Using routinely recorded data in the UK to assess outcomes in a randomised controlled trial: The Trials of Access.

BACKGROUND: In the UK, routinely recorded data may benefit prospective studies including randomised controlled trials (RCTs). In an on-going study, we aim to assess the feasibility of access and agreement of routinely recorded clinical and non-clinical data compared to data collected during a RCT using standard prospective methods. This paper will summarise available UK routinely recorded data sources and discuss our experience with the feasibility of accessing routinely recorded data for participants of a RCT before finally proposing recommendations for improving the access and implementation of routinely recorded data in RCTs. METHODS: Setting: the case study RCT is the Standard and New Antiepileptic Drugs II (SANAD II) trial, a pragmatic, UK, multicentre, phase IV RCT assessing the clinical and cost-effectiveness of antiepileptic drug treatments for newly diagnosed epilepsy. PARTICIPANTS: 98 participants have provided written consent to permit the request of routinely recorded data. Study procedures: routinely recorded clinical and non-clinical data were identified and data requested through formal applications from available data holders for the duration that participants have been recruited into SANAD II. The feasibility of accessing routinely recorded data during a RCT is assessed and recommendations for improving access proposed. RESULTS: Secondary-care clinical and socioeconomic data is recorded on a national basis and can be accessed, although there are limitations in the application process. Primary-care data are recorded by a number of organisations on a de-identified basis but access for specific individuals has not been feasible. Access to data recorded by non-clinical sources, including The Department for Work and Pensions and The Driving and Vehicle Licensing Agency, was not successful. CONCLUSIONS: Recommendations discussed include further research to assess the attributes of routinely recorded data, an assessment of public perceptions and the development of strategies to collaboratively improve access to routinely recorded data for research. TRIAL REGISTRATION: International Standard Randomised Controlled Trials, ISRCTN30294119 . Registered on 3 July 2012. EudraCT No: 2012-001884-64. Registered on 9 May 2012.

Risk of a seizure recurrence after a breakthrough seizure and the implications for driving: further analysis of the standard versus new antiepileptic drugs (SANAD) randomised controlled trial.

OBJECTIVES: A breakthrough seizure is one occurring after at least 12 months seizure freedom while on treatment. The Driver and Vehicle Licensing Agency (DVLA) allows an individual to return to driving once they have been seizure free for 12 months following a breakthrough seizure. This is based on the assumption that the risk of a further seizure in the next 12 months has dropped <20%. This analysis considers whether the prescribed 1 year off driving following a breakthrough seizure is sufficient for this and stratifies risk according to clinical characteristics. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS AND MAIN OUTCOME MEASURES: The multicentre UK-based Standard versus New Antiepileptic Drugs (SANAD) study was a randomised controlled trial assessing standard and new antiepileptic drugs for patients with newly diagnosed epilepsy. For participants aged at least 16 with a breakthrough seizure, data have been analysed to estimate the annual seizure recurrence risk following a period of 6, 9 and 12 months seizure freedom. Regression modelling was used to investigate how antiepileptic drug treatment and a number of clinical factors influence the risk of seizure recurrence. RESULTS: At 12 months following a breakthrough seizure, the overall unadjusted risk of a recurrence over the next 12 months is lower than 20%, risk 17% (95% CI 15% to 19%). However, some patient subgroups have been identified which have an annual recurrence risk significantly greater than 20% after an initial 12-month seizure-free period following a breakthrough seizure. CONCLUSIONS: This reanalysis of SANAD provides estimates of seizure recurrence risks following a breakthrough seizure that will inform policy and guidance about regaining an ordinary driving licence. Further guidance is needed as to how such data should be used. TRIAL REGISTRATION NUMBER: SANAD is registered with the International Standard Randomised Controlled Trial Number Register ISRCTN38354748.

Fibrin sealants in soft tissue surgery of the head and neck: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Fibrin sealants (FS) are commercially available products used in surgical wounds as adjuncts to haemostasis and closure of dead space. The role of FS in soft tissue head and neck surgery has not been established. OBJECTIVES: To assess whether FS improves wound-related outcomes in patients undergoing soft tissue surgery of the head and neck anatomical region that would commonly require a drain. TYPE OF REVIEW: Systematic review and meta-analysis of randomised controlled trials (RCTs). SEARCH STRATEGY: MEDLINE (1946-2016), EMBASE (1974-2016), PubMed (2016), CENTRAL (2016), ClinicalTrials.gov (2016), WHO International Clinical Trials Registry and Platform (2016), Research Gate (2016). EVALUATION METHOD: Two independent reviewers screened and selected studies. Included studies were assessed for risk of bias and data extracted using a predetermined data collection form. RESULTS: Of the 421 studies that were screened, 11 RCTs met the inclusion criteria. There were two RCTs on thyroidectomy, three on "surgery involving neck dissection" (central or lateral), five on rhytidectomy and one on parotidectomy. There was a tendency for FS to reduce "mean total drainage volume" (mean difference -26.86 mL, 95% CI -43.41 to -10.31, I2 =97%, P=.001). Subgroup analysis of thyroidectomy (mean difference -36.36 mL, 95% CI -72.82 to 0.10, I2 =79%, P=.05), "surgery involving neck dissection" (mean difference -33.21 mL, 95% CI -70.01 to 3.59, I2 =94%, P=.08) and rhytidectomy (mean difference -13.79 mL, 95% CI -17.57 to -10.01, I2 =0%, P < .00001) concurred with the overall analysis. There was a suggestion that FS may reduce "mean retention time of drains" by 1.24 days (95% CI -3.32 to 0.85, I2 =99%, P=.25) and "hospital length of stay" by 2.09 days (95% CI -5.18 to 0.99, I2 =97%, P=.18), but this was not statistically significant. There was also a suggestion that FS may protect against adverse events (RR 0.69, 95% CI 0.35 to 1.38, I2 =0%, P=.29) and haematoma/seroma formation (RR 0.49, 95% CI 0.22 to 1.07, I2 =0%, P=0.07). CONCLUSIONS: There was considerable heterogeneity within the RCTs included in this study, thus restricting definitive conclusions. FS has however shown a definite benefit in rhytidectomy and potential benefit in other soft tissue head and neck surgical procedures. Further pragmatic trials are required particularly in the field of lateral neck dissection.

How should individual participant data (IPD) from publicly funded clinical trials be shared?

BACKGROUND: Individual participant data (IPD) from completed clinical trials should be responsibly shared to support efficient clinical research, generate new knowledge and bring benefit to patients. The Medical Research Council (MRC) Hubs for Trials Methodology Research (HTMR) has developed guidance to facilitate the sharing of IPD from publicly funded clinical trials. METHODS: Development of the guidance was completed over four phases which included a focussed review of policy documents, a web-based survey of the UK Clinical Research Collaboration (CRC) Registered Clinical Trials Units (CTU) Network, participation of an expert committee and an open consultation with the UKCRC Registered CTU Network. The project was funded by the MRC HTMR (MR/L004933/1-R39). RESULTS: Good practice principles include: (i) the use of a controlled access approach, using a transparent and robust system to review requests and provide secure data access; (ii) seeking consent for sharing IPD from trial participants in all future clinical trials with adequate assurance that patient privacy and confidentiality can be maintained; and (iii) establishing an approach to resource the sharing of IPD which would include support from trial funders, sponsor organisations and users of IPD. The guidance has been endorsed by Cancer Research UK, MRC Methodology Research Programme Advisory Group, Wellcome Trust and the Executive Group of the UKCRC Registered CTU Network. The National Institute for Health Research (NIHR) has confirmed it is supportive of the application of this guidance. CONCLUSIONS: Implementation of these principles will improve transparency, increase the coherent sharing of IPD from publicly funded trials, and help publicly funded trials to adhere to trial funder and journal requirements for data sharing.

'Seizure First Aid Training' for people with epilepsy who attend emergency departments, and their family and friends: study protocol for intervention development and a pilot randomised controlled trial.

INTRODUCTION: People with chronic epilepsy (PWE) often make costly but clinically unnecessary emergency department (ED) visits. Offering them and their carers a self-management intervention that improves confidence and ability to manage seizures may lead to fewer visits. As no such intervention currently exists, we describe a project to develop and pilot one. METHODS AND ANALYSIS: To develop the intervention, an existing group-based seizure management course that has been offered by the Epilepsy Society within the voluntary sector to a broader audience will be adapted. Feedback from PWE, carers and representatives from the main groups caring for PWE will help refine the course so that it addresses the needs of ED attendees. Its behaviour change potential will also be optimised. A pilot randomised controlled trial will then be completed. 80 PWE aged ≥16 who have visited the ED in the prior 12 months on ≥2 occasions, along with one of their family members or friends, will be recruited from three NHS EDs. Dyads will be randomised to receive the intervention or treatment as usual alone. The proposed primary outcome is ED use in the 12 months following randomisation. For the pilot, this will be measured using routine hospital data. Secondary outcomes will be measured by patients and carers completing questionnaires 3, 6 and 12 months postrandomisation. Rates of recruitment, retention and unblinding will be calculated, along with the ED event rate in the control group and an estimate of the intervention's effect on the outcome measures. ETHICS AND DISSEMINATION: Ethical approval: NRES Committee North West-Liverpool East (Reference number 15/NW/0225). The project's findings will provide robust evidence on the acceptability of seizure management training and on the optimal design of a future definitive trial. The findings will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: ISRCTN13 871 327.

Will smaller plates lead to smaller waists? A systematic review and meta-analysis of the effect that experimental manipulation of dishware size has on energy consumption.

It has been suggested that providing consumers with smaller dishware may prove an effective way of helping people eat less and preventing weight gain, but experimental evidence supporting this has been mixed. The objective of the present work was to examine the current evidence base for whether experimentally manipulated differences in dishware size influence food consumption. We systematically reviewed studies that experimentally manipulated the dishware size participants served themselves at a meal with and measured subsequent food intake. We used inverse variance meta-analysis, calculating the standardized mean difference (SMD) in food intake between smaller and larger dishware size conditions. Nine experiments from eight publications were eligible for inclusion. The majority of experiments found no significance difference in food intake when participants ate from smaller vs. larger dishware. With all available data included, analysis indicated a marginal effect of dishware size on food intake, with larger dishware size associated with greater intake. However, this effect was small and there was a large amount of heterogeneity across studies (SMD: -0.18, 95% confidence interval: -0.35, 0.00, I(2) = 77%). Evidence to date does not show that dishware size has a consistent effect on food intake, so recommendations surrounding the use of smaller plates/dishware to improve public health may be premature.

Clinical effectiveness and cost-effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer: a systematic review and economic evaluation.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) has issued multiple guidance for the first-line management of patients with lung cancer and recommends different combinations of chemotherapy treatments. This review provides a synthesis of clinical effectiveness and cost-effectiveness evidence supporting current guidance. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of first-line chemotherapy currently licensed in Europe and recommended by NICE, for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). DATA SOURCES: Three electronic databases (MEDLINE, EMBASE and The Cochrane Library) were searched from 2001 to August 2010. REVIEW METHODS: Trials that compared first-line chemotherapy currently licensed in Europe and recommended by NICE in chemotherapy-naive adult patients with locally advanced or metastatic NSCLC were included. Data on key outcomes including, but not limited to, overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were extracted. For the assessment of cost-effectiveness, outcomes included incremental cost per quality-adjusted life-year (QALY) gained. Analyses were performed for three NSCLC subpopulations: patients with predominantly squamous disease, patients with predominantly non-squamous disease and patients with epidermal growth factor receptor (EGFR) mutation-positive (M+) status. Meta-analysis and mixed-treatment comparison methodology were conducted where appropriate. RESULTS: Twenty-three trials involving > 11,000 patients in total met the inclusion criteria. The quality of the trials was poor. In the case of patients with squamous disease, there were no statistically significant differences in OS between treatment regimes. The mixed-treatment comparison demonstrated that, in patients with non-squamous disease, pemetrexed (Alimta®, Eli Lilly and Company; PEM) + platinum (PLAT) increases OS statistically significantly compared with gemcitabine (Gemzar®, Eli Lilly and Company; GEM) + PLAT [hazard ratio (HR) = 0.85; 95% confidence interval (CI) 0.74 to 0.98] and that paclitaxel (Abraxane®, Celgene Corporation; PAX) + PLAT increases OS statistically significantly compared with docetaxel (Taxotere®, Sanofi-aventis; DOC) + PLAT (HR = 0.79, 95% CI 0.66 to 0.93). None of the comparisons found any statistically significant differences in OS among patients with EGFR M+ status. Direct meta-analysis showed a statistically significant improvement in PFS with gefitinib (Iressa®, AstraZeneca; GEF) compared with DOC + PLAT and PAX + PLAT (HR = 0.49; 95% CI 0.33 to 0.73; and HR = 0.38; 95% CI 0.24 to 0.60, respectively). No papers related to UK decision-making were identified. A de novo economic model was developed. Using list prices (British National Formulary), cisplatin (CIS) doublets are preferable to carboplatin doublets, but this is reversed if electronic market information tool prices are used, in which case drug administration costs then become more important than drug acquisition costs. For patients with both squamous and non-squamous disease, moving from low to moderate willingness-to-pay thresholds, the preferred drugs are PAX → GEM → DOC. However, in patients with non-squamous disease, PEM + CIS resulted in increased OS and would be considered cost-effective up to £35,000 per QALY gained. For patients with EGFR M+, use of GEF compared with PAX or DOC yields very high incremental cost-effectiveness ratios. Vinorelbine (Navelbine®, Pierre Fabre Pharmaceutical Inc.) was not shown to be cost-effective in any comparison. LIMITATIONS: Poor trial quality and a lack of evidence for all drug comparisons complicated and limited the data analysis. Outcomes and adverse effects are not consistently combined across the trials. Few trials reported quality-of-life data despite their relevance to patients and clinicians. CONCLUSIONS: The results of this comprehensive review are unique to NSCLC and will assist clinicians to make decisions regarding the treatment of patients with advanced NSCLC. The design of future lung cancer trials needs to reflect the influence of factors such as histology, genetics and the new prognostic biomarkers that are currently being identified. In addition, trials will need to be adequately powered so as to be able to test for statistically significant clinical effectiveness differences within patient populations. New initiatives are in place to record detailed information on the precise chemotherapy (and targeted chemotherapy) regimens being used, together with data on age, cell type, stage of disease and performance status, allowing for very detailed observational audits of management and outcomes at a population level. It would be useful if these initiatives could be expanded to include the collection of health economics data. FUNDING: The National Institute for Health Research Health Technology Assessment.

Management of Asthma in School age Children On Therapy (MASCOT): a randomised, double-blind, placebo-controlled, parallel study of efficacy and safety.

BACKGROUND: Asthma affects one in eight children in the UK. National management guidelines have been available for many years but, unlike in adults, studies in children have been few, with their methodologies often based on inappropriate adult models. Sound medical evidence in support of the national guidelines for asthma management in children is lacking. The MASCOT study has been developed to address this need. OBJECTIVES: To determine whether adding salmeterol or montelukast to low-dose inhaled corticosteroids (ICSs) can reduce the number of exacerbations requiring treatment with oral corticosteroids in children with uncontrolled asthma. DESIGN: A randomised, double-blind, placebo-controlled trial with a 4-week run-in period on a fluticasone propionate inhaler (100 µg twice daily) with inhaler technique correction. Patients who met the post run-in period eligibility criteria were randomised in the ratio of 1 : 1 : 1 and were followed for 48 weeks. SETTING: Secondary care hospitals based in England and Scotland with recruitment from primary and secondary care. PARTICIPANTS: Children aged 6-14 years with asthma requiring frequent short-acting beta-2 agonist relief, with symptoms of asthma resulting in nocturnal wakening and/or asthma that has interfered with usual activities. INTERVENTIONS: Three groups were compared: (1) inhaled fluticasone propionate 100 µg twice daily plus placebo tablet once daily; (2) inhaled fluticasone propionate 100 µg and salmeterol 50 µg twice daily (combination inhaler) plus placebo tablet once daily; and (3) inhaled fluticasone propionate 100 µg twice daily plus montelukast 5-mg tablet once daily. MAIN OUTCOME MEASURES: The primary outcome was the number of exacerbations requiring treatment with oral corticosteroids over 48 weeks. Secondary outcome measures included quality of life as measured by the Paediatric Asthma Quality of Life Questionnaire with Standardised Activities [PAQLQ(S)] and the Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ); time from randomisation to first exacerbation requiring treatment with a short course of oral corticosteroids; school attendance; hospital admissions; amount of rescue beta-2 agonist therapy prescribed; time from randomisation to treatment withdrawal (because of lack of efficacy or side effects); lung function at 48 weeks (as assessed by spirometry); cost-effectiveness; adverse events. RESULTS: The study was closed prematurely because of poor recruitment and the target sample size of 450 was not achieved. In total, 898 children were screened to enter the trial, 166 were registered for the 4-week run-in period and 63 were randomised (group 1: 19, group 2: 23, group 3: 21), with 38 contributing data for the primary outcome analysis. There were no significant differences between groups for any of the outcomes. Adverse events were similar between the groups except for nervous system disorders, which were more frequently reported on fluticasone plus montelukast. CONCLUSIONS: Based on the results of the MASCOT study it is not possible to conclude whether adding salmeterol or montelukast to ICSs can reduce the number of exacerbations requiring treatment with oral corticosteroids in children with uncontrolled asthma. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03556343. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 4. See the HTA programme website for further project information.

Clinical effectiveness of first-line chemoradiation for adult patients with locally advanced non-small cell lung cancer: a systematic review.

BACKGROUND: The National Institute for Health and Clinical Excellence has issued guidelines on the treatment of non-small cell lung cancer (NSCLC) and recommends that patients with stage IIIA-IIIB disease who are not amenable to surgery be treated with potentially curative chemoradiation (CTX-RT). This review was conducted as part of a larger systematic review of all first-line chemotherapy (CTX) and CTX-RT treatments for patients with locally advanced or metastatic NSCLC. However, it was considered that patients with potentially curable disease (e.g. stage IIIA) are different from those with advanced disease, who are suitable for palliative treatment only, and therefore the results should be reported separately. OBJECTIVE: To evaluate the clinical effectiveness of first-line CTX in addition to radiotherapy (RT) (CTX-RT vs CTX-RT) for adult patients with locally advanced NSCLC who are suitable for potentially curative treatment. DATA SOURCES: Three electronic databases (MEDLINE, EMBASE and The Cochrane Library) were searched from January 1990 to September 2010. REVIEW METHODS: Inclusion criteria comprised adult patients with locally advanced NSCLC, trials that compared any first-line CTX-RT therapy (induction, sequential, concurrent and consolidation) and outcomes of overall survival (OS) and/or progression-free survival (PFS). The results of clinical data extraction and quality assessment were summarised in tables and with narrative description. Direct meta-analyses using OS data were undertaken where possible: sequential CTX-RT compared with concurrent CTX-RT; sequential CTX-RT compared with concurrent/consolidation CTX-RT; and sequential CTX-RT compared with concurrent CTX-RT with or without consolidation. There were not sufficient data to perform meta-analysis on PFS. RESULTS: Of the 240 potentially relevant studies that were published post 2000, 19 met the inclusion criteria and compared CTX-RT with CTX-RT. The results from the OS meta-analysis comparing sequential CTX-RT with concurrent CTX-RT appear to show an OS advantage for concurrent CTX-RT arms over sequential arms; this result is not statistically significant [hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.50 to 1.25)]. The results from the OS meta-analysis comparing sequential CTX-RT with concurrent/consolidation CTX-RT appear to show a statistically significant OS advantage for concurrent/consolidation CTX-RT treatment over sequential treatment (HR 0.68; 95% CI 0.55 to 0.83). The results from the OS meta-analysis comparing sequential CTX-RT with concurrent CTX-RT with or without consolidation appear to show a statistically significant OS advantage for concurrent CTX-RT with or without consolidation over sequential treatment (HR 0.72; 95% CI 0.61 to 0.84). LIMITATIONS: This report provides a summary and critical appraisal of a comprehensive evidence base of CTX-RT trials; however, it is possible that additional trials have been reported since our last literature search. It is disappointing that the quality of the research in this area does not meet the accepted quality standards regarding trial design and reporting. CONCLUSIONS: This review identified that the research conducted in the area of CTX-RT was generally of poor quality and suffered from a lack of reporting of all important clinical findings, including OS. The 19 trials included in the systematic review were too disparate to form any conclusions as to the effectiveness of individual CTX agents or types of RT. The focus of primary research should be good methodological quality; appropriate allocation of concealment and randomisation, and comprehensive reporting of key outcomes, will enable meaningful synthesis and conclusions to be drawn. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Meta-analysis of immunohistochemical prognostic markers in resected pancreatic cancer.

BACKGROUND: The potential prognostic value of several commonly investigated immunohistochemical markers in resected pancreatic cancer is variably reported. The objective of this study was to conduct a systematic review of literature evaluating p53, p16, smad4, bcl-2, bax, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression as prognostic factors in resected pancreatic adenocarcinoma and to conduct a subsequent meta-analysis to quantify the overall prognostic effect. METHODS: Relevant literature was identified using Medline, EMBASE and ISI Web of Science. The primary end point was overall survival assessed on univariate analysis. Only studies analysing resected pancreatic adenocarcinoma were eligible for inclusion and the summary log(e) hazard ratio (logHR) and variance were pooled using an inverse variance approach. Evidence of heterogeneity was evaluated using the χ(2) test for heterogeneity and its impact on the meta-analysis was assessed by the I(2) statisic. Hazard ratios greater than one reflect adverse survival associated with positive immunostaining. RESULTS: Vascular endothelial growth factor emerged as the most potentially informative prognostic marker (11 eligible studies, n=767, HR=1.51 (95% confidence interval, CI=1.18-1.92)) with no evidence of any significant publication bias (Egger's test, P=0.269). Bcl-2 (5 eligible studies, n=314, HR=0.51 (95% CI=0.38-0.68)), bax (5 studies, n=274, HR=0.63 (95% CI=0.48-0.83)) and p16 (3 studies, n=229, HR=0.63 (95% CI=0.43-0.92)) also returned significant overall survival differences, but in smaller patient series due to a lack of evaluable literature. Neither p53 (17 studies, n=925, HR=1.22 (95% CI=0.96-1.56)), smad4 (5 studies, n=540, HR=0.88 (95% CI=0.61-1.27)) nor EGFR (4 studies, n=250, HR=1.35 (95% CI=0.80-2.27)) was found to represent significant prognostic factors when analysing the pooled patient data. There was evidence of significant heterogeneity in four of the seven study groups. CONCLUSION: These results support the case for immunohistochemical expression of VEGF representing a significant and reproducible marker of adverse prognosis in resected pancreatic cancer.

Risk of recurrence after a first seizure and implications for driving: further analysis of the Multicentre study of early Epilepsy and Single Seizures.

OBJECTIVE: To determine for how long after a first unprovoked seizure a driver must be seizure-free before the risk of recurrence in the next 12 months falls below 20%, enabling them to regain their driving licence. DESIGN: Randomised controlled trial: Multicentre study of early Epilepsy and Single Seizures (MESS). SETTING: UK hospital outpatient clinics from 1 January 1993 to 31 December 2000. PARTICIPANTS: People entered MESS if they had had one or more unprovoked seizures and both the participant and the clinician were uncertain about the need to start antiepileptic drug treatment. The subset of people used for this analysis comprised participants aged at least 16 years with a single unprovoked seizure. MAIN OUTCOME MEASURE: Risk of seizure recurrence in the 12 months after a seizure-free period of 6, 12, 18, or 24 months from the date of the first (index) seizure. Regression modelling was used to investigate how antiepileptic treatment and several clinical factors influence the risk of seizure recurrence. RESULTS: At six months after the index seizure the risk of recurrence in the next 12 months for those who start antiepileptic drugs was significantly below 20% (unadjusted risk 14%, 95% confidence interval 10% to 18%). For patients who did not start treatment the risk estimate was less than 20% but the upper limit of the confidence interval was greater than 20% (18%, 13% to 23%). Multivariable analyses identified subgroups with a significantly greater than 20% risk of seizure recurrence in the 12 months after a six month seizure-free period, such as those with a remote symptomatic seizure with abnormal electroencephalogram results. CONCLUSION: After a single unprovoked seizure this reanalysis of MESS provides estimates of seizure recurrence risks that will inform policy and guidance about regaining an ordinary driving licence. Further guidance is needed as to how such data should be utilised; in particular, whether a population approach should be taken with a focus on the unadjusted results or whether attempts should be made to individualise risk. Guidance is also required as to whether the focus should be on risk estimates only or on the confidence interval as well. If the focus is on the estimate only our unadjusted estimates suggest that treated and untreated patients are eligible to drive after being seizure-free for six months. If the focus is also on confidence intervals, direction is needed as to whether a conservative or liberal approach should be taken. TRIAL REGISTRATION: Current Controlled Trials ISRCTN98767960.

Pemetrexed for the first-line treatment of locally advanced or metastatic non-small cell lung cancer.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of pemetrexed for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), in accordance with the licensed indication, based upon the evidence submission from Eli Lilly Ltd to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The majority of the efficacy evidence described in the manufacturer's submission is derived from a phase III open-label randomised controlled trial (RCT) known as the JMDB trial. The trial achieved its primary objective to demonstrate non-inferiority of pemetrexed/cisplatin to gemcitabine/cisplatin for overall survival in all patients with NSCLC. Because no other studies were found comparing pemetrexed/cisplatin with any other relevant comparator, additional efficacy evidence was presented from two phase III RCTs comparing gemcitabine/cisplatin with gemcitabine/carboplatin and docetaxel/cisplatin. The manufacturer's submission reported from its indirect comparisons' analysis that median overall survival and progression-free survival and tumour response rates were more favourable for pemetrexed/cisplatin than for any other comparator. The manufacturer did not identify any published cost-effectiveness analyses of pemetrexed for the first-line treatment of patients with NSCLC. Therefore economic evidence was derived solely from a de novo economic model developed by the manufacturer. A Markov model was developed to evaluate the cost-effectiveness of pemetrexed/cisplatin compared to gemcitabine/cisplatin, docetaxel/cisplatin and gemcitabine/carboplatin. The clinical data used in the economic evaluation were primarily generated from the JMDB trial, with additional data from the two further trials used in the indirect comparisons analysis. The ERG identified a series of problems with this economic model. As a result, three different versions of the model were submitted to NICE and considered by the ERG. The ICERs estimated by this final version of the model ranged from 8056 pounds to 33,065 pounds per QALY, depending on the comparator, the population and the application of a continuation rule. The ERG considered that the model required extensive modification and redesign, and should be subjected to thorough validation against the JMDB trial results. A full quality audit was also required as it was likely that further model inconsistencies may be present that had not yet been identified. The manufacturer subsequently included evidence in the form of three cost effectiveness analyses (two models and an 'in-trial' analysis), stating that a thorough validation process had been followed according to the NICE request. The very short time available to the ERG to consider the new evidence precluded a comprehensive assessment. Instead, the ERG chose to present a simple exploratory analysis combining its own survival projections with key cost estimates obtained from the JMDB trial individual patient data. Compared to gemcitabine, this resulted in ICERs ranging from 17,162 pounds to 30,142 pounds per QALY, depending on the patient population, the maximum number of cycles of chemotherapy and whether a cycle based efficacy adjustment was applied or not. The guidance issued by NICE in September 2009 states that pemetrexed in combination with cisplatin is recommended as an option for the first-line treatment of patients with locally advanced or metastatic NSCLC only if the histology of the tumour has been confirmed as adenocarcinoma or large-cell carcinoma.

Adjuvant 5-fluorouracil and folinic acid vs observation for pancreatic cancer: composite data from the ESPAC-1 and -3(v1) trials.

The ESPAC-1, ESPAC-1 plus, and early ESPAC-3(v1) results (458 randomized patients; 364 deaths) were used to estimate the effectiveness of adjuvant 5FU/FA vs resection alone for pancreatic cancer using meta-analysis. The pooled hazard ratio of 0.70 (95% CI=0.55-0.88) P=0.003, and the median survival of 23.2 (95% CI=20.1-26.5) months with 5FU/FA vs 16.8 (95% CI=14.3-19.2) months with resection alone supports the use of adjuvant 5FU/FA in pancreatic cancer.

Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer: results of secondary end points analyses.

In advanced pancreatic cancer, level one evidence has established a significant survival advantage with chemotherapy, compared to best supportive care. The treatment-associated toxicity needs to be evaluated. This study examines the secondary outcome measures for chemotherapy in advanced pancreatic cancer using meta-analyses. A systematic review was undertaken employing Cochrane methodology, with search of databases, conference proceedings and trial registers. The secondary end points were progression-free survival (PFS)/time to progression (TTP) (summarised using the hazard ratio (HR)), response rate and toxicity (summarised using relative risk). There was no significant advantage of 5FU combinations vs 5FU alone for TTP (HR=1.02; 95% CI=0.85-1.23) and toxicity. Progression-free survival (HR 0.78; CI 0.70-0.88), TTP (HR=0.85; 95% CI=0.72-0.99) and overall response rate (RR=0.56; 95% CI=0.46-0.68) were significantly better for gemcitabine combination chemotherapy, but offset by the greater grade 3/4 toxicity thrombocytopenia (RR=1.94; 95% CI=1.32-2.84), leucopenia (RR=1.46; 95% CI=1.15-1.86), neutropenia (RR=1.48; 95% CI=1.07-2.05), nausea (RR=1.77; 95% CI=1.37-2.29), vomiting (RR=1.64; 95% CI=1.24-2.16) and diarrhoea (RR=2.73; 95% CI=1.87-3.98). There is no significant advantage on secondary end point analyses for administering 5FU in combination over 5FU alone. There is improved PFS/TTP and response rate, with gemcitabine-based combinations, although this comes with greater toxicity.

Cervical stitch (cerclage) for preventing pregnancy loss: individual patient data meta-analysis.

BACKGROUND: Several observational studies have claimed high success rates for cerclage in women with cervical insufficiency. A recent Cochrane review found no conclusive evidence of benefit, although significant heterogeneity was present for some of the important clinical outcomes. OBJECTIVES: We undertook an individual patient data (IPD) meta-analysis to examine effect of cerclage on neonatal and maternal outcomes. In an attempt to explain the heterogeneity, we investigated whether obstetric factors including multiple gestation are associated with effectiveness. SEARCH STRATEGY: Search methods described in the original Cochrane review were adopted and updated to December 2005. SELECTION CRITERIA: This IPD systematic review and meta-analysis was of randomised trials comparing cervical cerclage during pregnancy with expectant management or no cerclage in women with confirmed or suspected as having cervical insufficiency. ANALYSIS: Multilevel logistic regression models stratified by trial with random treatment effects were fitted to investigate the impact of obstetric factors and multiple gestation on treatment effect. Primary outcome measures were pregnancy loss or death before discharge from hospital and absence of neonatal morbidity. MAIN RESULTS: The meta-analysis included seven trials and 2091 randomised women. In singleton pregnancies, the reduction in pregnancy loss or death before discharge from hospital following cerclage failed to reach statistical significance (OR 0.81; 95% CI 0.60-1.10). Cerclage was found to have a detrimental effect on the outcome of pregnancy loss or death before discharge from hospital in multiple gestations (OR 5.88; 95% CI 1.14-30.19), although only a small number of multiple pregnancies were included in the analysis. Neither indication for cerclage nor obstetric history was found to have a statistically significant impact on the effect of cerclage. CONCLUSIONS: Cerclage may reduce the risk of pregnancy loss or neonatal death before discharge from hospital in singleton pregnancies thought to be at risk of preterm birth, but further large trials are needed to elucidate the risk-benefit ratio precisely. Cerclage in multiple pregnancies should be avoided. The efficacy of cerclage was not influenced by either indication for cerclage or mother's obstetric history.

A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. The SANAD trial.

OBJECTIVES: To compare clinicians' choice of one of the standard epilepsy drug treatments (carbamazepine or valproate) versus appropriate comparator new drugs. DESIGN: A clinical trial comprising two arms, one comparing new drugs in carbamazepine and the other with valproate. SETTING: A multicentre study recruiting patients with epilepsy from hospital outpatient clinics. PARTICIPANTS: Patients with an adequately documented history of two or more clinically definite unprovoked epileptic seizures within the last year for whom treatment with a single antiepileptic drug represented the best therapeutic option. INTERVENTIONS: Arm A was carbamazepine (CBZ) versus gabapentin (GBP) versus lamotrigine (LTG) versus oxcarbazepine (OXC) versus topiramate (TPM). Arm B valproate (VPS) versus LTG versus TPM. MAIN OUTCOME MEASURES: Time to treatment failure (withdrawal of the randomised drug for reasons of unacceptable adverse events or inadequate seizure control or a combination of the two) and time to achieve a 12-month remission of seizures. Time from randomisation to first seizure, 24-month remission of seizures, incidence of clinically important adverse events, quality of life (QoL) outcomes and health economic outcomes were also considered. RESULTS: Arm A recruited 1721 patients (88% with symptomatic or cryptogenic partial epilepsy and 10% with unclassified epilepsy). Arm B recruited 716 patients (63% with idiopathic generalised epilepsy and 25% with unclassified epilepsy). In Arm A LTG had the lowest incidence of treatment failure and was statistically superior to all drugs for this outcome with the exception of OXC. Some 12% and 8% fewer patients experienced treatment failure on LTG than CBZ, the standard drug, at 1 and 2 years after randomisation, respectively. The superiority of LTG over CBZ was due to its better tolerability but there is satisfactory evidence indicating that LTG is not clinically inferior to CBZ for measures of its efficacy. No consistent differences in QoL outcomes were found between treatment groups. Health economic analysis supported LTG being preferred to CBZ for both cost per seizure avoided and cost per quality-adjusted life-year gained. In Arm B for time to treatment failure, VPS, the standard drug, was preferred to both TPM and LTG, as it was the drug least likely to be associated with treatment failure for inadequate seizure control and was the preferred drug for time to achieving a 12-month remission. QoL assessments did not show any between-treatment differences. The health economic assessment supported the conclusion that VPS should remain the drug of first choice for idiopathic generalised or unclassified epilepsy, although there is a suggestion that TPM is a cost-effective alternative to VPS. CONCLUSIONS: The evidence suggests that LTG may be a clinical and cost-effective alternative to the existing standard drug treatment, CBZ, for patients diagnosed as having partial seizures. For patients with idiopathic generalised epilepsy or difficult to classify epilepsy, VPS remains the clinically most effective drug, although TPM may be a cost-effective alternative for some patients. Three new antiepileptic drugs have recently been licensed in the UK for the treatment of epilepsy (levetiracetam, zonisamide and pregabalin), therefore these drugs should be compared in a similarly designed trial.

Systematic review, including meta-analyses, on the management of locally advanced pancreatic cancer using radiation/combined modality therapy.

There is no consensus on the management of locally advanced pancreatic cancer, with either chemotherapy or combined modality approaches being employed (Maheshwari and Moser, 2005). No published meta-analysis (Fung et al, 2003; Banu et al, 2005; Liang, 2005; Bria et al, 2006; Milella et al, 2006) has included randomised controlled trials employing radiation therapy. The aim of this systematic review was to compare the following: (i) chemoradiation followed by chemotherapy (combined modality therapy) vs best supportive care (ii) radiotherapy vs chemoradiation (iii) radiotherapy vs combined modality therapy (iv) chemotherapy vs combined modality therapy (v) 5FU-based combined modality treatment vs another-agent-based combined modality therapy. Relevant randomised controlled trials were identified by searching databases, trial registers and conference proceedings. The primary end point was overall survival and secondary end points were progression-free survival/time-to-progression, response rate and adverse events. Survival data were summarised using hazard ratio (HR) and response-rate/adverse-event data with relative risk. Eleven trials involving 794 patients met the inclusion criteria. Length of survival with chemoradiation was increased compared with radiotherapy alone (two trials, 168 patients, HR 0.69; 95% confidence interval (CI) 0.51-0.94), but chemoradiation followed by chemotherapy did not lead to a survival advantage over chemotherapy alone (two trials, 134 patients, HR 0.79; CI 0.32-1.95). Meta-analyses could not be performed for the other comparisons. A survival benefit was demonstrated for chemoradiation over radiotherapy alone. Chemoradiation followed by chemotherapy did not demonstrate any survival advantage over chemotherapy alone, but important clinical differences cannot be ruled out due to the wide CI.

The influence of competing-risks setting on the choice of hypothesis test for treatment effect.

There is considerable debate regarding the choice of test for treatment difference in a randomized clinical trial in the presence of competing risks. This question arose in the study of standard and new antiepileptic drugs (SANAD) trial comparing new and standard antiepileptic drugs. This paper provides simulation results for the log-rank test comparing cause-specific hazard rates and Gray's test comparing cause-specific cumulative incidence curves. To inform the analysis of the SANAD trial, competing-risks settings were considered where both events are of interest, events may be negatively correlated, and the degree of correlation may differ in the 2 treatment groups. In settings where there are effects in opposite directions for the 2 event types, a likely situation for the SANAD trial, Gray's test has greater power to detect treatment differences than log-rank analysis. For the epilepsy application, conclusions were qualitatively similar for both log-rank and Gray's tests.