2.1, 2.4], respectively). At the individual patient level, GI and CV risk profiles were moderately well correlated for all NSAID cohorts (R range 0.48 to 0.62). There was no remarkable change in mean GI or CV risk profile of patients over calendar time since the market introduction of coxibs. DISCUSSION: Of the four NSAID cohorts, new coxib users tended to have the highest numbers of GI and CV risk factors, with no obvious change over calendar time. There was also evidence of correlation between GI and CV risk scores. Thus, selective prescribing of coxibs applies to people with co-existing CV as well as GI risk factors. This is important when comparing the safety and/or efficacy of new therapies to existing therapies, and emphasizes the difficulties encountered by prescribers in assessing levels of risk when initiating coxib treatment.

Prescriber adoption of newly approved selective COX-2 inhibitors.

INTRODUCTION: There is no consistent definition of prescribers who adopt new drug treatments early. This study examines if COX-2 inhibitors (coxibs) were prescribed by subsets of practitioners and describes GP adoption patterns of coxibs and existing NSAIDs over time. METHODS: A population-based drug utilisation study using a Dutch medication claims database. Prescribers of patients (18+yrs) prescribed an NSAID January 1999-December 2003 were identified. Four NSAID categories were chosen reflecting selectivity (coxibs, preferential COX-2 inhibitors and non-selective (ns) NSAIDs (sub-categorised as first or second line treatment)). The characteristics of prescribers issuing>10 prescriptions examined were: Type (GP, Specialist, Other); GP NSAID prescribing preference ratio (nsNSAIDs/coxib first prescription); coxib (ratio<3); prescriber proportion responsible for 100%, 80% and 50% of initiations. Odds Ratios (95%CI) were calculated (first-line nsNSAIDs as reference). Plots of prescribing proportions by quarter year were examined. RESULTS: NSAID cohorts comprised: first-line ns (N=38783); second-line ns (N=1459); COX-2 preferential (N=3107); coxib (N=4202) patients. For all four cohorts, GPs were the most common prescriber type (>67%); the most frequent prescribing preference was for first-line nsNSAIDs; 50% percentile prescribing proportions were low (<9%). GPs were equally as likely to prescribe coxibs as first-line nsNSAIDs [OR 1.0 (0.9, 1.1)]. Plots of 100% prescriber proportion for first-line nsNSAIDs and coxibs showed convergence; 50th percentile prescriber proportions plots were constant. CONCLUSIONS: Small subsets of prescribers accounted for the majority of initiations regardless of NSAID type. Further studies are needed on such prescribers to inform healthcare policies and encourage participation in post-marketing safety studies.

Utilisation and Safety of Deferasirox: Results from an Observational Cohort Study in England.

INTRODUCTION: Deferasirox (EXJADE®, Novartis, UK) is an oral iron-chelating agent primarily used to reduce chronic iron overload in patients receiving blood transfusions for various chronic anaemias and some non-transfusion dependant anaemias. OBJECTIVE: The aim of this study was to examine the utilisation and safety of deferasirox used in general practice in England. METHOD: A single exposure observational cohort study design was used. Patients were identified from dispensed prescriptions for deferasirox between September 2006 and September 2014. Outcome data were collected via postal questionnaires sent to prescribers ≥ 6 months after first dispensed prescription for an individual patient. Summary descriptive statistics were calculated. RESULTS: The evaluable cohort consisted of 122 patients, of which 41.8% were aged 2-17 years. Frequent reasons for prescribing were sickle cell anaemia (27/103 where specified, 26.2%) and beta thalassaemia (26, 25.2%). The majority of patients (43/51, 84.3%) were prescribed the licensed doses of 10 or 20 mg/kg/day at start. Prior measurements of serum creatinine were only reported for a small proportion this study (18/122, 14.8%). In total, 91 incident events were reported, including two of raised serum creatinine. CONCLUSION: These results show that deferasirox is largely being prescribed for its licensed indications in general practice in England and events reported were consistent with the known safety profile.

Safety of Atrovent® CFC-free inhaler: respiratory events reported from an observational cohort study in England.

OBJECTIVES: The aim of the study was to identify any unexpected clinical events associated with starting the new CFC-free formulation of Atrovent® MDI in general practice in England. METHODS: An active surveillance cohort study was conducted with a focus on selected clinical events, including respiratory symptoms, in past users of Atrovent® CFC MDI ('switchers') and Atrovent® naïve users. Incidence density rate ratios (with 99% confidence intervals) for events occurring in the first 3 months of exposure (risk period-ID1-3 ) compared to 3 months prior to starting treatment (reference period-IDR ) were calculated. RESULTS: The cohort consisted of 13 211 patients (median age 70 years, 50.1% female; 63.5% prior users of Atrovent® CFC MDI ('switchers')). Common respiratory events occurred at higher rates after starting treatment than before for switchers, for example lower respiratory tract infection (LRTI) [ID1 /IDR = 1.45 (99% CI: 1.17, 1.81)] and worsening asthma [ID1 /IDR = 1.58 (99% CI: 1.00, 2.51)]. Of these events only LRTI was significant for Atrovent® naïve patients [ID1 /IDR = 1.42 (99% CI: 1.04, 1.95)]. CONCLUSIONS: The results of this study suggest effect modification of risk as a result of prior Atrovent® CFC MDI use. Overall, Atrovent® CFC-free MDI appeared to be reasonably well tolerated in the immediate postmarketing period and the safety profile appeared similar to that of the CFC formulation.

Drugs and life-threatening ventricular arrhythmia risk: results from the DARE study cohort.

OBJECTIVES: To establish a unique sample of proarrhythmia cases, determine the characteristics of cases and estimate the contribution of individual drugs to the incidence of proarrhythmia within these cases. SETTING: Suspected proarrhythmia cases were referred by cardiologists across England between 2003 and 2011. Information on demography, symptoms, prior medical and drug histories and data from hospital notes were collected. PARTICIPANTS: Two expert cardiologists reviewed data for 293 referred cases: 130 were included. Inclusion criteria were new onset or exacerbation of pre-existing ventricular arrhythmias, QTc >500 ms, QTc >450 ms (men) or >470 ms (women) with cardiac syncope, all secondary to drug administration. Exclusion criteria were acute ischaemia and ischaemic polymorphic ventricular tachycardia at presentation, structural heart disease, consent withdrawn or deceased prior to study. Descriptive analysis of Caucasian cases (95% of included cases, n=124) and culpable drug exposures was performed. RESULTS: Of the 124 Caucasian cases, 95 (77%) were QTc interval prolongation-related; mean age was 62 years (SD 15), and 63% were female. Cardiovascular comorbidities included hypertension (53%) and patient-reported 'heart rhythm problems' (73%). Family history of sudden death (36%) and hypokalaemia at presentation (27%) were common. 165 culpable drug exposures were reported, including antiarrhythmics (42%), of which amiodarone and flecainide were the most common. Sotalol, a beta-blocking agent with antiarrhythmic activity, was also common (15%). 26% reported multiple drugs, of which 84% reported at least one cytochrome (CYP) P450 inhibitor. Potential pharmacodynamics interactions identified were mainly QT prolongation (59%). CONCLUSIONS: Antiarrhythmics, non-cardiac drugs and drug combinations were found to be culpable in a large cohort of 124 clinically validated proarrhythmia cases. Potential clinical factors that may warn the prescriber of potential proarrhythmia include older women, underlying cardiovascular comorbidity, family history of sudden death and hypokalaemia.

Serious skin reactions and selective COX-2 inhibitors: a case series from prescription-event monitoring in England.

BACKGROUND: The erythema multiforme (EM) spectrum of bullous eruptions (toxic epidermal necrolysis [TEN] and Stevens-Johnson syndrome [SJS]) are rare and serious skin reactions that have been reported for cyclo-oxygenase (COX)-2 selective inhibitors. Our objectives were to identify and describe cases of serious skin reactions reported during postmarketing studies of COX-2 selective inhibitors. METHODS: A retrospective review of information from reports of serious skin reactions reported during prescription-event monitoring (PEM) studies of rofecoxib, celecoxib, etoricoxib and valdecoxib conducted in England since 1999. Exposure data were derived from dispensed prescriptions written by primary care physicians for each study drug. Outcome data were derived from questionnaires posted to prescribers at least 9 months after the date of the first prescription for each patient (valdecoxib data collection ongoing at the time of this study). Reports of EM, exfoliative dermatitis, SJS, TEN and symptoms associated with EM (EM syndrome) were identified from the PEM database. Additional data on diagnosis, relevant risk factors and management were requested for each case from the prescriber. A causality assessment was undertaken by a Drug Safety Research Unit research fellow and referred for expert review to a consultant dermatologist. RESULTS: Nine cases of serious skin reactions and two cases of symptoms associated with EM (EM syndrome) were identified. No reports of TEN were recorded. Six skin reaction questionnaires were returned. Of the nine cases of serious skin reactions, four cases (all SJS; one for each COX-2 selective inhibitor studied) were assessed as possibly related to use of the study drug (for combined cohorts: incidence risk 0.008%, 4 of 52,644 patients; rate 0.019 per 1000 patient-months of treatment). These four cases (two male, two female; age range 54-64 years) occurred within 2 weeks of starting treatment; the patient prescribed rofecoxib had reported risk factors (history of allergy, adverse reaction [asthma] to ibuprofen). The two cases from the EM syndrome search (one female, 35 years; one male, 80 years) occurred within 2 weeks of starting treatment; both were assessed as possibly related to use of celecoxib but considered suggestive of angio-oedema/urticaria and hypersensitivity reactions. CONCLUSIONS: This case series provides useful and complementary information to other published studies about serious skin reactions reported during treatment with COX-2 selective inhibitors. The crude incidence of cases of SJS possibly related to the use of a COX-2 selective inhibitor in this case series is very low (0.008% for all four cohorts combined). Prescribers and patients should be aware of the severe and life-threatening risk of EM potentially associated with NSAIDs, including COX-2 selective inhibitors.

Comparison of the risk of drowsiness and sedation between levocetirizine and desloratadine: a prescription-event monitoring study in England.

BACKGROUND AND OBJECTIVES: Desloratadine and levocetirizine are histamine H(1) receptor antagonists (antihistamines) that were launched in the UK in 2001. Our objective was to compare the frequency with which drowsiness and sedation were reported for desloratadine and levocetirizine within the first 30 days of observation, as monitored using the observational cohort technique of prescription-event monitoring (PEM). METHODS: Exposure data were derived from dispensed prescriptions written by primary care physicians and outcome data were derived from questionnaires that were posted to prescribers at least 6 months after the date of the first prescription for each patient. The odds ratio (OR) was calculated using unconditional logistic regression modelling. The effect of age, sex, reported prescribing indication (allergic rhinitis with asthma/wheezing, allergic rhinitis without asthma/wheezing, 'other'), pattern of use and reported previous antihistamine use on the OR was examined. A time-to-event analysis was performed. RESULTS: The cohorts comprised >24,000 patients in total. Cohort demographics were similar (both cohorts: median age 37 years; 60% women); the most frequently reported prescribing indication for both drugs was allergic rhinitis without asthma/wheezing (54%). The incidence of first reports of drowsiness/sedation for levocetirizine or desloratadine was low (46 [0.37%] and 9 [0.08%], respectively) and statistically different (p < 0.0001). These events tended to occur earlier for desloratadine than levocetirizine (50% at 7 or 14 days of observation, respectively; p = 0.6487), but the cumulative time to event differed, with more events observed for levocetirizine than expected (p < 0.0001; 46 vs 28.09). The final estimates of risk were the sex-adjusted ORs for each prescribing indication category: allergic rhinitis with asthma/wheezing (3.51; 95% CI 0.71, 17.43; n = 3357), allergic rhinitis without asthma/wheezing (6.75; 95% CI 2.37, 19.22; n = 12,627) and 'other' (3.11; 95% CI 0.86, 11.31; n = 6725). DISCUSSION: Although the reporting rates of drowsiness and sedation are low for both drugs, patients prescribed levocetirizine are more likely to experience drowsiness and sedation in the first month of observation (after starting treatment) than patients prescribed desloratadine. For patients with allergic rhinitis without asthma/wheezing, the sex-adjusted odds of drowsiness/sedation were over six times greater in patients using levocetirizine than desloratadine in the first month of observation, with the OR being statistically significant. For the other two indication categories, allergic rhinitis with asthma/wheezing and 'other', the OR was not statistically significant. CONCLUSIONS: Although the risk of drowsiness/sedation is low, conditions such as allergic rhinitis are common, which makes any impact on patient cognitive function important. Doctors should be aware of this when prescribing these products to patients where daytime sedation is undesirable. However, essential components of the comparative benefit-risk evaluation of these two products include assessment of efficacy and patient preference (neither of which forms part of this study).

Utilisation and Tolerability of Aliskiren in the Primary Care Setting in England.

Aliskiren (Rasilez), a direct renin inhibitor, is indicated for the treatment of essential hypertension. A postmarketing prescription-event monitoring (PEM) study was conducted in England to monitor the safety and utilization of aliskiren. Summary statistics and event incidence densities were calculated. The cohort consisted of 6385 individuals with a median age of 68 years (interquartile range, 59-76). Aliskiren was largely prescribed for its licensed indication of hypertension (93.3%) and was reported as "effective" by the prescriber in 77.4% of individuals. Frequently reported clinical events during treatment were diarrhea (3.1% of on-treatment events), malaise/lassitude (3.0%), and nausea/vomiting (1.2%), which were also common reasons for treatment cessation. Renal events were rare, with 24 cases probably or possibly related to aliskiren use, and four of which were classified as acute renal failure using RIFLE (Risk Injury Failure Loss End-Stage Kidney Disease) criteria. These results should be used in conjunction with other clinical and pharmacoepidemiologic studies to optimize the safe prescribing of aliskiren.

Safety of Intranasal Quadrivalent Live Attenuated Influenza Vaccine (QLAIV) in Children and Adolescents: A Pilot Prospective Cohort Study in England.

INTRODUCTION: Fluenz Tetra is an intranasal quadrivalent live attenuated influenza vaccine (QLAIV) and is recommended as the vaccine of choice for children in the 2014/2015 influenza season vaccination programme in the UK. OBJECTIVE: The primary objective of the study was to estimate the crude incidence rate of adverse events of interest (AEIs) following vaccination with the nasal QLAIV early in the 2014/2015 influenza season in children and adolescents in England. METHODS: A pilot non-interventional cohort post-authorisation safety study (PASS) was conducted during the 2014/2015 influenza season in England. Vaccinees were recruited via the mass vaccination programme in England. Participant outcomes, validated by a healthcare professional (general practitioner) where appropriate, were captured through questionnaires (surface mail, telephone, e-questionnaire). Data analysis comprised descriptive statistics and calculation of event risks and incidence rates, stratified by age group and selected co-morbidities. RESULTS: The final evaluable cohort consisted of 385 participants; the median (interquartile range) age was 4 (3-9) years with a range of 2-17 years, and 53.2 % were female. The most frequently reported AEI was nasal congestion (n = 167; 43.4 %; 312.3 per 1000 patient-weeks [95 % CI 267.3-364.8]). Further frequently reported AEIs were malaise (n = 87; 22.6 %; 123.4 per 1000 patient-weeks [95 % CI 98.9-154.1]) and cough (n = 80; 20.8 %; 118.5 per 1000 patient-weeks [95 % CI 95.1-147.8]). Five hypersensitivity-type reactions were reported, although on follow-up none were true hypersensitivity reactions or required hospitalisation. No serious adverse events (SAEs) were reported, with no hospitalisations or deaths. No significant change in reactogenicity or other apparent safety signals was detected as part of this study. CONCLUSION: The pilot study showed no significant change in reactogenicity or other apparent safety signals from the data collected. Continued enhanced surveillance of seasonal influenza vaccines will ensure their ongoing safety for the prevention of serious illness from seasonal influenza outbreaks.