Getting our ducks in a row: The need for data utility comparisons of healthcare systems data for clinical trials.

BACKGROUND: Better use of healthcare systems data, collected as part of interactions between patients and the healthcare system, could transform planning and conduct of randomised controlled trials. Multiple challenges to widespread use include whether healthcare systems data captures sufficiently well the data traditionally captured on case report forms. "Data Utility Comparison Studies" (DUCkS) assess the utility of healthcare systems data for RCTs by comparison to data collected by the trial. Despite their importance, there are few published UK examples of DUCkS. METHODS-AND-RESULTS: Building from ongoing and selected recent examples of UK-led DUCkS in the literature, we set out experience-based considerations for the conduct of future DUCkS. Developed through informal iterative discussions in many forums, considerations are offered for planning, protocol development, data, analysis and reporting, with comparisons at "patient-level" or "trial-level", depending on the item of interest and trial status. DISCUSSION: DUCkS could be a valuable tool in assessing where healthcare systems data can be used for trials and in which trial teams can play a leading role. There is a pressing need for trials to be more efficient in their delivery and research waste must be reduced. Trials have been making inconsistent use of healthcare systems data, not least because of an absence of evidence of utility. DUCkS can also help to identify challenges in using healthcare systems data, such as linkage (access and timing) and data quality. We encourage trial teams to incorporate and report DUCkS in trials and funders and data providers to support them.

Monitoring metrics over time: Why clinical trialists need to systematically collect site performance metrics.

Background: Over the last decade, there has been an increasing interest in risk-based monitoring (RBM) in clinical trials, resulting in a number of guidelines from regulators and its inclusion in ICH GCP. However, there is a lack of detail on how to approach RBM from a practical perspective, and insufficient understanding of best practice. Purpose: We present a method for clinical trials units to track their metrics within clinical trials using descriptive statistics and visualisations. Research Design: We suggest descriptive statistics and visualisations within a SWAT methodology. Study Sample: We illustrate this method using the metrics from TEMPER, a monitoring study carried out in three trials at the MRC Clinical Trials Unit at UCL. Data Collection: The data collection for TEMPER is described in DOI: 10.1177/1740774518793379. Results: We show the results and discuss a protocol for a Study-Within-A-Trial (SWAT 167) for those wishing to use the method. Conclusions: The potential benefits metric tracking brings to clinical trials include enhanced assessment of sites for potential corrective action, improved evaluation and contextualisation of the influence of metrics and their thresholds, and the establishment of best practice in RBM. The standardisation of the collection of such monitoring data would benefit both individual trials and the clinical trials community.

Healthcare systems data in the context of clinical trials - A comparison of cardiovascular data from a clinical trial dataset with routinely collected data.

BACKGROUND: Routinely-collected healthcare systems data (HSD) are proposed to improve the efficiency of clinical trials. A comparison was undertaken between cardiovascular (CVS) data from a clinical trial database with two HSD resources. METHODS: Protocol-defined and clinically reviewed CVS events (heart failure (HF), acute coronary syndrome (ACS), thromboembolic stroke, venous and arterial thromboembolism) were identified within the trial data. Data (using pre-specified codes) was obtained from NHS Hospital Episode Statistics (HES) and National Institute for Cardiovascular Outcomes Research (NICOR) HF and myocardial ischaemia audits for trial participants recruited in England between 2010 and 2018 who had provided consent. The primary comparison was trial data versus HES inpatient (APC) main diagnosis (Box-1). Correlations are presented with descriptive statistics and Venn diagrams. Reasons for non-correlation were explored. RESULTS: From 1200 eligible participants, 71 protocol-defined clinically reviewed CVS events were recorded in the trial database. 45 resulted in a hospital admission and therefore could have been recorded by either HES APC/ NICOR. Of these, 27/45 (60%) were recorded by HES inpatient (Box-1) with an additional 30 potential events also identified. HF and ACS were potentially recorded in all 3 datasets; trial data recorded 18, HES APC 29 and NICOR 24 events respectively. 12/18 (67%) of the HF/ACS events in the trial dataset were recorded by NICOR. CONCLUSION: Concordance between datasets was lower than anticipated and the HSD used could not straightforwardly replace current trial practices, nor directly identify protocol-defined CVS events. Further work is required to improve the quality of HSD and consider event definitions when designing clinical trials incorporating HSD.

Lack of transparent reporting of trial monitoring approaches in randomised controlled trials: A systematic review of contemporary protocol papers.

BACKGROUND: Monitoring is essential to ensure patient safety and data integrity in clinical trials as per Good Clinical Practice. The Standard Protocol Items: Recommendations for Interventional Trials Statement and its checklist guides authors to include monitoring in their protocols. We investigated how well monitoring was reported in published 'protocol papers' for contemporary randomised controlled trials. METHODS: A systematic search was conducted in PubMed to identify eligible protocol papers published in selected journals between 1 January 2020 and 31 May 2020. Protocol papers were classified by whether they reported monitoring and, if so, by the details of monitoring. Data were summarised descriptively. RESULTS: Of 811 protocol papers for randomised controlled trials, 386 (48%; 95% CI: 44%-51%) explicitly reported some monitoring information. Of these, 20% (77/386) reported monitoring information consistent with an on-site monitoring approach, and 39% (152/386) with central monitoring, 26% (101/386) with a mixed approach, while 14% (54/386) did not provide sufficient information to specify an approach. Only 8% (30/386) of randomised controlled trials reported complete details about all of scope, frequency and organisation of monitoring; frequency of monitoring was the least reported. However, 6% (25/386) of papers used the term 'audit' to describe 'monitoring'. DISCUSSION: Monitoring information was reported in only approximately half of the protocol papers. Suboptimal reporting of monitoring hinders the clinical community from having the full information on which to judge the validity of a trial and jeopardises the value of protocol papers and the credibility of the trial itself. Greater efforts are needed to promote the transparent reporting of monitoring to journal editors and authors.

Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS): Protocol for a randomized controlled trial.

RATIONALE: Atrial fibrillation causes one-fifth of ischemic strokes, with a high risk of early recurrence. Although long-term anticoagulation is highly effective for stroke prevention in atrial fibrillation, initiation after stroke is usually delayed by concerns over intracranial hemorrhage risk. Direct oral anticoagulants offer a significantly lower risk of intracranial hemorrhage than other anticoagulants, potentially allowing earlier anticoagulation and prevention of recurrence, but the safety and efficacy of this approach has not been established. AIM: Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS) will investigate whether early treatment with a direct oral anticoagulant, within four days of stroke onset, is as effective or better than delayed initiation, 7 to 14 days from onset, in atrial fibrillation patients with acute ischemic stroke. METHODS AND DESIGN: OPTIMAS is a multicenter randomized controlled trial with blinded outcome adjudication. Participants with acute ischemic stroke and atrial fibrillation eligible for anticoagulation with a direct oral anticoagulant are randomized 1:1 to early or delayed initiation. As of December 2021, 88 centers in the United Kingdom have opened. STUDY OUTCOMES: The primary outcome is a composite of recurrent stroke (ischemic stroke or symptomatic intracranial hemorrhage) and systemic arterial embolism within 90 days. Secondary outcomes include major bleeding, functional status, anticoagulant adherence, quality of life, health and social care resource use, and length of hospital stay. SAMPLE SIZE TARGET: A total of 3478 participants assuming event rates of 11.5% in the control arm and 8% in the intervention arm, 90% power and 5% alpha. We will follow a non-inferiority gatekeeper analysis approach with a non-inferiority margin of 2 percentage points. DISCUSSION: OPTIMAS aims to provide high-quality evidence on the safety and efficacy of early direct oral anticoagulant initiation after atrial fibrillation-associated ischemic stroke.Trial registrations: ISRCTN: 17896007; ClinicalTrials.gov: NCT03759938.

Accessing routinely collected health data to improve clinical trials: recent experience of access.

BACKGROUND: Routinely collected electronic health records (EHRs) have the potential to enhance randomised controlled trials (RCTs) by facilitating recruitment and follow-up. Despite this, current EHR use is minimal in UK RCTs, in part due to ongoing concerns about the utility (reliability, completeness, accuracy) and accessibility of the data. The aim of this manuscript is to document the process, timelines and challenges of the application process to help improve the service both for the applicants and data holders. METHODS: This is a qualitative paper providing a descriptive narrative from one UK clinical trials unit (MRC CTU at UCL) on the experience of two trial teams' application process to access data from three large English national datasets: National Cancer Registration and Analysis Service (NCRAS), National Institute for Cardiovascular Outcomes Research (NICOR) and NHS Digital to establish themes for discussion. The underpinning reason for applying for the data was to compare EHRs with data collected through case report forms in two RCTs, Add-Aspirin (ISRCTN 74358648) and PATCH (ISRCTN 70406718). RESULTS: The Add-Aspirin trial, which had a pre-planned embedded sub-study to assess EHR, received data from NCRAS 13 months after the first application. In the PATCH trial, the decision to request data was made whilst the trial was recruiting. The study received data after 8 months from NICOR and 15 months for NHS Digital following final application submission. This concluded in May 2020. Prior to application submission, significant time and effort was needed particularly in relation to the PATCH trial where negotiations over consent and data linkage took many years. CONCLUSIONS: Our experience demonstrates that data access can be a prolonged and complex process. This is compounded if multiple data sources are required for the same project. This needs to be factored in when planning to use EHR within RCTs and is best considered prior to conception of the trial. Data holders and researchers are endeavouring to simplify and streamline the application process so that the potential of EHR can be realised for clinical trials.

Imiquimod versus podophyllotoxin, with and without human papillomavirus vaccine, for anogenital warts: the HIPvac factorial RCT.

BACKGROUND: The comparative efficacy, and cost-effectiveness, of imiquimod or podophyllotoxin cream, either alone or in combination with the quadrivalent HPV vaccine (Gardasil®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA) in the treatment and prevention of recurrence of anogenital warts is not known. OBJECTIVE: The objective was to compare the efficacy of imiquimod and podophyllotoxin creams to treat anogenital warts and to assess whether or not the addition of quadrivalent human papillomavirus vaccine increases wart clearance or prevention of recurrence. DESIGN: A randomised, controlled, multicentre, partially blinded factorial trial. Participants were randomised equally to four groups, combining either topical treatment with quadrivalent human papillomavirus vaccine or placebo. Randomisation was stratified by gender, a history of previous warts and human immunodeficiency virus status. There was an accompanying economic evaluation, conducted from the provider perspective over the trial duration. SETTING: The setting was 22 sexual health clinics in England and Wales. PARTICIPANTS: Participants were patients with a first or repeat episode of anogenital warts who had not been treated in the previous 3 months and had not previously received quadrivalent human papillomavirus vaccine. INTERVENTIONS: Participants were randomised to 5% imiquimod cream (Aldara®; Meda Pharmaceuticals, Takeley, UK) for up to 16 weeks or 0.15% podophyllotoxin cream (Warticon®; GlaxoSmithKlein plc, Brentford, UK) for 4 weeks, which was extended to up to 16 weeks if warts persisted. Participants were simultaneously randomised to quadrivalent human papillomavirus vaccine (Gardasil) or saline control at 0, 8 and 24 weeks. Cryotherapy was permitted after week 4 at the discretion of the investigator. MAIN OUTCOME MEASURES: The main outcome measures were a combined primary outcome of wart clearance at week 16 and remaining wart free at week 48. Efficacy analysis was by logistic regression with multiple imputation for missing follow-up values; economic evaluation considered the costs per quality-adjusted life-year. RESULTS: A total of 503 participants were enrolled and attended at least one follow-up visit. The mean age was 31 years, 66% of participants were male (24% of males were men who have sex with men), 50% had a previous history of warts and 2% were living with human immunodeficiency virus. For the primary outcome, the adjusted odds ratio for imiquimod cream versus podophyllotoxin cream was 0.81 (95% confidence interval 0.54 to 1.23), and for quadrivalent human papillomavirus vaccine versus placebo, the adjusted odds ratio was 1.46 (95% confidence interval 0.97 to 2.20). For the components of the primary outcome, the adjusted odds ratio for wart free at week 16 for imiquimod versus podophyllotoxin was 0.77 (95% confidence interval 0.52 to 1.14) and for quadrivalent human papillomavirus vaccine versus placebo was 1.30 (95% confidence interval 0.89 to 1.91). The adjusted odds ratio for remaining wart free at 48 weeks (in those who were wart free at week 16) for imiquimod versus podophyllotoxin was 0.98 (95% confidence interval 0.54 to 1.78) and for quadrivalent human papillomavirus vaccine versus placebo was 1.39 (95% confidence interval 0.73 to 2.63). Podophyllotoxin plus quadrivalent human papillomavirus vaccine had inconclusive cost-effectiveness compared with podophyllotoxin alone. LIMITATIONS: Hepatitis A vaccine as control was replaced by a saline placebo in a non-identical syringe, administered by someone outside the research team, for logistical reasons. Sample size was reduced from 1000 to 500 because of slow recruitment and other delays. CONCLUSIONS: A benefit of the vaccine was not demonstrated in this trial. The odds of clearance at week 16 and remaining clear at week 48 were 46% higher with vaccine, and consistent effects were seen for both wart clearance and recurrence separately, but these differences were not statistically significant. Imiquimod and podophyllotoxin creams had similar efficacy for wart clearance, but with a wide confidence interval. The trial results do not support earlier evidence of a lower recurrence with use of imiquimod than with use of podophyllotoxin. Podophyllotoxin without quadrivalent human papillomavirus vaccine is the most cost-effective strategy at the current vaccine list price. A further larger trial is needed to definitively investigate the effect of the vaccine; studies of the immune response in vaccine recipients are needed to investigate the mechanism of action. TRIAL REGISTRATION: Current Controlled Trials. Current Controlled Trials ISRCTN32729817 and EudraCT 2013-002951-14. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 47. See the NIHR Journals Library website for further project information.

The HIPvac [Human papillomavirus infection: a randomised controlled trial of Imiquimod cream (5%) versus Podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts] trial compared two commonly used creams to treat genital warts: 0.15% podophyllotoxin cream (Warticon^®; GlaxoSmithKlein plc, Brentford, UK) and 5% imiquimod cream (Aldara^®; Meda Pharmaceuticals, Takeley, UK). It also investigated whether or not a vaccine used to prevent human papillomavirus infection, quadrivalent human papillomavirus vaccine (Gardasil^®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA), could help treat warts or prevent them from coming back in patients whose warts had been cleared. The HIPvac trial was a randomised controlled trial involving 503 patients with warts attending sexual health clinics in England and Wales. The creams and the vaccine were well tolerated; there was some soreness where the cream was applied, but no unexpected side effects. When deciding which treatment was better, we looked at whether or not the warts had cleared by 16 weeks after starting treatment and, if cleared, whether or not they returned by 48 weeks. We compared the creams against each other, and the addition of vaccine against no vaccine (a placebo injection). Patients were allowed to have cryotherapy (freezing treatment) as well, if the investigator advised this. We also calculated the value for money of each type of treatment. The two creams were very similar in how well they worked to clear the warts. One difference was that podophyllotoxin cream worked slightly quicker. The number of patients given cryotherapy was about the same for both types of cream. We had expected that recurrence of warts after treatment with imiquimod cream might be less than after treatment with podophyllotoxin cream, but, in fact, the two creams were similar. Quadrivalent human papillomavirus vaccine did not improve clearance of warts or reduce the chance of recurrence, but the result remains inconclusive. If we had been able to recuit 1000 participants as originally planned, we might have been able to be more certain about whether there was any benefit of vaccination. Further research would be needed to investigate any possible effect. The two creams offered similar value for money in treating warts. Giving patients the vaccine in addition to the cream is not good value for money at its current list price, given the uncertainty about the benefit it offers.

Associations between the LEP -2548G/A Promoter and Baseline Weight and between LEPR Gln223Arg and Lys656Asn Variants and Change in BMI z Scores in Arab Children and Adolescents Treated with Risperidone.

Data on baseline (antipsychotics-naïve) age, weight, and height, and change in these at 3 subsequent follow-up time points up to 313.6 days (95% CI 303.5-323.7) were collected from 181 risperidone-treated children and adolescents (mean age 12.58 years, SD 4.99, range 2.17-17.7) attending a pediatric neurology clinic in Saudi Arabia. Owing to differences in genotypic distributions in the subsamples, results are reported for the white Arab population (n = 144). Age- and gender-normed body mass index (BMI)-standardized z scores (BMI z) were calculated (LMSgrowth program). Linear regression was performed for baseline weight and BMI z, while change in BMI z was assessed using random effects ordered logistic regression. The following single nucleotide polymorphisms (SNPs) were analyzed: rs7799039 in the LEP promoter, rs1805094 (previously rs8179183), rs1137100 and rs1137101 in the LEPR, and rs1414334 in HTR2C. We found a nominally significant association between rs7799309 and baseline weight, adjusting for height, age, gender, and diagnosis (A/G, p = 0.035, ß = -3.62 vs. G/G). The rs1137101 (G/G, p = 0.018, odds ratio [OR] = 4.13 vs. A/A) and rs1805094 C allele carriers (p = 0.019, OR = 0.51) showed nominally significant associations with change in BMI z categories. Our data support and replicate previous relevant associations for these variants (including with weight gain when on risperidone), whilst being the first report of such associations in patients of Arab ethnicity.

Human papillomavirus infection: protocol for a randomised controlled trial of imiquimod cream (5%) versus podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts (HIPvac trial).

BACKGROUND: Anogenital warts are the second most common sexually transmitted infection diagnosed in sexual health services in England. About 90% of genital warts are caused by human papillomavirus (HPV) types 6 or 11, and half of episodes diagnosed are recurrences. The best and most cost-effective treatment for patients with anogenital warts is unknown. The commonly used treatments are self-administered topical agents, podophyllotoxin (0.15% cream) or imiquimod (5% cream), or cryotherapy with liquid nitrogen. Quadrivalent HPV (qHPV) vaccination is effective in preventing infection, and disease, but whether it has any therapeutic effect is not known. METHODS AND DESIGN: To investigate the efficacy of clearance and prevention of recurrence of external anogenital warts by topical treatments, podophyllotoxin 0.15% cream or imiquimod 5% cream, in combination with a three-dose regimen of qHPV or control vaccination. 500 adult patients presenting with external anogenital warts with either a first or subsequent episode of anogenital warts will be entered into this randomised, controlled partially blinded 2 × 2 factorial trial. DISCUSSION: The trial is expected to provide the first high-quality evidence of the comparative efficacy and cost-effectiveness of the two topical treatments in current use, as well as investigate the potential benefit of HPV vaccination, in the management of anogenital warts. TRIAL REGISTRATION: The trial was registered prior to starting recruitment under the following reference numbers: International Standard Randomized Controlled Trial Number (ISRCTN) Registry - ISRCTN32729817 (registered 25 July 2014); European Union Clinical Trials Register (EudraCT) - 2013-002951-14 (registered 26 June 2013).

Oral penicillin prescribing for children in the UK: a comparison with BNF for Children age-band recommendations.

BACKGROUND: The British National Formulary for Children (BNFC) recommends dosing oral penicillins according to age-bands, weight-bands, or weight-based calculations. Because of the rising prevalence of childhood obesity, age-band-based prescribing could lead to subtherapeutic dosing. AIM: To investigate actual oral penicillin prescribing by GPs in the UK with reference to the current BNFC age-band recommendations. DESIGN AND SETTING: Descriptive analysis of UK prescriptions in the 2010 IMS Disease-Analyzer database (IMS-DA). METHOD: A detailed database analysis was undertaken of oral penicillin prescriptions for 0-18 year olds from the 2010 IMS-DA. The prescription analysis included all available data on formulation, strength (mg), prescription quantity unit, package size, prescribed quantity, and volume. RESULTS: Considering amoxicillin alone, no infants (aged <1 year) were prescribed the BNFC 2011 edition recommended unit dose (62.5 mg), while the majority received double the dose (125 mg); among children aged 1-5 years, 96% were prescribed the recommended unit dose (125 mg), but 40% of 6-12 year olds and 70% of 12-18 year olds were prescribed unit doses below the BNFC recommendations. For otitis media, only those children aged <1 year received the recommended dose of amoxicillin (40-90 mg/kg/day). Similar variations in dosing across age-bands were observed for phenoxymethylpenicillin and flucloxacillin. CONCLUSION: There is wide variation in the dosing of penicillins for children in UK primary care, with very few children being prescribed the current national recommended doses. There is an urgent need to review dosing guidelines, in relation to the weights of children today.

Pharmacological treatments prescribed to people with autism spectrum disorder (ASD) in primary health care.

RATIONALE: Autism spectrum disorders (ASDs) affect 1 % of children, having significant impact on health and social outcomes. Psychotropic medication use by individuals with ASD in the USA increased over time, and polypharmacy occurred in >50 % of those prescribed. In the UK, no psychotropic drugs are approved in ASDs, and little is known about patterns of pharmacological treatment in the ASD population and associated co-morbidities. METHODS: We used The Health Improvement Network, a nationally representative primary care database, to assess the prevalence of ASD diagnoses, psychotropic drug prescribing and neuropsychiatric co-morbidities of 0-24 year olds between 1992 and 2008. RESULTS: ASD prevalence increased 65-fold from 0.01 % (1992) to 0.50 % (2008). Psychotropic drugs were prescribed to 29 % (1,619/5,651) of the ASD cohort; the most prescribed drugs were sleep medication (9.7 % of prescribed patients), psychostimulants (7.9 %) and antipsychotics (7.3 %). More patients were given psychostimulants and sleep medications over time from 1.5-6.3 % and 2.2-5.9 % respectively. Thirty-seven per cent of the cohort had ≥ 1 record of a neuropsychiatric co-morbidity, the most common being developmental difficulties and learning disabilities (12.6 %), behavioural, conduct and personality disorders (11.1 %) and attention deficit hyperactivity disorder (7.5 %). CONCLUSIONS: British physicians are more conservative in prescribing practice than American colleagues. However, use of psychostimulants and antipsychotics is much higher in those with ASD than in the general population. Polypharmacy was seen in 34 % of prescribed patients in 2008. Additional studies examining use, efficacy, and long-term safety of antipsychotics and psychostimulants in autistic individuals are warranted.

An inventory of European data sources for the long-term safety evaluation of methylphenidate.

To compile an inventory of European healthcare databases with potential to study long-term effects of methylphenidate (MPH) in patients with attention deficit hyperactivity disorder (ADHD). Potential databases were identified through expert opinion, the website of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance, and literature search. An online survey was conducted among database providers/coordinators to ascertain the databases' appropriateness for inclusion into the inventory. It included questions about database characteristics, sample size, availability of information on drug exposure, clinical data and accessibility. Forty-two databases from 11 countries were identified and their coordinators invited to participate; responses were obtained for 22 (52.4 %) databases of which 15 record ADHD diagnoses. Eleven had sufficient data on ADHD diagnosis, drug exposure, and at least one type of outcome information (symptoms/clinical events, weight, height, blood pressure, heart rate) to assess MPH safety. These were Aarhus University Prescription Database, Danish National Birth Cohort (Denmark); German Health Interview and Examination Survey for Children and Adolescents; Health Search Database Thales, Italian ADHD Register, Lombardy Region ADHD Database (Italy); Avon Longitudinal Study of Parents and Children, General Practice Research Database, The Health Improvement Network, QResearch (UK) and IMS Disease Analyzer (UK, Germany, France). Of the 20 databases with no responses, information on seven from publications and/or websites was obtained; Pedianet and the Integrated Primary Care Information database were considered suitable. Many European healthcare databases can be used for multinational long-term safety studies of MPH. Methodological research is underway to investigate the feasibility of their pooling and analysis.

Weight gain and other metabolic adverse effects associated with atypical antipsychotic treatment of children and adolescents: a systematic review and meta-analysis.

OBJECTIVES: The aims of this study were to provide a systematic review and meta-analysis of the effects of atypical antipsychotics in children and adolescents on weight gain (primary objective) and other metabolic parameters (secondary objective). METHODS: A systematic literature review and meta-analysis of double-blind, randomized, controlled trials were conducted. The data sources used were as follows: EMBASE, PubMed, BIOSIS, International Pharmaceutical Abstracts, The Cochrane database (Clinical Trials), Clinical Trials Government Registry, The metaRegister of Controlled Trials, WHO (World Health Organization) Clinical Trials Registry Platform, and PsycINFO(®). Hand searching was also carried out by examining the reference lists of identified studies. Double-blind, randomized, controlled trials investigating the metabolic adverse effects (weight gain, lipid, glucose, and prolactin level abnormalities) associated with atypical antipsychotic use in children and adolescents aged ≤ 18 years were included, irrespective of whether the investigation of adverse effects was a primary or secondary endpoint. RESULTS: We identified 21 studies of drug versus placebo that met the inclusion criteria, with a total of 2,455 patients, 14 studies for risperidone (1,331 patients), three for olanzapine (276 patients), and four for aripiprazole (848 patients). Compared with placebo, the mean weight increases for each drug were olanzapine 3.45 kg (95 % CI 2.93-3.98), risperidone 1.77 kg (95 % CI 1.35-2.20), and aripiprazole 0.94 kg (95 % CI 0.65-1.24). Regarding other metabolic abnormalities, eight studies reported statistically significant increases in prolactin with risperidone; two reported a statistically significant increase in glucose, total cholesterol, and prolactin with olanzapine; and three studies reported a statistically significant decrease in prolactin with aripiprazole. Data on lipid, glucose, and prolactin level changes were too limited to allow us to perform a meta-analysis. CONCLUSIONS: Olanzapine, risperidone, and aripiprazole were all associated with statistically significant weight gain. Olanzapine was associated with the most weight gain and aripiprazole the least. For the secondary outcome, although a number of active comparator trials were identified, data were not available for meta-analysis and were too limited to allow firm conclusions to be drawn.

Persistence of pharmacological treatment into adulthood, in UK primary care, for ADHD patients who started treatment in childhood or adolescence.

BACKGROUND: ADHD guidelines in the UK suggest that children and adults who respond to pharmacological treatment should continue for as long as remains clinically effective, subject to regular review. To what extent patients persist with treatment from childhood and adolescence into adulthood is not clear. This study aims to describe, in UK primary care, the persistence of pharmacological treatment for patients with ADHD who started treatment aged 6-17 years and to estimate the percentage of patients who continued treatment from childhood and adolescence into adulthood. METHODS: The Health Improvement Network (THIN) database was used to identify patients with ADHD who received their first prescription for methylphenidate/ dexamfetamine/atomoxetine, aged 6-17 years. Patients were monitored until their 'censored date' (the earliest of the following dates: date the last prescription coded in the database ended, end of the study period (31st December 2008), date at which they transferred out of their practice, date of death, the last date the practice contributed data to the database). Persistence of treatment into adulthood was estimated using Kaplan Meier analysis. RESULTS: 610 patients had follow-up data into adulthood. 213 patients (93.4% male) started treatment between 6-12 years; median treatment duration 5.9 years. 131 (61.5%) stopped before 18 years, 82 (38.5%) were still on treatment age ≥18 years. 397 patients (86.4% male) started treatment between 13-17 years; median treatment duration was 1.6 years. 227 (57.2%) stopped before 18 years, 170 (42.8%) were still on treatment age ≥18 years. The number of females in both age categories was too small to formally test for differences between genders in persistence of treatment. CONCLUSION: Persistence of treatment into adulthood is lower (~40%) compared with published rates of persistence of the condition (~65% when symptomatic definition of remission used). Due to the limited number of patients with data past 18 years, it is important that ongoing monitoring of prescribing into later adulthood is undertaken, particularly to observe the effects of recommendations in new guidelines.

The epidemiology of pharmacologically treated attention deficit hyperactivity disorder (ADHD) in children, adolescents and adults in UK primary care.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder characterised by the symptoms of inattention, impulsivity and hyperactivity. ADHD was once perceived as a condition of childhood only; however increasing evidence has highlighted the existence of ADHD in older adolescents and adults. Estimates for the prevalence of ADHD in adults range from 2.5-4%. Few data exist on the prescribing trends of the stimulants methylphenidate and dexamfetamine, and the non-stimulant atomoxetine in the UK. The aim of this study was to investigate the annual prevalence and incidence of pharmacologically treated ADHD in children, adolescents and adults in UK primary care. METHODS: The Health Improvement Network (THIN) database was used to identify all patients aged over 6 years with a diagnosis of ADHD/hyperkinetic disorder and a prescription for methylphenidate, dexamfetamine or atomoxetine from 2003-2008. Annual prevalence and incidence of pharmacologically treated ADHD were calculated by age category and sex. RESULTS: The source population comprised 3,529,615 patients (48.9% male). A total of 118,929 prescriptions were recorded for the 4,530 patients in the pharmacologically treated ADHD cohort during the 6-year study. Prevalence (per 1000 persons in the mid-year THIN population) increased within each age category from 2003 to 2008 [6-12 years: from 4.8 (95% CI: 4.5-5.1) to 9.2 (95% CI: 8.8-9.6); 13-17 years: from 3.6 (95% CI: 3.3-3.9) to 7.4 (95% CI: 7.0-7.8); 18-24 years: from 0.3 (95% CI: 0.2-0.3) to 1.1 (95% CI: 1.0-1.3); 25-45 years: from 0.02 (95% CI: 0.01-0.03) to 0.08 (95% CI: 0.06-0.10); >45 years: from 0.01 (95% CI: 0.00-0.01) to 0.02 (95% CI: 0.01-0.03). Whilst male patients aged 6-12 years had the highest prevalence; the relative increase in prescribing was higher amongst female patients of the same age - the increase in prevalence in females aged 6-12 years was 2.1 fold compared to an increase of 1.9 fold for their male counterparts. Prevalence of treated ADHD decreased with increasing age. Incidence (per 1000 persons at risk in the mid-year THIN population) was highest for children aged 6-12 years. CONCLUSIONS: A trend of increasing prescribing prevalence of ADHD drug treatment was observed over the period 2003-2008. Prevalence of prescribing to adult patients increased; however the numbers treated are much lower than published estimates of the prevalence of ADHD. This study has added to the limited knowledge on ADHD prescribing in primary care, particularly in the area of drug treatment in adulthood.

Mortality in children and adolescents prescribed antipsychotic medication: a retrospective cohort study using the UK general practice research database.

BACKGROUND: Antipsychotic prescribing in children has risen in many countries; however, the safety of these agents in the young has not yet been fully established. Potentially fatal antipsychotic-related adverse events include cardiac complications and neuroleptic malignant syndrome. OBJECTIVE: The objective of this study was to investigate mortality in children and adolescents taking antipsychotic medication. METHODS: The General Practice Research Database (GPRD) was used as a data source for this study. Cases were identified from a cohort of patients previously studied. The study population encompassed all patients aged 18 years and under who received at least one prescription for an antipsychotic from 1 January 1992 to 31 December 2005. Patients were followed from the date of the first antipsychotic drug prescription until the earliest occurrence of a code of death, age >18 years or the end of the study period. Cases of death were identified by screening patients' medical records for clinical or referral events with events indicating death, or if a transferred-out patient has a 'transfer out reason' specified as 'death'. Confirmation of cases was carried out by examining individual patient profiles and from questionnaires sent to GPs. If necessary, the death certificates and/or post mortem reports were obtained by the source data verification service the GPRD provide. Once cases of death were identified, crude mortality rate (CMR) and standardized mortality ratio (SMR) were calculated. Baseline mortality rates were obtained from the Office for National Statistics. A modified WHO causality assessment was conducted to determine the likelihood of a relationship between the drug and an event of death. RESULTS: The cohort contained 2767 patients who received at least one antipsychotic prescription. There were 30 deceased cases in the cohort. The GP questionnaire response rate was 97%. Of the 30 cases, 24 were related to pre-existing medical conditions, including neoplastic diseases and HIV. After excluding these patients, six cases of death from 5963 person-years and 1958 treatment-years remained. The median age of death was 17 years (interquartile range 14-17.75). The overall CMR was 1.01 per 1000 person-years at risk (95% CI 0.20, 1.81) and SMR was 4.03 (95% CI 1.48, 8.76). Of the six cases, only one was deemed possibly associated with antipsychotic therapy, based on the causality assessment analysis conducted; CMR based on this case was 0.51 per 1000 treatment-years (95% CI 0.09, 2.89). The remaining five cases of death were unlikely to be associated with antipsychotic therapy. CONCLUSIONS: Our study demonstrated an elevated SMR in patients exposed to antipsychotics. However, the elevated SMR was unlikely caused by antipsychotic treatment, but would suggest the possibility of inadequate management or poor control of patients' underlying medical conditions prior to death.

Mortality rates and causes of death in children with epilepsy prescribed antiepileptic drugs: a retrospective cohort study using the UK General Practice Research Database.

BACKGROUND: Patients with epilepsy, including children, have an increased risk of mortality compared with the general population. Antiepileptic drugs (AEDs) were the most frequent class of drugs reported in a study looking at fatal suspected adverse drug reactions in children in the UK. OBJECTIVE: The objective of the study was to identify cases and causes of death in a paediatric patient cohort prescribed AEDs with an associated epilepsy diagnosis. METHODS: This was a retrospective cohort study supplemented with general practitioner-completed questionnaires, post-mortem reports and death certificates. The setting was UK primary care practices contributing to the General Practice Research Database. Participants were children and adolescents aged 0-18 years prescribed AEDs between 1993 and 2005. Causality assessment was undertaken by a consensus panel comprising paediatric specialists in neuropathology, neurology, neuropsychiatry, paediatric epilepsy, pharmacoepidemiology and pharmacy to determine crude mortality rate (CMR) and standardized mortality ratios (SMRs), and the likelihood of an association between AED(s) and the event of death. RESULTS: There were 6190 subjects in the cohort (contributing 26,890 person-years of data), of whom 151 died. Median age at death was 8.0 years. CMR was 56.2 per 10,000 person-years and the SMR was 22.4 (95% CI 18.9, 26.2). The majority of deceased subjects had severe underlying disorders. Death was attributable to epilepsy in 18 subjects; in 9 the cause of death was sudden unexpected death in epilepsy (SUDEP) [3.3 per 10 000 person-years (95% CI 1.5, 6.4)]. AEDs were probably (n = 2) or possibly (n = 3) associated causally with death in five subjects. Two status epilepticus deaths were associated causally with AED withdrawal. CONCLUSIONS: Children prescribed AEDs have an increased risk of mortality relative to the general population. Most of the deaths were in children with serious underlying disorders. A small number of SUDEP cases were identified. AEDs are not a major cause of death but in a small proportion of cases, a causal relationship between death and AEDs could not be excluded.

The prescribing of analgesics and non-steroidal anti-inflammatory drugs in paediatric primary care in the UK, Italy and the Netherlands.

Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are commonly prescribed drugs which are frequently used for the treatment of various painful conditions. However, particularly for the paediatric population, there is a lack of information on effectiveness, safety and appropriate formulation resulting in off-label use and undertreatment. The aim of this study was to investigate the prescribing patterns of non-steroid anti-inflammatory drugs and opioids in children and adolescents in three European countries. A retrospective cohort study was conducted using the same protocol in three primary care databases: Pedianet (Italy), IPCI (Netherlands) and IMS Disease Analyzer (UK). User prevalence rates were calculated for opioids (N02A) and non-steroidal anti-inflammatory drugs (NSAIDs) (M01A) based on ATC therapeutic and chemical levels and stratified by country, age and gender. The prescribing prevalence for NSAIDs was lower in the Netherlands compared to Italy and the UK. Ibuprofen was the most frequently prescribed drug in this group in Italy (20.8 users/1000 PY) and the UK (30.6 users/1000 PY) whereas diclofenac was dominant in the Netherlands (1.7 users/1000 PY). Among opioids, codeine and codeine combinations were most commonly prescribed; only little use was seen for other drugs. There is a great variety of different NSAIDs and opioids prescribed to children in Europe in primary care. This is due to a varying availability of drugs in different countries but also because of differing prescribing attitudes, reimbursement scheme and a lack of data on the effectiveness of individual drugs. Further research into the rationale for prescribing these drugs to children is clearly needed.