The UK BIO-TRAC Study: a cross-sectional study of product and batch traceability for biologics in clinical practice and electronic adverse drug reaction reporting in the UK

Introduction: Due to the complexity of biologics and the inherent challenges for manufacturing, it is important to know the specific brand name and batch number of suspected biologics in adverse drug reaction (ADR) reports. Objective: The aim of this study was to assess the extent to which biologics are traceable by brand name and batch number in UK hospital practice and in ADRs reported by patients and healthcare professionals. Methods: We performed an online hospital pharmacist survey to capture information on how specific product details are recorded during the processes of prescribing, dispensing and administration of biologics in routine UK hospital practice. We also assessed the proportion of ADR reports specifying brand name and batch number from electronic ADR reports submitted to the UK national spontaneous reporting database, the Yellow Card Scheme, between 1 January 2009 and 30 September 2017. Results: Brand name recording in routine hospital processes ranged from 79 to 91%, whereas batch numbers were less routinely recorded, ranging from 38 to 58%. Paper-based recording of product details was more commonly used for recording information. A total of 6108 electronic ADR reports were submitted to the Yellow Card Scheme for recombinant biologics, of which 38% and 15%, respectively, had an identifiable brand name and batch numbers. Whereas batch number traceability in electronic ADR reports improved slightly after the implementation of the European Union pharmacovigilance legislation in 2012, no improvement of brand name traceability was observed. Conclusion: Brand name and batch number traceability for biologics in UK ADR reports are generally low. Shortcomings in the systematic recording of product details in UK clinical practice may contribute to the limited traceability.</p

Should methods of correction for multiple comparisons be applied in pharmacovigilance?

Purpose. In pharmacovigilance, spontaneous reporting databases are devoted to the early detection of adverse event ‘signals’ of marketed drugs. A common limitation of these systems is the wide number of concurrently investigated associations, implying a high probability of generating positive signals simply by chance. However it is not clear if the application of methods aimed to adjust for the multiple testing problems are needed when at least some of the drug-outcome relationship under study are known. To this aim we applied a robust estimation method for the FDR (rFDR) particularly suitable in the pharmacovigilance context. Methods. We exploited the data available for the SAFEGUARD project to apply the rFDR estimation methods to detect potential false positive signals of adverse reactions attributable to the use of non-insulin blood glucose lowering drugs. Specifically, the number of signals generated from the conventional disproportionality measures and after the application of the rFDR adjustment method was compared. Results. Among the 311 evaluable pairs (i.e., drug-event pairs with at least one adverse event report), 106 (34%) signals were considered as significant from the conventional analysis. Among them 1 resulted in false positive signals according to rFDR method. Conclusions. The results of this study seem to suggest that when a restricted number of drug-outcome pairs is considered and warnings about some of them are known, multiple comparisons methods for recognizing false positive signals are not so useful as suggested by theoretical considerations

The Contribution of National Spontaneous Reporting Systems to Detect Signals of Torsadogenicity: Issues Emerging from the ARITMO Project

Introduction: Spontaneous reporting systems (SRSs) are pivotal for signal detection, especially for rare events with a high drug-attributable component, such as torsade de pointes (TdP). Use of different national SRSs is rarely attempted because of inherent difficulties, but should be considered on the assumption that rare events are diluted in international databases. Objective: The aim was to describe TdP-related events associated with antipsychotics, H1-antihistamines and anti-infectives in three national SRSs (in Italy, Germany and France) and highlight potential signals of torsadogenicity through a combined literature evaluation. Methods: A common search strategy was applied to extract TdP-related events: (1) TdP, (2) QT interval abnormalities, (3) ventricular fibrillation/tachycardia, and (4) sudden cardiac death. Signals of disproportionate reporting (SDRs) were calculated for TdP + QT interval abnormalities and defined by a lower limit of the 95 % confidence interval of the reporting odds ratio (ROR) >1. Among SDRs with at least three cases without concomitant pro-arrhythmic drugs, we defined potential new signal of torsadogenicity as drugs with no published evidence from (a) the crediblemeds® website (http://www.crediblemeds.com, as of November 1st, 2014); (b) studies on the FDA Adverse Event Reporting System (FAERS); and (c) safety trials or pharmaco-epidemiological studies (as of December 16th, 2014). Results: Overall, 3505 cases were retrieved (1372, 1468, and 801 for France, Germany and Italy, respectively). Antipsychotics were mainly recorded in Germany (792 cases), whereas antibiotics peaked at 515 and 491 (France and Italy, respectively). Forty-one drugs met criteria for SDRs in at least one single source, of which 31 were detected only from one single SRS: 18, ten and three (French, German and Italian SRS, respectively). By contrast, only five SDRs were detected in all national data sources (amisulpride, aripiprazole, haloperidol, olanzapine, risperidone). Overall, five potential new signals of torsadogenicity were identified: flupentixol, ganciclovir, levocetirizine, oxatomide and tiapride. Conclusions: We found differences across and within national SRSs in the reporting of drug-induced TdP, which finally resulted in five potential new signals of torsadogenicity. These findings warrant targeted pharmacovigilance studies to formally assess the existence of actual drug–event associations

Under-reporting of adverse drug reactions: A systematic review

The purpose of this review was to estimate the extent of under-reporting of adverse drug reactions (ADRs) to spontaneous reporting systems and to investigate whether there are differences between different types of ADRs. A systematic literature search was carried out to identify studies providing a numerical estimate of under-reporting. Studies were included regardless of the methodology used or the setting, e.g. hospital versus general practice. Estimates of under-reporting were either extracted directly from the published study or calculated from the study data. These were expressed as the percentage of ADRs detected from intensive data collection that were not reported to the relevant local, regional or national spontaneous reporting systems. The median under-reporting rate was calculated across all studies and within subcategories of studies using different methods or settings. In total, 37 studies using a wide variety of surveillance methods were identified from 12 countries. These generated 43 numerical estimates of under-reporting. The median under-reporting rate across the 37 studies was 94% (interquartile range 82-98%). There was no significant difference in the median under-reporting rates calculated for general practice and hospital-based studies. Five of the ten general practice studies provided evidence of a higher median under-reporting rate for all ADRs compared with more serious or severe ADRs (95% and 80%, respectively). In comparison, for five of the eight hospital-based studies the median under-reporting rate for more serious or severe ADRs remained high (95%). The median under-reporting rate was lower for 19 studies investigating specific serious/severe ADR-drug combinations but was still high at 85%. This systematic review provides evidence of significant and widespread under-reporting of ADRs to spontaneous reporting systems including serious or severe ADRs. Further work is required to assess the impact of under-reporting on public health decisions and the effects of initiatives to improve reporting such as internet reporting, pharmacist/nurse reporting and direct patient reporting as well as improved education and training of healthcare professionals.</p

Modified prescription-event monitoring studies: A tool for pharmacovigilance and risk management

Prescription-Event Monitoring (PEM) is a well established postmarketing surveillance technique designed to monitor the overall safety of newly marketed medicines as used in real-life clinical practice, usually in cohorts of at least 10000 patients.At the Drug Safety Research Unit in the UK we are now moving towards a more targeted safety surveillance known as Modified PEM (M-PEM). These studies combine the advantages of conventional PEM studies (in monitoring general safety and identification of unexpected risks of a medicine) with that of a more targeted safety study that addresses specific questions (to better understand known or partially known risks with a medicine). Through the use of enhanced data collection questionnaires, M-PEM expands the range of applications of conventional PEM, which include more detailed characterization of real-life drug use, adherence to prescribing recommendations and targeted analysis of events requiring special monitoring by regulatory authorities. A particularly useful application is the evaluation of the safety of a medicine in special populations or subgroups (e.g. patients switching from another therapy or patients with a particular risk factor) or following important changes in the products lifecycle (e.g. a licensing or formulation change). M-PEM studies therefore have an important contribution to make to pharmacovigilance and the risk management of medicines by providing valuable information on the use of new medications under real-life situations.</p

Analysis and reporting of adverse events in randomised controlled trials: a review.

Phillips R, Hazell L, Sauzet O, Cornelius V. Analysis and reporting of adverse events in randomised controlled trials: a review. BMJ open. 2019;9(2): e024537.OBJECTIVE: To ascertain contemporary approaches to the collection, reporting and analysis of adverse events (AEs) in randomised controlled trials (RCTs) with a primary efficacy outcome.; DESIGN: A review of clinical trials of drug interventions from four high impact medical journals.; DATA SOURCES: Electronic contents table of the BMJ, the Journal of the American Medical Association (JAMA), the Lancet and the New England Journal of Medicine (NEJM) were searched for reports of original RCTs published between September 2015 and September 2016.; METHODS: A prepiloted checklist was used and single data extraction was performed by three reviewers with independent check of a randomly sampled subset to verify quality. We extracted data on collection methods, assessment of severity and causality, reporting criteria, analysis methods and presentation of AE data.; RESULTS: We identified 184 eligible reports (BMJ n=3; JAMA n=38, Lancet n=62 and NEJM n=81). Sixty-two per cent reported some form of spontaneous AE collection but only 29% included details of specific prompts used to ascertain AE data. Numbers that withdrew from the trial were well reported (80%), however only 35% of these reported whether withdrawals were due to AEs. Results presented and analysis performed was predominantly on 'patients with at least one event' with 84% of studies ignoring repeated events. Despite a lack of power to undertake formal hypothesis testing, 47% performed such tests for binary outcomes.; CONCLUSIONS: This review highlighted that the collection, reporting and analysis of AE data in clinical trials is inconsistent and RCTs as a source of safety data are underused. Areas to improve include reducing information loss when analysing at patient level and inappropriate practice of underpowered multiple hypothesis testing. Implementation of standard reporting practices could enable a more accurate synthesis of safety data and development of guidance for statistical methodology to assess causality of AEs could facilitate better statistical practice. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ

Drug utilization of intrinsa® (testosterone patch) in England: Interim analysis of a prescription-event monitoring study to support risk management

Background: Intrinsa® is a transdermal testosterone patch that is indicated for use in hypoactive sexual desire disorder (HSDD) in women who have undergone bilateral oophorectomy and hysterectomy (surgically-induced menopause) receiving concomitant oestrogen therapy. Objective: To describe the utilization characteristics of the patients prescribed testosterone patch (Intrinsa®) based on an interim analysis of an ongoing Prescription-Event Monitoring study in England, and to assess, where possible, if the product is being used within the licensed therapeutic indication. Methods: In this interim analysis, patients were identified from dispensed prescriptions that had been issued by general practitioners (GPs) for Intrinsa ® from March 2007. 'Green form' questionnaires were sent to GPs 6 months following the date of the first prescription for Intrinsa® for each individual patient, requesting information including age, sex, start and stop dates of treatment (if stopped), prescribing indication and reasons for stopping. Additional questions were asked regarding the patient's menopausal status and use of concomitant oestrogen therapy. Results: The interim cohort consisted of 756 patients. The majority of patients were reported to be female (746 [98.7%]) with a median (interquartile range) age of 50 years (44-55 years). The most commonly reported indication was the licensed indication of HSDD in 580 patients (76.7%). Just under one-half of the patients (n = 364 [48.1%]) were reported to have been hysterectomized and bilaterally oophorectomized (surgically-induced menopause) prior to starting Intrinsa®; 127 patients (16.8%) were naturally menopausal. For 222 patients (29.4%) the GP specified that the patient was not using concomitant oestrogen therapy. Overall, only 219 patients (29.0%) in the cohort were being prescribed Intrinsa® according to the manufacturer's recommendations. Conclusions: This study has highlighted that some clinicians are prescribing this product outside the recommended terms of the licence, with less than 30% of patients receiving Intrinsa® according to prescribing guidelines. All events experienced by these patients will be analysed to detect any possible adverse events from using Intrinsa® outside of the licensed therapeutic indication. The findings support the ongoing postmarketing risk management of the product.</p

How do patients contribute to signal detection? : A retrospective analysis of spontaneous reporting of adverse drug reactions in the UK's Yellow Card Scheme

Background: In 2005, spontaneous reporting of adverse drug reactions (ADRs) to the UK's Yellow Card Scheme (YCS) was extended to include patient reports. Here, we investigate the potential pharmacovigilance impact of patient reporting. Objectives: The aim of the study was to investigate the relative contribution of patient reporting to signal detection through disproportionality analysis. Methods: Data were analysed from all reports submitted directly to the YCS between October 2005 and September 2007. Three datasets of drug-ADR pairs were created: one for patient reports, one for healthcare professional (HCP) reports and one for all reports combined. The proportional reporting ratio (PRR) method was used to identify signals of disproportionate reporting (SDRs) in each dataset. The number of SDRs identified from patient and HCP reports were compared, as well as the type of ADR and suspect drug involved. A sensitivity analysis was performed to examine how combining the patient and HCP reports may affect the SDRs identified. Results: Data were received for 5,180 patient and 20,949 HCP reports, relating to 16,566 and 28,775 drug-ADR pairs, respectively, with 4,340 (10.6 %) pairs found in both datasets. A significantly higher proportion of the SDRs identified from HCP reports involved reactions classified as serious by the Medicines and Healthcare products Regulatory Agency (MHRA), compared with patient reports (n = 931, 48.0 % vs. n = 185, 28.5 %), or involved newly marketed drugs (n = 596, 30.7 % vs. n = 71, 10.9 %). The proportion of SDRs assessed as not listed on the Summary of Product Characteristics (SPC) was similar in each group (~15 %, based on a random sample). After combining the patient and HCP reports, 278 (~11 %) of the SDRs identified when each group was analysed separately no longer met the SDR criteria, including 12 potentially serious ADRs not listed on the product's SPC. On the other hand, the combined dataset identified an additional 508 SDRs that were not identified when patient or HCP reports were analysed separately. Approximately 10 % (n = 47) of these additional SDRs were assessed as serious ADRs and were not listed on the product's SPC. Conclusions: Although this study is limited to the UK experience, overall, the results suggest that patient reporting may provide a positive complementary contribution to that of HCPs. Patient reporting may make an important contribution to drug safety by identifying different SDRs not identified from HCP reports alone. The combination of reports from patients and HCPs, however, when used for the purposes of signal detection through disproportionality analysis, may result in the loss of some information. One possible strategy is to conduct such analyses using reports from patients and HCPs combined, as well as separately for each group.</p