Drug Safety Research Unit Research Articles

The International Working Group on New Developments in Pharmacovigilance: Advancing Methods and Communication in Pharmacovigilance

In 2019, the International Working Group (IWG), focusing on New Developments in Pharmacovigilance, was established. This group is coordinated by the Drug Safety Research Unit in the United Kingdom, and the mission of the IWG is to progress pharmacovigilance methodologies and promote the safe and effective use of medicines and vaccines, thereby further protecting patients. Novel therapeutics are continuously being developed to alleviate medical conditions, but with advancing technologies, innovative pharmacovigilance methodologies need to be developed to effectively monitor the use and safety of these products. With reduced timelines proposed for premarketing clinical trials and increased application of real-world evidence supporting regulatory approvals, products may be used in real-world clinical practice in shorter timeframes than before. Therefore, the need for effective methods of monitoring medicines and collecting safety data in real-time is of paramount importance to public health. The IWG aims to advance existing methodologies used in the detection, monitoring, and analysis of safety data in pharmacovigilance and to communicate best practice proposals to support decision making in health care. The IWG will identify areas requiring review of current processes or methodologic research and will communicate the output of the IWG through peer-reviewed publications, reports, and presentation of findings at relevant conferences and scientific meetings. The IWG is currently reviewing two areas in pharmacovigilance; case-level causality assessment and the strengths and limitations of data sources. The IWG is advancing these areas by producing two scoping reviews which will be easily accessible to regulatory agencies, industry, academia, and interested persons or organizations. The scoping reviews comply with the IWGs mission to progress pharmacovigilance methodologies and promote the safe and effective use of medicines and vaccines. The present article shares details of the objectives of the IWG and provides an overview on the status of IWG activities.

J Guy Edwards, FRCPsych, FRCP, FRCGP (Hon), DPM, HonMFPH, Founding Editor of Human Psychopharmacology.

J Guy Edwards, FRCPsych, FRCP, FRCGP (Hon), DPM, HonMFPH, Founding Editor of Human Psychopharmacology.

Brexit means Brexit, but what of pharmacovigilance?

While uncertainty remains over exactly how the UK's exit from the European Union will pan out, there is little doubt that there will be disruption, at least in the short term, for the pharmaceutical industry. Issues surrounding the potential implications of Brexit for the medicines regulatory system, and for pharmacovigilance in particular, were discussed at a recent meeting in London, organised by the Drug Safety Research Unit. Steve Titmarsh reports.

Ron Mann

Professor Dr Ronald Mann, the founding editor of Pharmacoepidemiology and Drug Safety, died on 19 November 2013 from cardiorenal failure. Ron, as he was universally known, spent a professional lifetime in a quest to improve the scientific quality of drug safety data by the application of epidemiological principles, which he helped formulate. The quality and present standing of this journal in the field bear ample testimony to the success of his efforts. Following graduation in medicine, Ron trained as a physician. He spent 6 years in general practice, developing skills particularly in obstetrics, before joining the pharmaceutical industry, where he was to spend 19 years in the UK, Japan, Hong Kong, the USA and Belgium. It was in this role that he first became aware of the inadequacies of then current practices in drug safety in industry and clinical medicine and so it was a logical move for him to join the Division of Medicines of the UK Department of Health as a Medical Assessor, where his remit was to improve the system of adverse reaction reporting. He was later to describe his frustration at his inability to handle what are now known as large databases relating to drug safety, but adequate technology was not yet available. Ron became the Head of Drug Safety and, in his efforts to apply the methods of epidemiology to drug safety in what is now known as pharmacoepidemiology, he found a willing ally in Dr Sue Wood, who was to succeed him at the Medicines Control Agency (MCA). At this time, controversy about the safety of oral contraceptive steroids was becoming a major issue, and much of their work was devoted to understanding the public health implications of their use. After a spell as Medical Secretary of the Royal Society of Medicine (where he was able to indulge his other passion, the history of therapeutics), Ron moved to the University of Southampton, succeeding Dr Bill Inman as Director of the Drug Safety Research Unit (DSRU), where the technique of prescription event monitoring (PEM) had been pioneered and which Ron developed greatly. Under his guidance, PEM took its place with spontaneous adverse reaction reporting as a powerful tool in what is now known as passive surveillance of drug safety. One of Ron's greatest strengths was as a communicator, and it was in this vein that he created this journal, which he entitled Pharmacoepidemiology and Drug Safety, embodying the two disciplines which he believed were inseparable. He was also a prolific writer; his two major books, Modern Drug Use (1984), of which he was the sole author, and Drug Safety (1992), the multi-author book, of which he was the founding editor, are both standard textbooks in the field. But as well as Ron's huge scientific achievements, it is also as a delightful colleague that we will remember him. His kindness and helpfulness to junior colleagues at the MCA and the DSRU are legion. Our friendship with Ron developed when we were both members of the Committee on Safety of Medicines, and to listen to his reminiscences of a long and varied career lightened many afternoons at Market Towers. As a medical student at Westminster Hospital Medical School, he was awarded the King's Scholarship, which had been established by the late King George VI. In this role, we understand that Ron's main duty was to accompany the King, annually, to a service in St George's Chapel and to find the appropriate place in the King's hymnal during the proceedings. While assisting, as a trainee physician, in a cisternal puncture in a patient with tuberculous meningitis, the glass syringe broke, showering Ron with tuberculous pus, from which he contracted pulmonary tuberculosis. After treatment with streptomycin and 2 years of bed rest at King Edward VII Hospital in Midhurst, West Sussex, he recovered, but he recalled to us that these 2 years in bed were the worst of his life. Ron Mann was one of the people who made a real difference. We salute his contributions to drug safety and to the public health, we thank him for the advice and guidance he gave us and we are grateful for being able to call him our friend.

Neuropsychiatric Events with Varenicline: a Modified Prescription-Event Monitoring Study in General Practice in England

Varenicline (Champix(®)), launched in the UK in December 2006, is indicated for the treatment of smoking cessation in adults (≥18years of age). In 2008, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK issued a warning suggesting that varenicline was associated with disparate neuropsychiatric symptoms, including depression, suicidal thoughts and behaviour. In response to this regulatory warning, the Drug Safety Research Unit conducted a modified prescription-event monitoring (M-PEM) study to monitor the safety of varenicline. The aim of this study was to estimate the incidence and examine the pattern of neuropsychiatric events reported to general practitioners (GPs) in England during the immediate postmarketing period for varenicline. A postmarketing surveillance study was conducted using the observational cohort technique of M-PEM. Patients were identified from dispensed prescriptions issued by primary care physicians between December 2006 and March 2007. Data on exposure, previous history of psychiatric illness and events reported during and after treatment were collected from questionnaires. In order to determine whether hazards for neuropsychiatric events of interest (depression, anxiety, aggression, suicidal ideation, non-fatal self-harm) were non-constant over time (which could indicate a possible association with the drug), the pattern of events was examined by plotting the smoothed hazard function estimate and then fitting a Weibull model. The Weibull model shape parameter (β) and 95% confidence interval were used as a test for a non-constant hazard function (where a value of 1 indicates a constant hazard over time). In addition to this analysis, the difference in incidence densities (IDs) between month 1 and months 2-3 were calculated and compared. The cohort comprised of 12,159 patients (median age 47years [interquartile range 19]; 56.9% [n=6924 female]). The number of events reported during treatment, reason for stopping, adverse drug reactions (ADRs), and the p-value for the Weibull shape parameter were as follows: depression (n=94; 42; 19; p=0.144); anxiety (n=94; 49; 9; p=0.009); aggression (n=7; 4; 2; p=0.465); suicidal ideation (n=8; 4; 1; p=0.989) and non-fatal self-harm (n=5; 1; 0; p=0.771). No differences in the IDs between months 1 and months 2-3 were found for any of the events. Whilst between 7 and 17% of neuropsychiatric events were attributed to the drug by GPs and approximately 20-50% were given as reasons for stopping, no signal was raised using the ID differences approach, and only anxiety was flagged as a potential signal for an ADR using the Weibull model. The signal for anxiety requires further evaluation to determine whether the drug plays a part in the development of anxiety or whether it is a withdrawal symptom caused by smoking cessation. Analysis methods will lack power when the numbers of events are low even when a large number of participants are included in the study.

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 10 000 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.

New Postgraduate Qualifications in Pharmacovigilance from the Drug Safety Research Unit in the UK

The Drug Safety Research Unit in the UK has recently launched new postgraduate certificate, diploma and masters courses in pharmacovigilance, in association with the University of Portsmouth. These courses have been developed to address the continuing demand for quality accredited education in pharmacovigilance and are aimed particularly at drug safety staff working in the pharmaceutical industry, regulatory bodies or academia. Flexibility is ensured by the availability of a wide choice of units, the use of online facilities for learning and assessment, and the possibility that previous relevant training or experience may be counted towards the awards.

Hypoglycaemia with pioglitazone: analysis of data from the Prescription‐Event Monitoring study

To investigate the relationship between patients' characteristics, use of concomitant anti-diabetic therapies and the incidence of hypoglycaemia, an acute complication of the treatment of diabetes mellitus reported by general practitioners (GPs) during the first 9 months of the treatment with pioglitazone. We used data collected for the Prescription-Event Monitoring (PEM) study conducted by the Drug Safety Research Unit for patients prescribed pioglitazone between November 2000 and June 2001 by their GP in England. A Cox proportional-hazards regression model was used to assess this relationship. The original pioglitazone PEM cohort included 12,772 patients (mean age 60.9 years); 53% (6777) were male. A total of 77 patients experienced at least one hypoglycaemic episode (9.64 per 1000 patient-years). Women were estimated to have twice the hazard of having a hypoglycaemic event compared with men [hazard ratio (HR) 2.05; confidence interval (CI) 1.24, 3.41]. Patients taking combination therapy with sulfonylurea or insulin were estimated to have approximately three and four times the hazard of having an event compared with those who were not taking these adjunctive therapies [HR=3.11 (CI 1.64, 5.88); HR=4.15 (CI 1.74, 9.91), respectively]. Patients treated with adjunctive metformin were 25% less likely to experience hypoglycaemia than those who did not take concomitant metformin (HR=0.75; CI 0.44, 1.27). This study has shown that the treatment with pioglitazone was associated with a low incidence of hypoglycaemia. The factors possibly increasing the risk of hypoglycaemia were concomitant therapy with sulfonylurea or insulin and female gender.

Ron Mann's scientific contributions as the second Director of the DSRU

Ron Mann became the second Director of the Drug Safety Research Unit (DSRU) in 1994. His task as the successor to Bill Inman, the charismatic founder and first Director of the Unit, could not have been easy at the outset. However, Ron came to the DSRU armed with many years of experience as a clinician, senior pharmaceutical physician and head of pharmacovigilance at the Medicines Division at the Department of Health (which later became the MCA and now the MHRA), and thus possessed both the scientific credentials as well as the networking and political skills to enable him to carry out the job. While his relatively short period from 1994 to 1999 at the DSRU was affected by health problems and the loss of his third wife, he made significant achievements in two major areas: advancing the method of Prescription-Event Monitoring (PEM) and developing collaborations with colleagues to conduct large pharmacoepidemiological studies both nationally and internationally. Copyright © 2010 John Wiley & Sons, Ltd.

Safety and Drug Utilization Profile of Varenicline as Used in General Practice in England

Varenicline tartrate (Champix), a new smoking cessation medicine, was launched in the UK in December 2006. Varenicline is a highly selective partial agonist of the alpha(4)beta(2) nicotinic acetylcholine receptor (alpha(4)beta(2) receptor). The partial agonistic binding leads to alleviation of symptoms of craving and withdrawal, and simultaneously prevents nicotine from binding to the alpha(4)beta(2) receptor thereby causing reduction in the rewarding and reinforcing effects of smoking. Regulatory concerns have arisen about psychiatric events associated with varenicline, including depression, suicidal ideation and changes in behaviour/emotion. To present the interim results of an ongoing study by the Drug Safety Research Unit (DSRU) monitoring the safety of varenicline. The observational cohort study is being conducted to study the postmarketing safety of varenicline, using modified prescription-event monitoring (PEM) methodology. Patients are identified from dispensed prescriptions issued by general practitioners (GPs) from December 2006. Demographic, clinical event (during the course and 1 month after stopping varenicline, reasons for discontinuing and suspected adverse drug reactions [ADRs] to varenicline) and drug utilization data are collected from detailed study-specific questionnaires posted to GPs at least 4 months after the date of first prescription for each patient. Event incidence densities (IDs; number of first reports of an event/1000 patient-months of exposure) are calculated. The interim cohort comprises 2,682 patients: median age 47 years (interquartile range [IQR] 38-56), 60.7% females (n = 1627). Nausea/vomiting was the most frequent clinical reason for stopping varenicline (n = 91; 35.3% of clinical reasons) and the most frequently reported suspected ADR to varenicline (n = 60, 50.9% of patients for whom an ADR was reported). The most frequently reported psychiatric events (causality not implied) during treatment included (n; % of cohort): sleep disorder (43; 1.6%), anxiety (33; 1.2%), depression (29; 1.1%), abnormal dreams (26; 1.0%) and mood change (17; 0.6%). Two cases of attempted suicide were reported during treatment with varenicline (one patient took an overdose of a benzodiazepine with alcohol, the other slashed their wrist). Both these patients had previous history of psychiatric illness and precipitating factors for the event. This study reflects 'real life' use of varenicline. Nausea/vomiting - the event most frequently reported as an ADR and as reason for stopping treatment - is listed in the UK Summary of Product Characteristics (SPC). The most frequently reported psychiatric events are listed in the UK SPC. All patients with suicidal events either had a past medical history of psychiatric illness prior to starting varenicline and/or a precipitating factor for the event. Clinicians should closely monitor patients with pre-existing psychiatric illness who are taking varenicline. Further evaluation of events of interest including psychiatric events is ongoing. Results presented are expected to change as the cohort size increases. Results of this study should be taken into account together with other clinical and pharmacoepidemiological studies.

Hypoglycaemia with Pioglitazone: Analysis of data from the Prescription-Event Monitoring (PEM) study

Aims and objectives To investigate the relationship between patients’ characteristics, use of concomitant anti-diabetic therapies and the incidence of hypoglycaemia, an acute complication of the treatment of diabetes mellitus reported by general practitioners (GPs) during the first 9 months of the treatment with pioglitazone. Methods We used data collected for the Prescription-Event Monitoring (PEM) study conducted by the Drug Safety Research Unit for patients prescribed pioglitazone between November 2000 and June 2001 by their GP in England. A Cox proportional-hazards regression model was used to assess this relationship. Results The original pioglitazone PEM cohort included 12 772 patients (mean age 60.9 years); 53% (6777) were male. A total of 77 patients experienced at least one hypoglycaemic episode (9.64 per 1000 patient-years). Women were estimated to have twice the hazard of having a hypoglycaemic event compared with men [hazard ratio (HR) 2.05; confidence interval (CI) 1.24, 3.41]. Patients taking combination therapy with sulfonylurea or insulin were estimated to have approximately three and four times the hazard of having an event compared with those who were not taking these adjunctive therapies [HR = 3.11 (CI 1.64, 5.88); HR = 4.15 (CI 1.74, 9.91), respectively]. Patients treated with adjunctive metformin were 25% less likely to experience hypoglycaemia than those who did not take concomitant metformin (HR = 0.75; CI 0.44, 1.27). Conclusions This study has shown that the treatment with pioglitazone was associated with a low incidence of hypoglycaemia. The factors possibly increasing the risk of hypoglycaemia were concomitant therapy with sulfonylurea or insulin and female gender.

Exposure to Mirtazapine During Pregnancy

Mirtazapine is a novel piperazinoazepine antidepressant, unrelated to any known class of antidepressants. Currently, apart from a few case reports and case series in the literature, there are no studies evaluating the safety of this drug during pregnancy. To determine whether mirtazapine increases the risk for major malformations in newborns when used by pregnant women. The study design was prospective, with 2 comparison groups: disease-matched pregnant women diagnosed with depression taking other antidepressants and pregnant women exposed to nonteratogens. The primary outcome was major malformations in neonates; secondary endpoints included spontaneous abortions, therapeutic abortions, gestational age at birth, and mean birth weight. Women were recruited from 5 teratogen information services in Toronto, Canada; Farmington, Conn., U.S.A.; Jerusalem, Israel; Rome, Italy; Sydney, Australia; and from the Drug Safety Research Unit in Southampton, United Kingdom. Women were recruited into the study from June 2002 to August 2005. We were able to follow 104 pregnancy outcomes in each drug group. There were 77 live births, 1 stillbirth, 20 spontaneous abortions, 6 therapeutic abortions, and 2 major malformations in the mirtazapine group. The mean +/- SD birth weight was 3335 +/- 654 g and the mean +/- SD gestational age at delivery was 38.9 +/- 2.5 weeks. Most (95%) of the women took mirtazapine in the first trimester, but only 25% of the women took it throughout pregnancy. The differences among the 3 groups were in the rate of spontaneous abortions, which was higher in both antidepressant groups (19% in the mirtazapine group and 17% in the other antidepressant group) than in the nonteratogen group (11%), but none of the differences were statistically significant. The rate of preterm births (prior to 37 weeks' gestation) was also higher in the mirtazapine group (10%) and in the other antidepressant group (7%) than in the nonteratogen group (2%). The difference was statistically significant between the mirtazapine group and the nonteratogen group (p = .04). Mirtazapine does not appear to increase the baseline rate of major malformations of 1% to 3%. However, the higher number of spontaneous abortions in the antidepressant groups confirms the higher rates of spontaneous abortions in pregnant women taking antidepressant medications found in previous studies.

Adverse drug events: counting is not enough, action is needed

estimate — that 10.4% of patients attending general practice experience an ADE — almost 2 million people have an ADE annually. Moreover, their findings show that these ADEs are not trivial, with about 1 million being moderate or severe and 138 000 requiring hospitalisation, a finding consistent with previous estimates. 3 Many of these ADEs are preventable, although the exact proportion of preventable events can be debated. There have now been more than 30 Australian studies estimating the number of ADEs in different settings. 3 It is clear that counting is not enough — it is time for action, but what can be done? Every developed country is trying to cope with the problem of ADEs. Australia has many structures and initiatives in place to reduce the occurrence of ADEs, and preventing ADEs necessarily involves them all. 3 Regulatory agencies, the medicines industry, quality use of medicines organisations and information providers, safety and quality organisations, professional bodies, health professionals and consumers can all assist. Prevention of ADEs cannot occur without better knowledge. It is noteworthy that the Therapeutic Goods Administration has adopted the European Medicines Agency guideline on pharmacovigilance planning. Increased pharmacovigilance, including observational studies, will require a substantial increase in resources. In Canada, less than 10% of the budget for drug regulation is allocated to issues concerning marketed products, including safety. Yet, in 50% of new drugs, serious adverse drug reactions are detected after market approval. 4 We need systems that can deal with the reality that only limited numbers of highly selected patients are studied before a drug is marketed. Regulators may have to consider restricting prescribing of new medications if they have limited safety information, particularly when equally efficacious therapy is available. New systems for detecting early signals of potential adverse drug reactions in expanded populations could complement the current reporting system for adverse drug reactions. An example is the Drug Safety Research Unit in the United Kingdom, which captures information on the first 10 000 patients using a newly marketed drug. 5 We need to capitalise on and expand the importance and significance of consumer reporting.

Serious Skin Reactions and Selective COX-2 Inhibitors

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. 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. 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. 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.

Atypical antipsychotic use during the first trimester of pregnancy may not increase major malformations

McKenna K, Koren G, Tetelbaum M, et al . Pregnancy outcome of women using atypical antipsychotic drugs: A prospective comparative study. J Clin Psychiatry 2005;66:444–9.[OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] Q Do antipsychotics...

Pregnancy Outcome of Women Using Atypical Antipsychotic Drugs

A substantial number of women of childbearing age suffer from schizophrenia and other mental illnesses that require the use of antipsychotic drugs. Atypical antipsychotics have been on the market since the mid-1990s, and to date there are no prospective comparative studies regarding use during pregnancy. (1) To determine whether atypical antipsychotics increase the rate of major malformations above the 1% to 3% baseline risk seen in the general population. (2) To examine rates of spontaneous and therapeutic abortions, rates of stillbirths, birth weight, and gestational age at birth. The cohort was composed of pregnant women who contacted the Motherisk Program in Canada or the Israeli Teratogen Information Service in Israel and women who were recruited from the Drug Safety Research Unit database in England. Women who had been exposed to atypical antipsychotics were matched to a comparison group of pregnant women who had not been exposed to these agents. Data were obtained on 151 pregnancy outcomes that included exposure to olanzapine (N= 60), risperidone (N = 49), quetiapine (N = 36), and clozapine (N = 6). Among women exposed to an atypical antipsychotic, there were 110 live births (72.8%), 22 spontaneous abortions (14.5%), 15 therapeutic abortions (9.9%), and 4 stillbirths (2.6%). Among babies of women in this group, there was 1 major malformation (0.9%), and the mean +/-SD birth weight was 3341 +/-685 g. There were no statistically significant differences in any of the pregnancy outcomes of interest between the exposed and comparison groups, with the exceptions of the rate of low birth weight, which was 10% in exposed babies compared with 2% in the comparison group (p = .05), and the rate of therapeutic abortions (p = .003). These results suggest that atypical antipsychotics do not appear to be associated with an increased risk for major malformations.

The Safety and Effectiveness of Newer Antiepileptics: A Comparative Postmarketing Cohort Study

Clinical trials for the newer antiepileptic drugs (AEDs) have provided inconclusive information to evaluate comparative risk benefit. The authors use data from postmarketing observational cohort studies to compare the failure of treatment with lamotrigine, vigabatrin, and gabapentin in patients with refractory epilepsy. The Drug Safety Research Unit has conducted prescription event monitoring (PEM) studies for lamotrigine, vigabatrin, and gabapentin to monitor their safety when used in primary care. The primary outcome of this study was time to treatment failure in patients who had been prescribed the drug after the start of the PEM study. Patients on gabapentin had reduced time to treatment failure compared to those on the other 2 drugs. The age- and sex-adjusted hazard ratio of failure was 1.53 (95% confidence interval [CI] = 1.38-1.70) for gabapentin compared to lamotrigine and 1.19 (95% CI = 1.10-1.30) for vigabatrin compared to lamotrigine. The observed differences between the 3 study drugs might be confounded by a higher proportion of patients treated with gabapentin having refractory epilepsy, a shorter duration of the gabapentin PEM study, and a lower relative dose of gabapentin (approved at the time of the PEM study). The current study provides information about the routine usage of newer AEDs, which complements evidence from clinical trials regarding the efficacy and safety of these AEDs. Although this study showed differences on times to treatment failure between lamotrigine, vigabatrin, and gabapentin, the results are only useful when considered together with results from other studies seeking to answer the same questions.

Results of a postal survey of the reasons for non‐response by doctors in a Prescription Event Monitoring study of drug safety

A Prescription Event Monitoring (PEM) study was carried out by the Drug Safety Research Unit (DSRU) to monitor the safety of irbesartan, an angiotensin II antagonist, immediately after launch in the United Kingdom in September 1997. The DSRU 'green form' questionnaire response rate was lower than expected. The manufacturer was conducting a concurrent postmarketing surveillance study. The aim of this cross-sectional study, was to identify reasons for non-response by general practitioners in England. In PEM, questionnaires are posted to the prescribing general practitioner approximately 6 months after the date of the first prescription for each patient, requesting details of clinical events recorded in the patients' notes since starting treatment. Those that failed to respond were sent a second questionnaire, including tick box questions to elucidate reasons for non-response. A total of 21.3% (3088/14502) second send forms were returned. There were 1747 tick box responses. The most common reason specified for non-response was 'I was too busy' (31.2%) followed by 'no payment included' (13.4%). Participation in another study accounted for only 3.4%. The concurrent postmarketing surveillance study was not a significant factor. The general practitioner's workload appeared to have a far larger impact. While research remains a non-core activity and receives no payment, participation is likely to fall. Researchers need to find means of benefiting the general practitioner if participation is to continue.

Automated signal generation in prescription-event monitoring.

Signal generation is a method of highlighting potential safety issues in a drug that then need to be investigated further. Previously automated signal generation has mainly been applied to spontaneous reporting systems. The Drug Safety Research Unit (DSRU) performs observational postmarketing studies on selected newly marketed medicines in England using a method known as prescription-event monitoring (PEM). The DSRU has investigated automated procedures for the generation of signals using the event data from PEM studies. Proportional reporting ratios (PRRs) and incidence rate ratios (IRRs) were studied as possible tools for signal generation in PEM data. The PEM database contains 78 completed studies of drugs prescribed in primary care from a variety of therapeutic classes. Retrospective studies were carried out to identify the implications of changing the comparator group of drugs, along with analysing the results at different levels in the DSRU's hierarchical dictionary and performing signal generation after 30 and 180 days of observation since starting the drug. Automated signal generation is a useful hypothesis generating method that is likely to prove to be useful both in clinical trials and postmarketing studies. PRRs are simple to apply and do not require a denominator. IRRs take into account the time subjects were exposed to the drug prior to the event of interest, and offers a useful, and more in depth look into the data. However, with both methods it is important to perform signal generation at multiple levels in the dictionary and with careful selection of the comparator group.

Prescription-event monitoring in Japan (J-PEM).

In prescription-event monitoring in Japan (J-PEM), patients are identified by prescriptions in individual pharmacies where drugs are dispensed. The methodology is somewhat different to that used by the Drug Safety Research Unit in the UK, in that two questionnaires, one to the pharmacist and the other to the doctor are sent for each patient and the method of concurrent control is employed in J-PEM. In the data analysis, the list of events reported as a suspected reaction or a reason for stopping the drug is made to generate a signal. In addition, a signal may be generated for some events with the statistically significant difference of crude rates followed by the regression analysis or a follow-up study. In J-PEM, Medical Dictionary for Regulatory Activities (MedDRA) terminology is used for data entry and data analysis. Lowest level terms (LLTs) in MedDRA are used in data entry while a signal is generated using preferred terms (PTs). However, to generate a signal effectively, some PTs may be grouped as one term. In addition, if two terms are so similar, it may be instructed that one of those two terms is normally selected in data entry to avoid confusion. Many more PEM studies could be undertaken to determine if MedDRA can be used for effective signal generation, but the usefulness of MedDRA in J-PEM is still to be determined.