Lorna Hazell

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.

Adverse drug reaction reporting in the UK: a retrospective observational comparison of yellow card reports submitted by patients and healthcare professionals.

AbstractBackground: In the UK, spontaneous reporting of suspected adverse drug reactions (ADRs) by healthcare professionals has been in operation since 1964 through the Yellow Card Scheme (YCS). From 2005, patients themselves have been able to submit Yellow Card reports. Objective: To compare patient characteristics, suspected drugs and suspected ADRs reported by patients with those reported by healthcare professionals using the YCS. Design and Setting: Retrospective observational study in the UK. Methods: Participants were patients reported to the Medicines and Healthcare products Regulatory Agency (MHRA), either by themselves, a representative or a healthcare professional, as having one or more suspected ADRs between October 2005 and September 2007. The main outcome measures were ADRs and time taken to report. Results: In total, 26 129 Yellow Card reports from patients and healthcare professionals were received from the MHRA for the 2-year study period (19.8% patient and 80.2% healthcare professional). More Yellow Card reports were made for female than male patients (p < 0.001). Patients reported a significantly higher number of suspected ADRs per report than healthcare professionals (median [interquartile range IQR] of 3 [2–5] vs 2 [1–3], respectively; p<0.001). A higher proportion of patient reports (16.1%) contained more than one suspect drug than healthcare professional reports (9%; p < 0.001). Healthcare professional reports had a higher proportion of ADRs that caused hospitalization (18.8% vs 12.9%), were life threatening (11.1% vs 6.2%) or caused death (2.6% vs 0.7%) than patient reports (all p<0.001). Patient reporters took a significantly longer time to report their reaction than healthcare professionals (median [IQR] of 104 [27–463] vs 28 [13–75] days respectively; p<0.001). Direct comparisons of the seriousness of the ADRs were not possible because of important differences between patient and healthcare professional versions of the Yellow Cards. Conclusions: This is the first substantial, published study in the UK to compare Yellow Card reports from patients and healthcare professionals. Whilst patients report more suspected ADRs to more suspect drugs than healthcare professionals, healthcare professionals tend to report more serious reactions that result in hospitalization, are life threatening or cause death. Further research is required to investigate the extent to which the extra information from patient reporters contributes to signal identification when assessing drug safety.

The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: systematic review and meta-analysis of published observational studies

BackgroundPatients with type 2 diabetes mellitus (T2DM) are at high risk of heart failure. A summary of the effects of blood glucose-lowering drugs other than glitazones on the risk of heart failure in routine clinical practice is lacking. The objective of this study was to conduct a systematic review and meta-analysis of observational studies on the risk of heart failure when using blood glucose-lowering drugs.MethodsWe systematically identified and reviewed cohort and case–control studies in which the main exposure of interest was noninsulin blood glucose-lowering medications in patients with T2DM. We searched Medline, Embase, and the Cochrane Library to identify publications meeting prespecified eligibility criteria. The quality of included studies was assessed with the Newcastle-Ottawa Scale and the RTI item bank. Results were combined using fixed and random-effects models when at least 3 independent data points were available for a drug-drug comparison.ResultsThe summary relative risk of heart failure in rosiglitazone users versus pioglitazone users (95% CI) was 1.16 (1.05-1.28) (5 cohort studies). Heterogeneity was present (I2 = 66%). For new users (n = 4) the summary relative risk was 1.21 (1.14-1.30) and the heterogeneity was reduced (I2 = 31%);. The summary relative risk for rosiglitazone versus metformin was 1.36 (95% CI, 1.17-1.59) (n = 3). The summary relative risk (95% CI) of heart failure in sulfonylureas users versus metformin users was 1.17 (95% CI, 1.06-1.29) (5 cohort studies; I2 = 24%) and 1.22 (1.02-1.46) when restricted to new users (2 studies).Information on other comparisons was very scarce. Information on dose and duration of treatment effects was lacking for most comparisons. Few studies accounted for disease severity; therefore, confounding by indication might be present in the majority of the within-study comparisons of this meta-analysis.ConclusionsUse of glitazones and sulfonylureas was associated with an increased risk of heart failure compared with metformin use. However, indication bias cannot be ruled out. Ongoing large multidatabase studies will help to evaluate the risk of heart failure in treated patients with diabetes, including those using newer blood glucose-lowering therapies.

Modified Prescription-Event Monitoring Studies

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 product’s 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.

The safety profile of tadalafil as prescribed in general practice in England: results from a prescription‐event monitoring study involving 16 129 patients

To examine the safety of tadalafil as used in general practice in England, and to compare the mortality rate due to ischaemic heart disease (IHD) in tadalafil users with that in the male population in England.

An observational cohort study investigating the cardiovascular safety of tadalafil when prescribed in primary care in England: mortality due to ischaemic heart disease

To examine the cardiovascular safety of tadalafil, a phosphodiesterase type‐5 inhibitor used for treating erectile dysfunction in patients prescribed this drug by general practitioners (GPs) in England in 2003, focusing on mortality due to ischaemic heart disease (IHD).

Evidence for the hERG Liability of Antihistamines, Antipsychotics, and Anti-Infective Agents: A Systematic Literature Review From the ARITMO Project

A systematic review was performed to categorize the hERG (human ether‐a‐go‐go–related gene) liability of antihistamines, antipsychotics, and anti‐infectives and to compare it with current clinical risk of torsade de pointes (TdP). Eligible studies were hERG assays reporting half‐minimal inhibitory concentrations (IC50). A “hERG safety margin” was calculated from the IC50 divided by the peak human plasma concentration (free Cmax). A margin below 30 defined hERG liability. Each drug was assigned an “uncertainty score” based on volume, consistency, precision, and internal and external validity of evidence. The hERG liability was compared to existing knowledge on TdP risk (www.credibledrugs.org). Of 1828 studies, 82 were eligible, allowing calculation of safety margins for 61 drugs. Thirty‐one drugs (51%) had evidence of hERG liability including 6 with no previous mention of TdP risk (eg, desloratadine, lopinavir). Conversely, 16 drugs (26%) had no evidence of hERG liability including 6 with known, or at least conditional or possible, TdP risk (eg, chlorpromazine, sulpiride). The main sources of uncertainty were the validity of the experimental conditions used (antihistamines and antipsychotics) and nonuse of reference compounds (anti‐infectives). In summary, hERG liability was categorized for 3 widely used drug classes, incorporating a qualitative assessment of the strength of available evidence. Some concordance with TdP risk was observed, although several drugs had hERG liability without evidence of clinical risk and vice versa. This may be due to gaps in clinical evidence, limitations of hERG/Cmax data, or other patient/drug‐specific factors that contribute to real‐life TdP risk.

Drug utilization of Intrinsa (testosterone patch) in England: interim analysis of a prescription-event monitoring study to support risk management.

AbstractBackground: 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.

Should methods of correction for multiple comparisons be applied in pharmacovigilance? Reasoning around an investigation on safety of oral antidiabetic drugs

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 r FDR 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 r FDR 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.