[Show abstract][Hide abstract] ABSTRACT: Background Chalmers and Glasziou’s paper published in 2014 recommends research funding bodies should mandate that proposals for additional primary research are built on systematic reviews of existing evidence showing what is already known. Jones et al. identified 11 (23 %) of 48 trials funded during 2006–8 by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme did not reference a systematic review. This study did not explore the reasons for trials not referencing a systematic review or consider trials using any other evidence in the absence of a systematic review. Referencing a systematic review may not be possible in certain circumstances, for instance if the systematic review does not address the question being proposed in the trial. The current study extended Jones’ study by exploring the reasons for why trials did not reference a systematic review and included a more recent cohort of trials funded in 2013 to determine if there were any changes in the referencing or use of systematic reviews. Methods Two cohorts of NIHR HTA randomised controlled trials were included. Cohort I included the same trials as Jones et al. (with the exception of one trial which was discontinued). Cohort II included NIHR HTA trials funded in 2013. Data extraction was undertaken independently by two reviewers using full applications and trial protocols. Descriptive statistics was used and no formal statistical analyses were conducted. Results Five (11 %) trials of the 47 funded during 2006–2008 did not reference a systematic review. These 5 trials had warranted reasons for not referencing systematic reviews. All trials from Cohort II referenced a systematic review. A quarter of all those trials with a preceding systematic review used a different primary outcome than those stated in the reviews. Conclusions The NIHR requires that proposals for new primary research are justified by existing evidence and the findings of this study confirm the adherence to this requirement with a high rate of applications using systematic reviews.
Full-text · Article · Dec 2015 · BMC Medical Research Methodology
[Show abstract][Hide abstract] ABSTRACT: Background:
Bevacizumab (Avastin(®), Roche), which is used in cancer therapy, is the 'parent' molecule from which ranibizumab (Lucentis(®), Novartis) was derived for the treatment of neovascular age-related macular degeneration (nAMD). There were reports in the literature on the effectiveness of bevacizumab in treating nAMD, but no trials. The cost per dose of bevacizumab is about 5-10% that of ranibizumab. This trial was a head-to-head comparison of these two drugs.
To compare the clinical effectiveness and cost-effectiveness of ranibizumab and bevacizumab, and two treatment regimens, for nAMD.
Multicentre, factorial randomised controlled trial with within-trial cost-utility and cost-minimisation analyses from the perspective of the UK NHS. Participants, health professionals and researchers were masked to allocation of drug but not regimen. Computer-generated random allocations to combinations of ranibizumab or bevacizumab, and continuous or discontinuous regimen, were stratified by centre, blocked and concealed.
Twenty-three ophthalmology departments in NHS hospitals.
Patients ≥ 50 years old with active nAMD in the study eye with best corrected distance visual acuity (BCVA) ≥ 25 letters measured on a Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Previous treatment for nAMD, long-standing disease, lesion diameter > 6000 µm, thick blood at the fovea and any other confounding ocular disease were exclusion criteria. One eye per participant was studied; the fellow eye was treated according to usual care, if required.
Ranibizumab and bevacizumab were procured commercially. Doses were ranibizumab 0.5 mg or bevacizumab 1.25 mg. The repackaged bevacizumab was quality assured. All participants were treated at visits 0, 1 and 2. Participants randomised to the continuous regimen were treated monthly thereafter. Participants randomised to the discontinuous regimen were not retreated after visit 2 unless pre-specified criteria for active disease were met. If retreatment was needed, monthly injections over 3 months were mandated.
Main outcome measures:
The primary outcome was BCVA. The non-inferiority margin was 3.5 letters. Secondary outcomes were contrast sensitivity; near visual acuity; reading index; neovascular lesion morphology; generic and disease-specific patient-reported outcomes, including macular disease-specific quality of life; survival free from treatment failure; resource use; quality-adjusted life-years (QALYs); and development of new geographic atrophy (GA) (outcome added during the trial). Results are reported for the study eye, except for patient-reported outcomes.
Between 27 March 2008 and 15 October 2010, 610 participants were allocated and treated (314 ranibizumab, 296 bevacizumab; at 3 months, 305 continuous, 300 discontinuous). After 2 years, bevacizumab was neither non-inferior nor inferior to ranibizumab [-1.37 letters, 95% confidence interval (CI) -3.75 to +1.01 letters] and discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1.63 letters, 95% CI -4.01 to +0.75 letters). Lesion thickness at the fovea was similar by drug [geometric mean ratio (GMR) 0.96, 95% CI 0.90 to 1.03; p = 0.24] but 9% less with continuous treatment (GMR 0.91, 95% CI 0.85 to 0.97; p = 0.004). Odds of developing new GA during the trial were similar by drug [odds ratio (OR) 0.87, 95% CI 0.61 to 1.25; p = 0.46] but significantly higher with continuous treatment (OR 1.47, 95% CI 1.03 to 2.11; p = 0.033). Safety outcomes did not differ by drug but mortality was lower with continuous treatment (OR 0.47, 95% CI 0.22 to 1.03; p = 0.05). Continuous ranibizumab cost £3.5M per QALY compared with continuous bevacizumab; continuous bevacizumab cost £30,220 per QALY compared with discontinuous bevacizumab. These results were robust in sensitivity analyses.
Ranibizumab and bevacizumab have similar efficacy. Discontinuing treatment and restarting when required results in slightly worse efficacy. Safety was worse with discontinuous treatment, although new GA developed more often with continuous treatment. Ranibizumab is not cost-effective, although it remains uncertain whether or not continuous bevacizumab is cost-effective compared with discontinuous bevacizumab at £20,000 per QALY threshold. Future studies should focus on the ocular safety of the two drugs, further optimisation of treatment regimens and criteria for stopping treatment.
Current Controlled Trials ISRCTN92166560.
This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 78. See the NIHR Journals Library website for further project information.
[Show abstract][Hide abstract] ABSTRACT: Background:
Otitis media with effusion (OME) is a very common problem in primary care, but one that lacks an evidence-based non-surgical treatment.
To determine the clinical effectiveness of nasal balloon autoinflation for the treatment of OME in children.
A pragmatic, two-arm, open randomised controlled trial.
Forty-three general practices from 17 UK primary care trusts recruited between January 2012 and February 2013.
School children aged 4-11 years with a history of OME symptoms or related concerns in the previous 3 months, and a type B tympanogram, diagnostic of a middle ear effusion, in one or both ears.
Three hundred and twenty children were randomised, 160 to each group, using independent web-based computer-generated randomisation (with minimisation based on age, sex and baseline severity of OME) to either nasal balloon autoinflation performed three times per day for 1-3 months plus usual care, or usual care alone.
Main outcome measures:
The proportion of children demonstrating clearance of middle ear fluid in at least one ear (with normal tympanograms) at 1 and 3 months, assessed blind to treatment. An ear-related measure of quality of life (QoL) [a 14-point questionnaire on the impact of OME (OMQ-14)], weekly diary recorded symptoms, compliance and adverse events were all secondary outcomes.
At 1 month, the proportion of children with normal tympanograms was 47.3% (62/131) in those allocated to autoinflation and 35.6% (47/132) in those receiving usual care [adjusted relative risk (RR) 1.36, 95% confidence interval (CI) 0.99 to 1.88]. At 3 months, the proportions were 49.6% (62/125) and 38.3% (46/120), respectively (adjusted RR 1.37, 95% CI 1.03 to 1.83; number needed to treat = 9). The change in OMQ-14 also favoured the intervention arm (adjusted global score difference -0.42; p = 0.001). Reported compliance was good: 89% in the first month and 80% in months 2 and 3. Adverse events included otalgia in 4% of treated children compared with 1% in the control group. Minor nosebleeds (14% vs. 15%) and respiratory tract infections (18% vs. 13%) were noted.
We found the use of autoinflation in young children with OME to be feasible in primary care and effective in both clearing effusions and improving child and parent ear-related QoL and symptoms. This method has scope to be used more widely. Further research is needed for very young children, and to inform prudent use in different health settings.
Current Controlled Trials ISRCTN55208702.
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. 19, No. 72. See the NIHR Journals Library website for further project information.
[Show abstract][Hide abstract] ABSTRACT: By 2011, the Health Technology Assessment (HTA) programme had published the results of over 100 trials with another 220 in progress. The aim of the project was to develop and pilot 'metadata' on clinical trials funded by the HTA programme.
The aim of the project was to develop and pilot questions describing clinical trials funded by the HTA programme in terms of it meeting the needs of the NHS with scientifically robust studies. The objectives were to develop relevant classification systems and definitions for use in answering relevant questions and to assess their utility.
Published monographs and internal HTA documents.
A database was developed, 'populated' using retrospective data and used to answer questions under six prespecified themes. Questions were screened for feasibility in terms of data availability and/or ease of extraction. Answers were assessed by the authors in terms of completeness, success of the classification system used and resources required. Each question was scored to be retained, amended or dropped.
One hundred and twenty-five randomised trials were included in the database from 109 monographs. Neither the International Standard Randomised Controlled Trial Number nor the term 'randomised trial' in the title proved a reliable way of identifying randomised trials. Only limited data were available on how the trials aimed to meet the needs of the NHS. Most trials were shown to follow their protocols but updates were often necessary as hardly any trials recruited as planned. Details were often lacking on planned statistical analyses, but we did not have access to the relevant statistical plans. Almost all the trials reported on cost-effectiveness, often in terms of both the primary outcome and quality-adjusted life-years. The cost of trials was shown to depend on the number of centres and the duration of the trial. Of the 78 questions explored, 61 were well answered, 33 fully with 28 requiring amendment were the analysis updated. The other 17 could not be answered with readily available data.
The study was limited by being confined to 125 randomised trials by one funder.
Metadata on randomised controlled trials can be expanded to include aspects of design, performance, results and costs. The HTA programme should continue and extend the work reported here.
The National Institute for Health Research HTA programme.
Full-text · Article · Feb 2015 · Health technology assessment (Winchester, England)
[Show abstract][Hide abstract] ABSTRACT: Mit der Neuverfassung des National Health Service 2010 wurden Rechte und Zuständigkeiten konkretisiert; die Kosten-Nutzen-Bewertung wurde beim National Institute for Clinical and Social Excellence (NICE) und beim Joint Committee on Vaccinations and Immunisations (JCVI) angesiedelt. Das National Screening Committe und die Health Protection Agency können die Regierung auch auf Grundlage von Kosten-Nutzen-Bewertungen beraten. Die Behörden und Einrichtungen richten sich dabei nach den Methoden des NICE.
Die gesundheitsökonomischen Methoden des NICE werden allgemein unter dem Begriff des Extrawelfarismus subsumiert, um sie von der neoklassischen Wohlfahrstheorie abzugrenzen. Im Kern schlägt sich dies in unterschiedlichen Erhebungs- und Bewertungsmethoden des Nutzens (QALYs) und der Kosten (Perspektive des NHS) nieder. Zu erwähnen ist außerdem, dass sich die Diskontierung über die Zeit und zwischen den verschiedenen Einrichtungen unterschiedlich entwickelt. Im Zusammenhang mit der Einführung des Value Based Pricing wurde und wird in einer Ende Juni endenden öffentlichen Debatte darüber gestritten, ob sich die Methoden des NICE nicht näher an die des britischen Finanzministeriums (UK Treasury) anlehnen sollten.
Da man einige Entscheidungen des NICE zu Arzneimitteln als politisch inakzeptabel ansah, wurden besondere Budgets für Interventionen eingeführt, deren Erstattung von NICE abgelehnt wurden. Dazu gehören das Multiple Sclerosis Risk Sharing Scheme (2002) und der Cancer Drugs Fund (2010) sowie besondere Prämien für Interventionen am Ende des Lebens und für Innovationen. Seit 2009 werden über Patient Access Schemes Preissenkungen gefordert, sodass die Schwellenwerte des NICE erreicht werden. Insgesamt muss man sagen, dass der NHS in England auf der Basis von Kosteneffektivität die Erstattung von sehr wenigen Interventionen abgelehnt hat.
No preview · Article · Dec 2014 · Zeitschrift für Evidenz Fortbildung und Qualität im Gesundheitswesen
[Show abstract][Hide abstract] ABSTRACT: Aims:
We wish to assess the clinical and cost-effectiveness of remote monitoring of heart failure patients with cardiac implanted electronic devices.
REM-HF is a multicentre, randomized, non-blinded, parallel trial designed to compare weekly remote monitoring-driven management with usual care for patients with cardiac implanted electronic devices (ICD, CRT-D, or CRT-P). The trial is event driven, and the final analysis will be performed when 546 events have been observed or the study is terminated at the interim analysis. We have randomized 1650 patients to be followed up for a minimum of 2 years. Patients will remain in the trial up to study termination. The first patient was randomized in September 2011 and the study is expected to complete in early 2016. The primary combined endpoint is time to first event of all-cause death or unplanned hospitalization for cardiovascular reasons. An economic evaluation will be performed, estimating the cost per quality-adjusted life year, with direct costs estimated from the National Health Service perspective and quality of life assessed by the EQ-5D, Short-Form 12, and Kansas City Cardiomyopathy Questionnaires. The study design has been informed by a feasibility study.
REM-HF is a multicentre randomized study that will provide important data on the effect of remote monitoring-driven management of implanted cardiac devices on morbidity and mortality, as well as the cost-effectiveness of this approach.
Full-text · Article · Sep 2014 · European Journal of Heart Failure
[Show abstract][Hide abstract] ABSTRACT: Objective To assess the incremental cost and cost-effectiveness of continuous and discontinuous regimens of bevacizumab (Avastin) and ranibizumab (Lucentis) for neovascular age-related macular degeneration (nAMD) from a UK National Health Service (NHS) perspective.
Design A within-trial cost-utility analysis with a 2-year time horizon, based on a multicentre factorial, non-inferiority randomised controlled trial.
Setting 23 hospital ophthalmology clinics.
Participants 610 patients aged ≥50 years with untreated nAMD in the study eye.
Interventions 0.5 mg ranibizumab or 1.25 mg bevacizumab given continuously (monthly) or discontinuously (as-needed) for 2 years.
Main outcome measures Quality-adjusted life-years (QALYs).
Results Total 2-year costs ranged from £3002/patient ($4700; 95% CI £2601 to £3403) for discontinuous bevacizumab to £18 590/patient ($29 106; 95% CI £18 258 to £18 922) for continuous ranibizumab. Ranibizumab was significantly more costly than bevacizumab for both continuous (+£14 989/patient ($23 468); 95% CI £14 522 to £15 456; p<0.001) and discontinuous treatment (+£8498 ($13 305); 95% CI £7700 to £9295; p<0.001), with negligible difference in QALYs. Continuous ranibizumab would only be cost-effective compared with continuous bevacizumab if the NHS were willing to pay £3.5 million ($5.5 million) per additional QALY gained. Patients receiving continuous bevacizumab accrued higher total costs (+£599 ($938); 95% CI £91 to £1107; p=0.021) than those receiving discontinuous bevacizumab, but also accrued non-significantly more QALYs (+0.020; 95% CI −0.032 to 0.071; p=0.452). Continuous bevacizumab therefore cost £30 220 ($47 316) per QALY gained versus discontinuous bevacizumab. However, bootstrapping demonstrated that if the NHS is willing to pay £20 000/QALY gained, there is a 37% chance that continuous bevacizumab is cost-effective versus discontinuous bevacizumab.
Conclusions Ranibizumab is not cost-effective compared with bevacizumab, being substantially more costly and producing little or no QALY gain. Discontinuous bevacizumab is likely to be the most cost-effective of the four treatment strategies evaluated in this UK trial, although there is a 37% chance that continuous bevacizumab is cost-effective.
Trial registration number ISRCTN92166560.
[Show abstract][Hide abstract] ABSTRACT: The New Forest Parenting Programme (NFPP) is a home-delivered, evidence-based parenting programme to target symptoms of attention-deficit/hyperactivity disorder (ADHD) in preschool children. It has been adapted for use with 'hard-to-reach' or 'difficult-to-treat' children. This trial will compare the adapted-NFPP with a generic parenting group-based programme, Incredible Years (IY), which has been recommended for children with preschool-type ADHD symptoms.Methods/design: This multicentre randomized controlled trial comprises three arms: adapted-NFPP, IY and treatment as usual (TAU). A sample of 329 parents of preschool-aged children with a research diagnosis of ADHD enriched for hard-to-reach and potentially treatment-resistant children will be allocated to the arms in the ratio 3:3:1. Participants in the adapted-NFPP and IY arms receive an induction visit followed by 12 weekly parenting sessions of 11/2 hours (adapted-NFPP) or 21/2 hours (IY) over 2.5 years. Adapted-NFPP will be delivered as a one-to-one home-based intervention; IY, as a group-based intervention. TAU participants are offered a parenting programme at the end of the study. The primary objective is to test whether the adapted-NFPP produces beneficial effects in terms of core ADHD symptoms. Secondary objectives include examination of the treatment impact on secondary outcomes, a study of cost-effectiveness and examination of the mediating role of treatment-induced changes in parenting behaviour and neuropsychological function. The primary outcome is change in ADHD symptoms, as measured by the parent-completed version of the SNAP-IV questionnaire, adjusted for pretreatment SNAP-IV score. Secondary outcome measures are: a validated index of behaviour during child's solo play; teacher-reported SNAP-IV (ADHD scale); teacher and parent Eyberg Child Behaviour Inventory - Oppositional Defiant Disorder scale; Revised Client Service Receipt Inventory - Health Economics Costs measure and EuroQol (EQ5D) health-related quality-of-life measure. Follow-up measures will be collected 6 months after treatment for participants allocated to adapted-NFPP and IY.
This trial will provide evidence as to whether the adapted-NFPP is more effective and cost-effective than the recommended treatment and TAU. It will also provide information about mediating factors (improved parenting and neuropsychological function) and moderating factors (parent and child genetic factors) in any increased benefit.Trial registration: Current Controlled Trials, ISRCTN39288126.
[Show abstract][Hide abstract] ABSTRACT: Antibiotics are still prescribed to most patients attending primary care with acute sore throat, despite evidence that there is modest benefit overall from antibiotics. Targeting antibiotics using either clinical scoring methods or rapid antigen detection tests (RADTs) could help. However, there is debate about which groups of streptococci are important (particularly Lancefield groups C and G), and uncertainty about the variables that most clearly predict the presence of streptococci.
This study aimed to compare clinical scores or RADTs with delayed antibiotic prescribing.
The study comprised a RADT in vitro study; two diagnostic cohorts to develop streptococcal scores (score 1; score 2); and, finally, an open pragmatic randomised controlled trial with nested qualitative and cost-effectiveness studies.
The setting was UK primary care general practices.
Participants were patients aged ≥ 3 years with acute sore throat.
An internet program randomised patients to targeted antibiotic use according to (1) delayed antibiotics (control group), (2) clinical score or (3) RADT used according to clinical score.
The main outcome measures were self-reported antibiotic use and symptom duration and severity on seven-point Likert scales (primary outcome: mean sore throat/difficulty swallowing score in the first 2-4 days).
The IMI TestPack Plus Strep A (Inverness Medical, Bedford, UK) was sensitive, specific and easy to use. Lancefield group A/C/G streptococci were found in 40% of cohort 2 and 34% of cohort 1. A five-point score predicting the presence of A/C/G streptococci [FeverPAIN: Fever; Purulence; Attend rapidly (≤ 3 days); severe Inflammation; and No cough or coryza] had moderate predictive value (bootstrapped estimates of area under receiver operating characteristic curve: 0.73 cohort 1, 0.71 cohort 2) and identified a substantial number of participants at low risk of streptococcal infection. In total, 38% of cohort 1 and 36% of cohort 2 scored ≤ 1 for FeverPAIN, associated with streptococcal percentages of 13% and 18%, respectively. In an adaptive trial design, the preliminary score (score 1; n = 1129) was replaced by FeverPAIN (n = 631). For score 1, there were no significant differences between groups. For FeverPAIN, symptom severity was documented in 80% of patients, and was lower in the clinical score group than in the delayed prescribing group (-0.33; 95% confidence interval -0.64 to -0.02; p = 0.039; equivalent to one in three rating sore throat a slight rather than moderately bad problem), and a similar reduction was observed for the RADT group (-0.30; -0.61 to 0.00; p = 0.053). Moderately bad or worse symptoms resolved significantly faster (30%) in the clinical score group (hazard ratio 1.30; 1.03 to 1.63) but not the RADT group (1.11; 0.88 to 1.40). In the delayed group, 75/164 (46%) used antibiotics, and 29% fewer used antibiotics in the clinical score group (risk ratio 0.71; 0.50 to 0.95; p = 0.018) and 27% fewer in the RADT group (0.73; 0.52 to 0.98; p = 0.033). No significant differences in complications or reconsultations were found. The clinical score group dominated both other groups for both the cost/quality-adjusted life-years and cost/change in symptom severity analyses, being both less costly and more effective, and cost-effectiveness acceptability curves indicated the clinical score to be the most likely to be cost-effective from an NHS perspective. Patients were positive about RADTs. Health professionals' concerns about test validity, the time the test took and medicalising self-limiting illness lessened after using the tests. For both RADTs and clinical scores, there were tensions with established clinical experience.
Targeting antibiotics using a clinical score (FeverPAIN) efficiently improves symptoms and reduces antibiotic use. RADTs used in combination with FeverPAIN provide no clear advantages over FeverPAIN alone, and RADTs are unlikely to be incorporated into practice until health professionals' concerns are met and they have experience of using them. Clinical scores also face barriers related to clinicians' perceptions of their utility in the face of experience. This study has demonstrated the limitation of using one data set to develop a clinical score. FeverPAIN, derived from two data sets, appears to be valid and its use improves outcomes, but diagnostic studies to confirm the validity of FeverPAIN in other data sets and settings are needed. Experienced clinicians need to identify barriers to the use of clinical scoring methods. Implementation studies that address perceived barriers in the use of FeverPAIN are needed.
Current Controlled Trials ISRCTN32027234.
This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 6. See the NIHR Journals Library website for further project information.