Correlates of spontaneous reporting of adverse drug reactions within primary care: the paradox of low prescribers who are high reporters

AIM(S) To examine Primary Care Trust (PCT) demographics influencing general practitioner (GP) involvement in pharmacovigilance. METHODS PCT adverse drug reaction (ADR) reports to the Yellow Card scheme between April 2004 and March 2006 were obtained for the UK West Midlands region. Reports were analysed by all drugs, and most commonly reported drugs (‘top drugs’). PCT data, adjusted for population size, were aggregated. Prescribing statistics and other characteristics were obtained for each PCT, and associations between these characteristics and ADR reporting rates were examined. RESULTS During 2004–06, 1175 reports were received from PCTs. Two hundred and eighty (24%) of these reports were for 14 ‘top drugs’. The mean rate of reporting for PCTs was 213 reports per million population. A total of 153 million items were prescribed during 2004–06, of which 33% were ‘top drugs’. Reports for all drugs and ‘top drugs’ were inversely correlated with the number of prescriptions issued per thousand population (rs = -0.413, 95% CI -0.673, -0.062, P < 0.05, and r = -0.420, 95% CI -0.678, -0.071, P < 0.05, respectively). Reporting was significantly negatively correlated with the percentages of male GPs within a PCT, GPs over 55 years of age, single-handed GPs within a PCT, the average list size of a GP within a PCT, the overall deprivation scores and average QOF total points. ADR reports did not correlate significantly with the proportion of the population over 65 years old. CONCLUSIONS Some PCT characteristics appear to be associated with low levels of ADR reporting. The association of low prescribing areas with high ADR reporting rates replicates previous findings.

Meta-analysis of the population and phenotypic expression of CYP2C9/2C19 polymorphism on drug metabolism in different ethnicities

The term "pharmacogenetics" has been defined as the scientific study of inherited factors that affect the human drug response. Many pharmacogenetie studies have been published since 1995 and have focussed on the principal enzyme family involved in drug metabolism, the cytochrome P450 family, particularly cytochrome P4502C9 and 2C19. In order to investigate the pharmacogenetic aspect of pharmacotherapy, the relevant studies describing the association of pharmacogenetic factor(s) in drug responses must be retrieved from existing literature using a systematic review approach. In addition, the estimation of variant allele prevalence for the gene under study between different ethnic populations is important for pharmacogenetic studies. In this thesis, the prevalence of CYP2C9/2C19 alleles between different ethnicities has been estimated through meta-analysis and the population genetic principle. The clinical outcome of CYP2C9/2C19 allelic variation on the pharmacotherapy of epilepsy has been investigated; although many new antiepileptic drugs have been launched into the market, carbamazepine, phenobarbital and phenytoin are still the major agents in the pharmacotherapy of epilepsy. Therefore, phenytoin was chosen as a model AED and the effect of CYP2C9/2C19 genetic polymorphism on phenytoin metabolism was further examined.An estimation of the allele prevalence was undertaken for three CYP2C9/2C19 alleles respectively using a meta-analysis of studies that fit the Hardy-Weinberg equilibrium. The prevalence of CYP2C9*1 is approximately 81%, 96%, 97% and 94% in Caucasian, Chinese, Japanese, African populations respectively; the pooled prevalence of CYP2C19*1 is about 86%, 57%, 58% and 85% in these ethnic populations respectively. However, the studies of association between CYP2C9/2C19 polymorphism and phenytoin metabolism failed to achieve any qualitative or quantitative conclusion. Therefore, mephenytoin metabolism was examined as a probe drug for association between CYP2C19 polymorphism and mephenytoin metabolic ratio. Similarly, analysis of association between CYP2C9 polymorphism and warfarin dose requirement was undertaken.It was confirmed that subjects carrying two mutated CYP2C19 alleles have higher S/R mephenytoin ratio due to deficient CYP2C19 enzyme activity. The studies of warfarin and CYP2C9 polymorphism did not provide a conclusive result due to poor comparability between studies.The genetic polymorphism of drug metabolism enzymes has been studied extensively, however other genetic factors, such as multiple drug resistance genes (MDR) and genes encoding ion channels, which may contribute to variability in function of drug transporters and targets, require more attention in future pharmacogenetic studies of antiepileptic drugs.

The impact of drug information on the prescribing of drugs

Using prescription analyses and questionnaires, the way drug information was used by general medical practitioners during the drug adoption process was studied. Three new drugs were considered; an innovation and two 'me-too' products. The innovation was accepted by general practitioners via a contagion process, information passing among doctors. The 'me-too' preparations were accepted more slowly and by a process which did not include the contagion effect. 'Industrial' information such as direct mail was used more at the 'awareness' stage of the adoption process while 'professional' sources of information such as articles in medical journals were used more to evaluate a new product. It was shown that 'industrial' information was preferred by older single practice doctors who did not specialise, had a first degree only and who did not dispense their own prescriptions. Doctors were divided into early and late-prescribers by using the date they first prescribed the innovatory drug. Their approach to drug information sources was further studied and it was shown that the early-prescriber issued slightly more prescriptions per month, had a larger list size, read fewer journals and generally rated industrial sources of information more highly than late-prescribers. The prescribing habits of three consultant rheumatologists were analysed and compared with those of the general practitioners in the community which they served. Very little association was noted and the influence of the consultant on the prescribing habits of general practitioners was concluded to be low. The consultants influence was suggested to be of two components, active and passive; the active component being the most influential. Journal advertising and advertisement placement were studied for one of the 'me-too' drugs. It was concluded that advertisement placement should be based on the reading patterns of general practitioners and not on ad-hoc data gathered by representatives as was the present practice. A model was proposed relating the 'time to prescribe' a new drug to the variables suggested throughout this work. Four of these variables were shown to be significant. These were, the list size, the medical age of the prescriber, the number of new preparations prescribed in a given time and the number of partners in the practice.

Interpreting adverse signals in diabetes drug development programs

Detection and interpretation of adverse signals during preclinical and clinical stages of drug development inform the benefit-risk assessment that determines suitability for use in real-world situations. This review considers some recent signals associated with diabetes therapies, illustrating the difficulties in ascribing causality and evaluating absolute risk, predictability, prevention, and containment. Individual clinical trials are necessarily restricted for patient selection, number, and duration; they can introduce allocation and ascertainment bias and they often rely on biomarkers to estimate long-term clinical outcomes. In diabetes, the risk perspective is inevitably confounded by emergent comorbid conditions and potential interactions that limit therapeutic choice, hence the need for new therapies and better use of existing therapies to address the consequences of protracted glucotoxicity. However, for some therapies, the adverse effects may take several years to emerge, and it is evident that faint initial signals under trial conditions cannot be expected to foretell all eventualities. Thus, as information and experience accumulate with time, it should be accepted that benefit-risk deliberations will be refined, and adjustments to prescribing indications may become appropriate. © 2013 by the American Diabetes Association.