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1.  How long has NICE taken to produce Technology Appraisal guidance? A retrospective study to estimate predictors of time to guidance 
BMJ Open  2013;3(1):e001870.
To assess how long the UK's National Institute for Health and Clinical Excellence's (NICE) Technology Appraisal Programme has taken to produce guidance and to determine independent predictors of time to guidance.
Retrospective time to event (survival) analysis.
Technology Appraisal guidance produced by NICE.
All appraisals referred to NICE by February 2010 were included, except those referred prior to 2001 and a number that were suspended.
Outcome measure
Duration from the start of an appraisal (when the scope document was released) until publication of guidance.
Single Technology Appraisals (STAs) were published significantly faster than Multiple Technology Appraisals (MTAs) with median durations of 48.0 (IQR; 44.3–75.4) and 74.0 (IQR; 60.9–114.0) weeks, respectively (p <0.0001). Median time to publication exceeded published process timelines, even after adjusting for appeals. Results from the modelling suggest that STAs published guidance significantly faster than MTAs after adjusting for other covariates (by 36.2 weeks (95% CI −46.05 to −26.42 weeks)) and that appeals against provisional guidance significantly increased the time to publication (by 42.83 weeks (95% CI 35.50 to 50.17 weeks)). There was no evidence that STAs of cancer-related technologies took longer to complete compared with STAs of other technologies after adjusting for potentially confounding variables and only weak evidence suggesting that the time to produce guidance is increasing each year (by 1.40 weeks (95% CI −0.35 to 2.94 weeks)).
The results from this study suggest that the STA process has resulted in significantly faster guidance compared with the MTA process irrespective of the topic, but that these gains are lost if appeals are made against provisional guidance. While NICE processes continue to evolve over time, a trade-off might be that decisions take longer but at present there is no evidence of a significant increase in duration.
PMCID: PMC3549260  PMID: 23315516
Health Economics; Public Health; Statistics & Research Methods
2.  An evaluation of the impact of NICE guidance on GP prescribing. 
BACKGROUND: One of the aims of the National Institute for Clinical Excellence (NICE) is to promote faster access to the best treatments. However, there is no published research on the impact that NICE guidance has had on prescribing decisions. AIMS: To explore the attitudes of general practitioners (GPs) to NICE guidance and to investigate any changes in prescribing patterns. DESIGN: Descriptive cross-sectional study. SETTING: North Devon Primary Care Trust. METHOD: Five technology appraisals most likely to impact on GP prescribing were investigated. Prescribing analysis and cost (PACT) data were analysed for changes in prescribing patterns before and after the publication of each technology appraisal. A postal questionnaire, developed from semi-structured interviews, was sent to all GPs within a single primary care trust (PCT) to explore factors that were encouraging or discouraging adherence to NICE guidance. RESULTS: PACT data showed that there was an increase in the prescribing of the drugs studied immediately after NICE guidance, with the exception of zanamivir (Relenza [GlaxoSmithKline]); only one zanamivir inhaler was prescribed during the study period. Although there was an increase in the prescribing of maintenance doses of proton pump inhibitors, there was also an increase in treatment doses. Eighty-one (82.7%) questionnaires were completed and returned. In general, there was a balance between the factors that encouraged and those that discouraged adherence. The main exception was zanamivir, where factors that discouraged adherence greatly exceeded factors that encouraged adherence. CONCLUSIONS: This study showed that NICE guidance in isolation had little impact on GP prescribing. Where the guidance coincided with information from other sources, or personal experience, there was some evidence that technology appraisals triggered an increase in prescribing, but that this was not always sustained. The recommendations of NICE concerning zanamivir were universally rejected and there was evidence that this had undermined confidence in NICE recommendations in general.
PMCID: PMC1314802  PMID: 14965388
3.  What is the Quality of Economic Evaluations of Non-Drug Therapies? A Systematic Review and Critical Appraisal of Economic Evaluations of Radiotherapy for Cancer 
Breast, cervical and colorectal cancers are the three most frequent cancers in women, while lung, prostate and colorectal cancers are the most frequent in men. Much attention has been given to the economic evaluation of pharmaceuticals for treatment of cancer by the National Institute for Health and Care Excellence (NICE) in the UK and similar authorities internationally, while economic analysis developed for other types of anti-cancer interventions, including radiotherapy and surgery, are less common.
Our objective was to review methods used in published cost-effectiveness studies evaluating radiotherapy for breast, cervical, colorectal, head and neck and prostate cancer, and to compare the economic evaluation methods applied with those defined in the guidelines used by the NICE technology appraisal programme.
A systematic search of seven databases (MEDLINE, EMBASE, CDSR, NHSEED, HTA, DARE, EconLit) as well as research registers, the NICE website and conference proceedings was conducted in July 2012. Only economic evaluations of radiotherapy interventions in individuals diagnosed with cancer that included quality-adjusted life-years (QALYs) or life-years (LYs) were included. Included studies were appraised on the basis of satisfying essential, preferred and UK-specific methods requirements, building on the NICE Reference Case for economic evaluations and on other methods guidelines.
A total of 29 studies satisfied the inclusion criteria (breast 14, colorectal 2, prostate 10, cervical 0, head and neck 3). Only two studies were conducted in the UK (13 in the USA). Among essential methods criteria, the main issue was that only three (10 %) of the studies used clinical-effectiveness estimates identified through systematic review of the literature. Similarly, only eight (28 %) studies sourced health-related quality-of-life data directly from patients with the condition of interest. Other essential criteria (e.g. clear description of comparators, patient group indication and appropriate time horizon) were generally fulfilled, while most of the UK-specific requirements were not met.
Based on this review there is a dearth of up-to-date, robust evidence on the cost effectiveness of radiotherapy in cancer suitable to support decision making in the UK. Studies selected did not fully satisfy essential method standards currently recommended by NICE.
PMCID: PMC4175431  PMID: 25060829
4.  When Does NICE Recommend the Use of Health Technologies Within a Programme of Evidence Development? 
Pharmacoeconomics  2013;31(2):137-149.
There is growing interest internationally in linking reimbursement decisions with recommendations for further research. In the UK, the National Institute for Health and Clinical Excellence (NICE) can issue guidance to approve the routine use of a health intervention, reject routine use or recommend use within a research programme. These latter recommendations have restricted use to ‘only in research’ (OIR) or have recommended further research alongside routine use (‘approval with research’ or AWR). However, it is not currently clear when such recommendations are likely to be made.
This study aims to identify NICE technology appraisals where OIR or AWR recommendations were made and to examine the key considerations that led to those decisions.
Draft and final guidance including OIR/AWR recommendations were identified. The documents were reviewed to establish the characteristics of the technology appraisal, the cost effectiveness of the technologies, the key considerations that led to the recommendations and the types of research required.
In total, 29 final and 31 draft guidance documents included OIR/AWR recommendations up to January 2010. Overall, 86 % of final guidance included OIR recommendations. Of these, the majority were for technologies considered to be cost ineffective (83 %) and the majority of final guidance (66 %) specified the need for further evidence on relative effectiveness. The use of OIR/AWR recommendations is decreasing over time and they have rarely been used in appraisals conducted through the single technology appraisal process.
NICE has used its ability to recommend technologies within research programmes, although predominantly within the multiple technology appraisal process. OIR recommendations have been most frequently issued for technologies considered cost ineffective and the most frequently cited consideration is uncertainty related to relative effectiveness. Key considerations cited for most AWR recommendations and some OIR recommendations included a need for further evidence on long-term outcomes and adverse effects of treatment.
Electronic supplementary material
The online version of this article (doi:10.1007/s40273-012-0013-6) contains supplementary material, which is available to authorized users.
PMCID: PMC3561612  PMID: 23329429
5.  Pipeline™ Embolization Device for the Treatment of Complex Intracranial Aneurysms 
As part of its Medical Technologies Evaluation Programme, the National Institute of Health and Clinical Excellence (NICE) invited the manufacturer, Covidien, to provide clinical and economic evidence for the evaluation of the Pipeline™ embolization device (PED) for the treatment of complex intracranial aneurysms. Cedar; a consortium between Cardiff and Vale University Health Board and Cardiff University, was commissioned to act as an External Assessment Centre (EAC) for NICE to independently critique the manufacturers’ submissions. This article gives an overview of the evidence provided, the findings of the EAC and the final guidance published by NICE.
The scope issued by NICE considered PED as the intervention in a patient population with complex unruptured intracranial aneurysms (IAs), specifically large/giant, wide-necked and fusiform aneurysms. The comparator treatments identified were stent-assisted coiling, parent vessel occlusion, neurosurgical techniques and conservative management. The manufacturer claimed that PED fulfils a currently unmet clinical need in the treatment of large or giant, wide-necked or fusiform IAs.
Thirteen studies were identified by the manufacturer as being relevant to the decision problem, with two of these included for data extraction. The EAC identified 16 studies as relevant, three of which had been published after the manufacturer’s search. Data extraction was carried out on these studies as, although many were low level research comprising of case reports and case series, they provided useful, pertinent safety and outcome data.
No relevant economic studies of the device were identified; therefore, a new economic model was designed by the manufacturer. The base-case scenario provided recognized the costs of PED to be higher than the costs for endovascular parent vessel occlusion, neurosurgical parent vessel occlusion, neurosurgical clipping and conservative management. However, PED was found to be cost saving compared with stent-assisted coiling, with a saving of £13,110 per patient.
Analysis of the clinical data suggested that treatment with PED has high rates of clinical success with high rates of aneurysm occlusion and acceptable adverse events for the patient population. Economic evidence suggested that the costs in the base-case for PED may have been underestimated, meaning that PED would only become cost saving in patients who would otherwise require treatment with 32 coils or more. NICE Medical Technologies Guidance MTG10, issued in May 2012, recommends the adoption of PED in selected patients within the UK National Health Service (NHS).
PMCID: PMC3563954  PMID: 23341264
6.  Rituximab for the First-Line Maintenance Treatment of Follicular Non-Hodgkin’s Lymphoma 
Pharmacoeconomics  2013;31(5):403-413.
The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of rituximab (RTX) [Roche] to submit evidence for the clinical and cost effectiveness of RTX as first-line maintenance treatment for patients with follicular non-Hodgkin’s lymphoma (fNHL) whose disease has responded to induction therapy with RTX plus cytotoxic chemotherapy (R-CTX) in accordance with the Institute’s Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article summarizes the ERG’s review of the evidence submitted by the manufacturer and provides a summary of the Appraisal Committee’s (AC) decision. The clinical evidence was derived from a multi-centred, open-label, randomized phase III study (PRIMA) comparing first-line maintenance treatment with RTX with observation only in 1,018 patients with previously untreated advanced fNHL. Median time to event (MTE) for the primary endpoint of progression-free survival (PFS) in the RTX arm was not estimable due to data immaturity; median PFS in the observation arm was 48.36 months. A statistically significant benefit of RTX maintenance therapy for PFS was reported (hazard ratio [HR] 0.55, 95 % CI 0.44–0.68; p < 0.0001). Statistically significant differences in favour of RTX were also reported for a range of secondary endpoints. Assessment of overall survival benefit could be not made due to insufficient events. The ERG’s main concern with the clinical-effectiveness data presented was their lack of maturity. The submitted incremental cost-effectiveness ratio was within the NICE threshold. The ERG questioned the model on a number of grounds, particularly the use of Markov methodology rather than patient simulations, the impact of patient age on the outcome and the projective PFS modelling. The ERG considered it impossible to draw firm conclusions regarding the clinical or cost effectiveness of the intervention as the dataset was as yet too immature. At a third meeting, the AC concluded that RTX could be recommended as first-line maintenance treatment for patients with fNHL whose disease has responded to induction R-CTX.
PMCID: PMC3654180  PMID: 23576017
7.  A qualitative study of manufacturers' submissions to the UK NICE single technology appraisal process 
BMJ Open  2012;2(1):e000562.
As part of the National Institute for Health and Clinical Excellence (NICE) Single Technology Appraisal (STA) process, manufacturers present submissions outlining the clinical and cost-effectiveness of new technologies. These submissions are critically appraised by Evidence Review Groups (ERGs), who produce a report, which forms part of the evidence considered by the NICE Appraisal Committees. The purpose of this research was first to identify common issues and concerns identified by the ERGs in their analyses of manufacturers' submissions (MS). The aim was then to use these as a basis to develop feedback for manufacturers.
A qualitative study using a content analysis approach to examine two sources of evidence, the first 30 ERG reports and 21 clarification letters associated with these STAs.
UK HTA programme.
Primary and secondary outcome measures
Common issues and concerns in MS.
There were positive comments regarding the quality of the MS, many of which were clearly written. The majority, however, were generally of poor quality and issues and concerns identified across the ERG reports and clarification letters included: criticisms related to the data being used especially data employed in the cost-effectiveness model, failure to perform a necessary analysis and poor reporting of processes used in the MS. Aspects of the decision problem were also often poorly or inadequately addressed by manufacturers. The majority of points raised for clarification related to the economic data analysis. Internal inconsistencies between the clinical and economic sections of the submission were frequently highlighted. These were used as the basis for the development of 12 suggestions for manufacturers.
Much can be done to improve the quality of MS in the NICE STA process. Suggestions include the need for clear and transparent reporting of methods and analyses.
Article summary
Article focus
As part of the NICE STA process, ERGs critically appraise manufacturer submissions in their reports and write clarification letters requesting more information from manufacturers. Two sources of evidence, ERG reports and the clarification letters associated with these STAs were analysed using a content analysis approach. The aim of this study was to identify issues and concerns identified by the ERGs in their analyses of submissions and use these to develop feedback to manufacturers.
Key messages
A qualitative analysis of 30 ERG reports and 21 clarification letters was undertaken to identify recurring issues and concerns in manufacturers' submissions. The issues and concerns identified in this analysis were used to inform the development of a set of 12 suggestions to manufacturers to improve the quality of future submissions to NICE.
Strengths and limitations of this study
The research study applied validated methods and used multiple reviewers to check and verify data and analyses. Only the first 30 completed ERG reports and 21 associated clarification letters were examined in this analysis. There may be some misinterpretations in these analyses as documentary analysis was the only method used.
PMCID: PMC3277905  PMID: 22318664
8.  Impact of the National Institute for Health and Care Excellence (NICE) guidance on medical technology uptake: analysis of the uptake of spinal cord stimulation in England 2008–2012 
BMJ Open  2014;4(1):e004182.
The National Institute for Health and Care Excellence (NICE) Technology Appraisal Guidance on spinal cord stimulation (SCS) was published in 2008 and updated in 2012 with no change. This guidance recommends SCS as a cost-effective treatment for patients with neuropathic pain.
To assess the impact of NICE guidance by comparing SCS uptake in England pre-NICE (2008–2009) and post-NICE (2009–2012) guidance. We also compared the English SCS uptake rate with that of Belgium, the Netherlands, France and Germany.
SCS implant data for England was obtained from the Hospital Episode Statistics (HES) database and compared with other European countries where comparable data were available.
The HES data showed small increases in SCS implantation and replacement/revision procedures, and a large increase in SCS trials between 2008 and 2012. The increase in the total number of SCS procedures per million of population in England is driven primarily by revision/replacements and increased trial activity. Marked variability in SCS uptake at both health regions and primary care trust level was observed.
Despite the positive NICE recommendation for the routine use of SCS, we found no evidence of a significant impact on SCS uptake in England. Rates of SCS implantation in England are lower than many other European countries.
PMCID: PMC3902463  PMID: 24398364
9.  Clinical guidelines in pediatric headache: evaluation of quality using the AGREE II instrument 
The Appraisal of Guidelines for Research and Evaluation (AGREE II) tool is a validated questionnaire used to assess the methodological quality of clinical guidelines (CGs). We used the AGREE II tool to assess the development process, the methodological quality, and the quality of reporting of available pediatric CGs for the management of headache in children. We also studied the variability in responses related to the characteristics of eleven Italian neuropediatric centers, showing similarities and differences in the main recommendations reported in CGs.
A systematic literature search was conducted from January 2002 to June 2013 on Mediline, the Cochrane database, the National Guideline Clearinghouse website and the NHS evidence search tool, using the following terms: headache, cephalalgia, guidelines and children (MESH or text words). Six CGs providing information on the diagnosis and management of headache and specific recommendations for children were selected. Eleven neuropediatric centers assessed the overall quality and the appropriateness of all available CGs using of the AGREE II instrument.
Six CGs meeting the inclusion and exclusion criteria were identified and assessed by 11 reviewers. Our study showed that the NICE CGs was “strongly recommended” while the French and Danish CGs were mainly “not recommended”. The comparison between the overall quality score of the French CGs and the NICE CGs was statistically significant (6.54 ± 0.69 vs 4.18 ± 1.08; p =0.001). The correlation analysis between quality domain score and guideline publication date showed a statistically significant association only for the “editorial independence” domain (r = 0.842 p = 0.035). The intra-class coefficients showed that the 11 reviewers had the highest agreement for the Lewis CGs (r = 0.857), and the lowest one for the NICE CGs (r = 0.656). Statistical analyses showed that professionals from outpatient services dedicated pediatric headache assigned a higher overall quality score to the NICE CGs as compared to professionals from non-outpatient services (6.86 ± 0.38 vs 6.0 ± 0.82; p = 0.038).
CGs resulted definitely of low-moderate quality and non “homogeneous”. Further major efforts are needed to update the existing CGs according to the principles of evidence based medicine.
PMCID: PMC4167157  PMID: 25178699
Guidelines; Pediatric headache; Agree II instrument; Quality of guidelines; Children
10.  The perplexity of prescribing and switching of biologic drugs in rheumatoid arthritis: a UK regional audit of practice 
Biologic drugs are expensive treatments used in rheumatoid arthritis (RA). Switching among them is common practice in patients who have had an inadequate response or intolerable adverse events. The National Institute of Health and Clinical Excellence (NICE) UK, which aims to curtail postcode prescribing, has provided guidance on the sequential prescription of these drugs. This study sought to evaluate the extent to which rheumatology centres across the Midlands were complying with NICE guidance on the switching of biologic drugs in RA, as well as analyse the various prescribing patterns of these drugs.
Data was collected via a web-based tool on RA patients who had undergone at least one switch of a biologic drug during 2011. The standards specified in NICE technology appraisals (TA130, TA186, TA195, TA198, and TA225) were used to assess compliance with NICE guidance. Descriptive statistical analysis was performed.
There were 335 biologic drug switches in 317 patients. The most common reason given for switching to a drug was NICE guidelines (242, 72.2%), followed by Physician's choice (122, 33.4%). Lack of effect was the most common reason for discontinuing a drug (224, 67%). For patients on Rituximab, Methotrexate was used in 133 switches (76.9% of the time). Overall NICE compliance for all units was 65% (range 50 to 100%), with anti-TNFα to anti-TNFα switches for inefficacy making up the majority of non-compliant switches.
This study draws attention to the enigma and disparity of commissioning and prescribing of biologic drugs in RA. Currently the evidence would not support switching of a biologic drug for non-clinical purposes such as economic pressures. Flexibility in prescribing should be encouraged: biologic therapy should be individualised based on the mode of action and likely tolerability of these drugs. Further work should focus on the evidence for using particular sequences of biologic drugs.
PMCID: PMC4164745  PMID: 25182696
Rheumatoid arthritis; Commissioning; Biologic therapies
11.  Do different clinical evidence bases lead to discordant health-technology assessment decisions? An in-depth case series across three jurisdictions 
Health-technology assessment (HTA) plays an important role in informing drug-reimbursement decision-making in many countries. HTA processes for the Pharmaceutical Benefits Advisory Committee (PBAC) in Australia, the Common Drug Review (CDR) in Canada, and the National Institute for Health and Clinical Excellence (NICE) in England and Wales are among the most established in the world. In this study, we performed nine in-depth case studies to assess whether different clinical evidence bases may have influenced listing recommendations made by PBAC, CDR, and NICE.
Nine drugs were selected for which the three agencies had provided listing recommendations for the same indication between 2007 and 2010. We reviewed the evidence considered for each listing recommendation, identified the similarities and differences among the clinical evidence bases considered, and evaluated the extent to which different clinical evidence bases could have contributed to different decisions based on HTA body comments and public assessment of the evidence.
HTA agencies reached the same recommendation for reimbursement (recommended for listing) for four drugs and different recommendations for five drugs. In all cases, each agency used different evidence bases in their recommendations. The agencies considered overlapping sets of clinical comparators and trials when evaluating the same drug. While PBAC and NICE considered indirect and/or mixed-treatment comparisons, CDR did not. In some cases, CDR and/or NICE excluded trials from review if the drug and/or the comparator were not administered according to the relevant marketing authorization.
In the listing recommendations reviewed, considerable variability exists in the clinical evidence considered by PBAC, CDR, and NICE for drug-listing recommendations. Differences in evidence resulted from differences in the consideration of indirect and mixed-treatment comparison data and differences in medical practice in each jurisdiction.
PMCID: PMC3565559  PMID: 23403392
health-technology assessment; reimbursement decisions; evidence
12.  Imatinib in gastrointestinal stromal tumour: Northern Cancer Network experience 
ecancermedicalscience  2009;3:162.
Imatinib treatment in metastatic or inoperable gastrointestinal stromal tumours (GIST) has shifted the paradigm of treatment of this disease. Successful clinical trials of imatinib led to rapid regulatory approval and, in England and Wales, National Institute for Health and Clinical Excellence (NICE) guidance on use of this technology. NICE recommend detailed audit of their guidelines in clinical practice. This audit reflects that guidance and was designed to document the use of imatinib in routine clinical practice.
We conducted a retrospective audit of patients with GIST treated with imatinib from 1 February 2002 to 31 March 2007. Information gathered included patient demographics, disease characteristics and details of treatment administered, treatment response, toxicities and follow-up data. The primary objective was to record disease control rate (DCR), defined as a lack of progression on computed tomography at three months. Secondary end points of this audit were progression-free and overall survival. These were compared with published clinical trial results.
Thirty-six consecutive patients with a diagnosis of GIST treated with imatinib were identified. Median age of patients was 70.1 years. At the time of analysis, patients have been followed up for a median of 41.6 months. In total, patients were treated for a median of 15.8 months. Treatment was generally well tolerated with a small percentage of patients experiencing grade 3/4 toxicities. Disease control was observed in 30 patients (DCR, 83.3%, 95% CI 67.2–93.6, intention to treat analysis). The median progression free survival (PFS) in this cohort was 23.7 months (95% CI 12.9–34.4); while the median overall survival was 39.7 months (95% CI 22.8–56.5).
Our data demonstrated that the treatment of unselected GIST patients within the NICE guidance compares favourably to previously published data of randomized registration studies of imatinib. Of note, the median age of this cohort is some ten years older than that reported in the trials. Imatinib was well tolerated with acceptable treatment-related adverse events.
PMCID: PMC3223987  PMID: 22276023
13.  Evidence Synthesis for Decision Making 1 
Medical Decision Making  2013;33(5):597-606.
We introduce the series of 7 tutorial papers on evidence synthesis methods for decision making, based on the Technical Support Documents in Evidence Synthesis prepared for the National Institute for Health and Clinical Excellence (NICE) Decision Support Unit. Although oriented to NICE’s Technology Appraisal process, which examines new pharmaceutical products in a cost-effectiveness framework, the methods presented throughout the tutorials are equally relevant to clinical guideline development and to comparisons between medical devices, or public health interventions. Detailed guidance is given on how to use the other tutorials in the series, which propose a single evidence synthesis framework that covers fixed and random effects models, pairwise meta-analysis, indirect comparisons, and network meta-analysis, and where outcomes expressed in several different reporting formats can be analyzed without recourse to normal approximations. We describe the principles of evidence synthesis required by the 2008 revision of the NICE Guide to the Methods of Technology Appraisal and explain how the approach proposed in these tutorials was designed to conform to those requirements. We finish with some suggestions on how to present the evidence, the synthesis methods, and the results.
PMCID: PMC3704205  PMID: 23804506
cost-effectiveness analysis; Bayesian meta-analysis; systematic reviews
14.  Trends in procedures for infertility and caesarean sections: was NICE disinvestment guidance implemented? NICE recommendation reminders 
BMC Public Health  2013;13:112.
National Institute for Health and Clinical Excellence (NICE) clinical guidelines and subsequent NICE issued ‘recommendation reminders’ advocate discontinuing two fertility procedures and caesarean sections in women with hepatitis. We assess whether NICE guidance in 2004 and recommendation reminders were associated with a change in the rate of clinical procedures performed.
Routine inpatient Hospital Episode Statistics (HES) data were extracted from the HES database for 1st April 1998 to 31st March 2010 using OPCS procedure codes for varicocele operations in infertile men, endometrial biopsies in infertile women and caesarean sections in women with hepatitis B or C. We used Joinpoint regression to identify points in time when the trend in procedure rates changed markedly, to identify any influence of the release of NICE guidance.
Between 1998-2010, planned caesarean sections in women with and without hepatitis B or C increased yearly (annual percentage change (APC) 4.9%, 95% CI 2.1% to 7.7%) in women with hepatitis, compared with women without (APC 4.0% [95% CI 2.7% to 5.3%] up to 2001, APC -0.6% [95% CI -2.8% to 1.8%] up to 2004 and 1.3% [95% CI 0.8% to 1.8%] up to 2010). In infertile women under 40 years of age, endometrial biopsies for investigation of infertility increased, APC 6.0% (95% CI 3.6% to 8.4%) up to 2003, APC 1.5% (95% CI -4.3% to 7.7%) to 2007 followed by APC 12.8% (95% CI 1.0% to 26.0%) to 2010. Varicocele procedures remained relatively static between 1998 and 2010 (APC -0.5%, 95% CI -2.3% to 1.3%).
There was no decline in use of the three studied procedures, contrary to NICE guidance, and no change in uptake associated with the timing of NICE guidance or recommendation reminders. ‘Do not do’ recommendation reminders may be ineffective at improving clinical practice or achieving disinvestment.
PMCID: PMC3608251  PMID: 23388377
NICE; Clinical guidelines; Fertility; Caesarean
15.  Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration 
PLoS Medicine  2008;5(2):e45.
Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance. Yet, the efficacy of the antidepressants may also depend on the severity of initial depression scores. The purpose of this analysis is to establish the relation of baseline severity and antidepressant efficacy using a relevant dataset of published and unpublished clinical trials.
Methods and Findings
We obtained data on all clinical trials submitted to the US Food and Drug Administration (FDA) for the licensing of the four new-generation antidepressants for which full datasets were available. We then used meta-analytic techniques to assess linear and quadratic effects of initial severity on improvement scores for drug and placebo groups and on drug–placebo difference scores. Drug–placebo differences increased as a function of initial severity, rising from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression, reaching conventional criteria for clinical significance only for patients at the upper end of the very severely depressed category. Meta-regression analyses indicated that the relation of baseline severity and improvement was curvilinear in drug groups and showed a strong, negative linear component in placebo groups.
Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.
Kirsch and colleagues show that, in antidepressant trials, there is a greater difference in efficacy between drug and placebo amongst more severely depressed patients. However, this difference seems to result from a poorer response to placebo amongst more depressed patients.
Editors' Summary
Everyone feels miserable occasionally. But for some people—those with depression—these sad feelings last for months or years and interfere with daily life. Depression is a serious medical illness caused by imbalances in the brain chemicals that regulate mood. It affects one in six people at some time during their life, making them feel hopeless, worthless, unmotivated, even suicidal. Doctors measure the severity of depression using the “Hamilton Rating Scale of Depression” (HRSD), a 17–21 item questionnaire. The answers to each question are given a score and a total score for the questionnaire of more than 18 indicates severe depression. Mild depression is often treated with psychotherapy or talk therapy (for example, cognitive–behavioral therapy helps people to change negative ways of thinking and behaving). For more severe depression, current treatment is usually a combination of psychotherapy and an antidepressant drug, which is hypothesized to normalize the brain chemicals that affect mood. Antidepressants include “tricyclics,” “monoamine oxidases,” and “selective serotonin reuptake inhibitors” (SSRIs). SSRIs are the newest antidepressants and include fluoxetine, venlafaxine, nefazodone, and paroxetine.
Why Was This Study Done?
Although the US Food and Drug Administration (FDA), the UK National Institute for Health and Clinical Excellence (NICE), and other licensing authorities have approved SSRIs for the treatment of depression, some doubts remain about their clinical efficacy. Before an antidepressant is approved for use in patients, it must undergo clinical trials that compare its ability to improve the HRSD scores of patients with that of a placebo, a dummy tablet that contains no drug. Each individual trial provides some information about the new drug's effectiveness but additional information can be gained by combining the results of all the trials in a “meta-analysis,” a statistical method for combining the results of many studies. A previously published meta-analysis of the published and unpublished trials on SSRIs submitted to the FDA during licensing has indicated that these drugs have only a marginal clinical benefit. On average, the SSRIs improved the HRSD score of patients by 1.8 points more than the placebo, whereas NICE has defined a significant clinical benefit for antidepressants as a drug–placebo difference in the improvement of the HRSD score of 3 points. However, average improvement scores may obscure beneficial effects between different groups of patient, so in the meta-analysis in this paper, the researchers investigated whether the baseline severity of depression affects antidepressant efficacy.
What Did the Researchers Do and Find?
The researchers obtained data on all the clinical trials submitted to the FDA for the licensing of fluoxetine, venlafaxine, nefazodone, and paroxetine. They then used meta-analytic techniques to investigate whether the initial severity of depression affected the HRSD improvement scores for the drug and placebo groups in these trials. They confirmed first that the overall effect of these new generation of antidepressants was below the recommended criteria for clinical significance. Then they showed that there was virtually no difference in the improvement scores for drug and placebo in patients with moderate depression and only a small and clinically insignificant difference among patients with very severe depression. The difference in improvement between the antidepressant and placebo reached clinical significance, however, in patients with initial HRSD scores of more than 28—that is, in the most severely depressed patients. Additional analyses indicated that the apparent clinical effectiveness of the antidepressants among these most severely depressed patients reflected a decreased responsiveness to placebo rather than an increased responsiveness to antidepressants.
What Do These Findings Mean?
These findings suggest that, compared with placebo, the new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression, but show significant effects only in the most severely depressed patients. The findings also show that the effect for these patients seems to be due to decreased responsiveness to placebo, rather than increased responsiveness to medication. Given these results, the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective. In addition, the finding that extremely depressed patients are less responsive to placebo than less severely depressed patients but have similar responses to antidepressants is a potentially important insight into how patients with depression respond to antidepressants and placebos that should be investigated further.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus encyclopedia contains a page on depression (in English and Spanish)
Detailed information for patients and caregivers is available on all aspects of depression (including symptoms and treatment) from the US National Institute of Medical Health and from the UK National Health Service Direct Health Encyclopedia
MedlinePlus provides a list of links to further information on depression
Clinical Guidance for professionals, patients, caregivers and the public is provided by the UK National Institute for Health and Clinical Excellence
PMCID: PMC2253608  PMID: 18303940
16.  Oncology drug health technology assessment recommendations: Canadian versus UK experiences 
Canada has two health technology assessment (HTA) agencies responsible for oncology drug funding recommendations: the Institut National d’Excellence en Santé et Services Sociaux (INESSS) for the province of Québec and the pan-Canadian Oncology Drug Review for the rest of Canada. The objective of the research was to review and compare the recommendations of these two agencies alongside an international comparator – the National Institute for Health and Care Excellence (NICE) in the United Kingdom – with respect to their recommendations records and the influence of clinical and cost-effectiveness evidence on the recommendations.
Recommendations were identified from the three agencies from January 1, 2002 to June 1, 2013. Recommendations were limited to five cancer sites (lung, breast, colon, kidney, blood) and to metastatic/advanced settings. Descriptive analyses examined the frequency of positive recommendations and factors related to a positive recommendation. For each recommendation, only publicly available information posted on the agency website was used to abstract data.
There was a wide variation in the rate of positive recommendations, ranging from 48% for NICE to 95% for Canada’s national process (among the 74% of its recommendations that were publicly posted). Interagency agreement was low, with full agreement for only six of the 14 drugs commonly reviewed by all three agencies. Evidence of a survival gain was not necessary for a positive recommendation; progression-free survival was acceptable. Different approaches were taken when addressing unacceptable cost-effectiveness. NICE was most likely to yield a negative recommendation on these grounds, whereas Canada’s national process was most likely to yield a positive recommendation with a required pricing arrangement.
In this analysis, the primary reason for the observed divergence between agency recommendations appeared to be the availability of mechanisms in each jurisdiction to address cost-effectiveness subsequent to the HTA assessment process. Furthermore, caution is needed when interpreting cross-agency comparisons between HTA agencies, as recommendations may not correspond directly to subsequent funding decisions and actual patient access. This may be a concern, given the high international profile of assessments conducted by the reviewed HTA agencies.
PMCID: PMC4106959  PMID: 25075196
reimbursement; decision-making; oncology; health technology assessment; funding decisions; metastatic/advanced cancer
17.  Guidelines for the Management of Soft Tissue Sarcomas 
Sarcoma  2010;2010:506182.
These guidelines were drawn up following a consensus meeting of UK sarcoma specialists convened under the auspices of the British Sarcoma Group and are intended to provide a framework for the multidisciplinary care of patients with soft tissue sarcomas. The guidelines published by the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) were used as the basis for discussion and adapted according to UK clinical practice and local requirements. Note was also taken of the National Institute for Health and Clinical Excellence (NICE) improving outcomes guidance (IOG) for people with sarcoma and existing technology appraisals. The guidelines are not intended to challenge NICE guidance but discrepancies may exist where current guidance does not reflect an international standard of care owing to the ever-evolving nature of cancer treatment. It is acknowledged that these guidelines will require updating on a regular basis. An appendix lists the key recommendations which are summarised below. Any patient with a suspected soft tissue sarcoma should be referred to a diagnostic centre and managed by a specialist sarcoma multidisciplinary team. Surgical excision followed by post operative radiotherapy is the standard management of high grade limb sarcomas although occasionally amputation remains the only option. Pre-operative treatment with chemotherapy or radiotherapy should be considered for patients with borderline resectable tumours. Isolated limb perfusion may permit limb salvage in some cases where amputation is the only other option. Adjuvant chemotherapy is not routinely recommended but may be considered in certain specific situations. Regular follow up is recommended to assess local control and the development of metastatic disease. Single agent doxorubicin is the standard first line therapy for metastatic disease. Ifosfamide is an alternative if anthracyclines are contraindicated. Combination therapy may be considered in individual patients. Second line agents include ifosfamide, dacarbazine, trabectedin and the combination of gemcitabine + docetaxel. Surgical resection of local recurrence and pulmonary metastases should be considered in individual patients. There is specific guidance on the management of retroperitoneal and uterine sarcomas.
PMCID: PMC2903951  PMID: 20634933
18.  The NICE ADHD health technology assessment: A review and critique 
Health technology assessments (HTAs) by the National Institute for Health and Clinical Excellence (NICE) enjoy high levels of international attention. The present analysis addresses NICE's appraisal of methylphenidate, atomoxetine and dexamphetamine for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents, published in March 2006.
A qualitative study of NICE Technology Appraisal No. 98 was done focusing on the >600-page technology assessment report, which aimed at evaluating ADHD treatment strategies by a clinical effectiveness review and an economic analysis using meta-analytical techniques and a cost-effectiveness model.
The technology assessment was unable to differentiate between the various drugs in terms of efficacy, and its economic model was ultimately driven by cost differences. While the assessment concluded that the economic model "clearly identified an optimal treatment strategy" with first-line dexamphetamine, the NICE appraisal committee subsequently found it impossible to distinguish between the different strategies on grounds of cost-effectiveness. Analyzing the assessment reveals gaps and inconsistencies concerning data selection (ultimately relying on a small number of short-term studies only), data synthesis (pooling of heterogeneous study designs and clinical endpoints), and economic model structure (identifying double-counting of nonresponders as a likely source of bias, alongside further methodological anomalies).
Many conclusions of the NICE technology assessment rest on shaky grounds. There remains a need for a new, state-of-the-art systematic review of ADHD treatment strategies including economic evaluation, which ideally should address outcomes beyond children's health-related quality of life, such as long-term sequelae of the disorder and caregiver burden.
PMCID: PMC2265261  PMID: 18197978
19.  A Comparison of Cost Effectiveness Using Data from Randomized Trials or Actual Clinical Practice: Selective Cox-2 Inhibitors as an Example 
PLoS Medicine  2009;6(12):e1000194.
Tjeerd-Pieter van Staa and colleagues estimate the likely cost effectiveness of selective Cox-2 inhibitors prescribed during routine clinical practice, as compared to the cost effectiveness predicted from randomized controlled trial data.
Data on absolute risks of outcomes and patterns of drug use in cost-effectiveness analyses are often based on randomised clinical trials (RCTs). The objective of this study was to evaluate the external validity of published cost-effectiveness studies by comparing the data used in these studies (typically based on RCTs) to observational data from actual clinical practice. Selective Cox-2 inhibitors (coxibs) were used as an example.
Methods and Findings
The UK General Practice Research Database (GPRD) was used to estimate the exposure characteristics and individual probabilities of upper gastrointestinal (GI) events during current exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) or coxibs. A basic cost-effectiveness model was developed evaluating two alternative strategies: prescription of a conventional NSAID or coxib. Outcomes included upper GI events as recorded in GPRD and hospitalisation for upper GI events recorded in the national registry of hospitalisations (Hospital Episode Statistics) linked to GPRD. Prescription costs were based on the prescribed number of tables as recorded in GPRD and the 2006 cost data from the British National Formulary. The study population included over 1 million patients prescribed conventional NSAIDs or coxibs. Only a minority of patients used the drugs long-term and daily (34.5% of conventional NSAIDs and 44.2% of coxibs), whereas coxib RCTs required daily use for at least 6–9 months. The mean cost of preventing one upper GI event as recorded in GPRD was US$104k (ranging from US$64k with long-term daily use to US$182k with intermittent use) and US$298k for hospitalizations. The mean costs (for GPRD events) over calendar time were US$58k during 1990–1993 and US$174k during 2002–2005. Using RCT data rather than GPRD data for event probabilities, the mean cost was US$16k with the VIGOR RCT and US$20k with the CLASS RCT.
The published cost-effectiveness analyses of coxibs lacked external validity, did not represent patients in actual clinical practice, and should not have been used to inform prescribing policies. External validity should be an explicit requirement for cost-effectiveness analyses.
Please see later in the article for the Editors' Summary
Editors' Summary
Before a new treatment for a specific disease becomes an established part of clinical practice, it goes through a long process of development and clinical testing. This process starts with extensive studies of the new treatment in the laboratory and in animals and then moves into clinical trials. The most important of these trials are randomized controlled trials (RCTs), studies in which the efficacy and safety of the new drug and an established drug are compared by giving the two drugs to randomized groups of patients with the disease. The final hurdle that a drug or any other healthcare technology often has to jump before being adopted for widespread clinical use is a health technology assessment, which aims to provide policymakers, clinicians, and patients with information about the balance between the clinical and financial costs of the drug and its benefits (its cost-effectiveness). In England and Wales, for example, the National Institute for Health and Clinical Excellence (NICE), which promotes clinical excellence and the effective use of resources within the National Health Service, routinely commissions such assessments.
Why Was This Study Done?
Data on the risks of various outcomes associated with a new treatment are needed for cost-effectiveness analyses. These data are usually obtained from RCTs, but although RCTs are the best way of determining a drug's potency in experienced hands under ideal conditions (its efficacy), they may not be a good way to determine a drug's success in an average clinical setting (its effectiveness). In this study, the researchers compare the data from RCTs that have been used in several published cost-effectiveness analyses of a class of drugs called selective cyclooxygenase-2 inhibitors (“coxibs”) with observational data from actual clinical practice. They then ask whether the published cost-effectiveness studies, which generally used RCT data, should have been used to inform coxib prescribing policies. Coxibs are nonsteroidal anti-inflammatory drugs (NSAIDs) that were developed in the 1990s to treat arthritis and other chronic inflammatory conditions. Conventional NSAIDs can cause gastric ulcers and bleeding from the gut (upper gastrointestinal events) if taken for a long time. The use of coxibs avoids this problem.
What Did the Researchers Do and Find?
The researchers extracted data on the real-life use of conventional NSAIDs and coxibs and on the incidence of upper gastrointestinal events from the UK General Practice Research Database (GPRD) and from the national registry of hospitalizations. Only a minority of the million patients who were prescribed conventional NSAIDs (average cost per prescription US$17.80) or coxibs (average cost per prescription US$47.04) for a variety of inflammatory conditions took them on a long-term daily basis, whereas in the RCTs of coxibs, patients with a few carefully defined conditions took NSAIDs daily for at least 6–9 months. The researchers then developed a cost-effectiveness model to evaluate the costs of the alternative strategies of prescribing a conventional NSAID or a coxib. The mean additional cost of preventing one gastrointestinal event recorded in the GPRD by using a coxib instead of a NSAID, they report, was US$104,000; the mean cost of preventing one hospitalization for such an event was US$298,000. By contrast, the mean cost of preventing one gastrointestinal event by using a coxib instead of a NSAID calculated from data obtained in RCTs was about US$20,000.
What Do These Findings Mean?
These findings suggest that the published cost-effectiveness analyses of coxibs greatly underestimate the cost of preventing gastrointestinal events by replacing prescriptions of conventional NSAIDs with prescriptions of coxibs. That is, if data from actual clinical practice had been used in cost-effectiveness analyses rather than data from RCTs, the conclusions of the published cost-effectiveness analyses of coxibs would have been radically different and may have led to different prescribing guidelines for this class of drug. More generally, these findings provide a good illustration of how important it is to ensure that cost-effectiveness analyses have “external” validity by using realistic estimates for event rates and costs rather than relying on data from RCTs that do not always reflect the real-world situation. The researchers suggest, therefore, that health technology assessments should move from evaluating cost-efficacy in ideal populations with ideal interventions to evaluating cost-effectiveness in real populations with real interventions.
Additional Information
Please access these Web sites via the online version of this summary at
The UK National Institute for Health Research provides information about health technology assessment
The National Institute for Health and Clinical Excellence Web site describes how this organization provides guidance on promoting good health within the England and Wales National Health Service
Information on the UK General Practice Research Database is available
Wikipedia has pages on health technology assessment and on selective cyclooxygenase-2 inhibitors (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC2779340  PMID: 19997499
20.  What's the evidence that NICE guidance has been implemented? Results from a national evaluation using time series analysis, audit of patients' notes, and interviews 
BMJ : British Medical Journal  2004;329(7473):999.
Objectives To assess the extent and pattern of implementation of guidance issued by the National Institute for Clinical Excellence (NICE).
Design Interrupted time series analysis, review of case notes, survey, and interviews.
Setting Acute and primary care trusts in England and Wales.
Participants All primary care prescribing, hospital pharmacies; a random sample of 20 acute trusts, 17 mental health trusts, and 21 primary care trusts; and senior clinicians and managers from five acute trusts.
Main outcome measures Rates of prescribing and use of procedures and medical devices relative to evidence based guidance.
Results 6308 usable patient audit forms were returned. Implementation of NICE guidance varied by trust and by topic. Prescribing of some taxanes for cancer (P < 0.002) and orlistat for obesity (P < 0.001) significantly increased in line with guidance. Prescribing of drugs for Alzheimer's disease and prophylactic extraction of wisdom teeth showed trends consistent with, but not obviously a consequence of, the guidance. Prescribing practice often did not accord with the details of the guidance. No change was apparent in the use of hearing aids, hip prostheses, implantable cardioverter defibrillators, laparoscopic hernia repair, and laparoscopic colorectal cancer surgery after NICE guidance had been issued.
Conclusions Implementation of NICE guidance has been variable. Guidance seems more likely to be adopted when there is strong professional support, a stable and convincing evidence base, and no increased or unfunded costs, in organisations that have established good systems for tracking guidance implementation and where the professionals involved are not isolated. Guidance needs to be clear and reflect the clinical context.
PMCID: PMC524545  PMID: 15514342
21.  A systematic review of the safety information contained within the Summaries of Product Characteristics of medications licensed in the United Kingdom for Attention Deficit Hyperactivity Disorder. how does the safety prescribing advice compare with national guidance? 
The safety of paediatric medications is paramount and contraindications provide clear pragmatic advice. Further advice may be accessed through Summaries of Product Characteristics (SPCs) and relevant national guidelines. The SPC can be considered the ultimate independent guideline and is regularly updated. In 2008, the authors undertook a systematic review of the SPC contraindications of medications licensed in the United Kingdom (UK) for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). At that time, there were fewer contraindications reported in the SPC for atomoxetine than methylphenidate and the specific contraindications varied considerably amongst methylphenidate formulations. In 2009, the European Medicines Agency (EMA) mandated harmonisation of methylphenidate SPCs. Between September and November 2011, there were three changes to the atomoxetine SPC that resulted in revised prescribing information. In addition, Clinical Guidance has also been produced by the National Institute for Health and Clinical Excellence (NICE) (2008), the Scottish Intercollegiate Guidelines Network (SIGN) (2009) and the British National Formulary for Children (BNFC).
An updated systematic review of the Contraindications sections of the SPCs of all medications currently licensed for treatment of ADHD in the UK was undertaken and independent statements regarding contraindications and relevant warnings and precautions were then compared with UK national guidance with the aim of assessing any disparity and potential areas of confusion for prescribers.
As of November 2011, there were seven medications available in the UK for the treatment of ADHD. There are 15 contraindications for most formulations of methylphenidate, 14 for dexamfetamine and 5 for atomoxetine. Significant differences exist between the SPCs and national guidance part due to the ongoing reactive process of amending the former as new information becomes known. In addition, recommendations are made outside UK SPC licensed indications and a significant contraindication for methylphenidate (suicidal behaviours) is missing from both the NICE and SIGN guidelines. Particular disparity exists relating to monitoring for suicidal and psychiatric side effects. The BNFC has not yet been updated in line with the European Union (EU) Directive on methylphenidate; it does not include any contraindications for atomoxetine but describes contraindications for methylphenidate that are no longer in the SPC.
Clinicians seeking prescribing advice from critical independent sources of data, such as SPCs and national guidelines, may be confused by the disparity that exists. There are major differences between guidelines and SPCs and neither should be referred to in isolation. The SPC represents the most relevant source of safety data to aid prescribing of medications for ADHD as they present the most current safety data in line with increased exposure. National guidelines may need more regular updates.
PMCID: PMC3317854  PMID: 22234242
ADHD; guidelines; summary of product characteristics; drug safety; NICE; SIGN
22.  The effectiveness of schemes that refine referrals between primary and secondary care—the UK experience with glaucoma referrals: the Health Innovation & Education Cluster (HIEC) Glaucoma Pathways Project 
BMJ Open  2013;3(7):e002715.
A comparison of glaucoma referral refinement schemes (GRRS) in the UK during a time period of considerable change in national policy and guidance.
Retrospective multisite review.
The outcomes of clinical examinations by optometrists with a specialist interest in glaucoma (OSIs) were compared with optometrists with no specialist interest in glaucoma (non-OSIs). Data from Huntingdon and Nottingham assessed non-OSI findings, while Manchester and Gloucestershire reviewed OSI findings.
1086 patients. 434 patients were from Huntingdon, 179 from Manchester, 204 from Gloucestershire and 269 from Nottingham.
The first-visit discharge rate (FVDR) for all time periods for OSIs was 14.1% compared with 36.1% from non-OSIs (difference 22%, CI 16.9% to 26.7%; p<0.001). The FVDR increased after the April 2009 National Institute for Health and Clinical Excellence (NICE) glaucoma guidelines compared with pre-NICE, which was particularly evident when pre-NICE was compared with the current practice time period (OSIs 6.2–17.2%, difference 11%, CI −24.7% to 4.3%; p=0.18, non-OSIs 29.2–43.9%, difference 14.7%, CI −27.8% to −0.30%; p=0.03). Elevated intraocular pressure (IOP) was the commonest reason for referral for OSIs and non-OSIs, 28.7% and 36.1%, respectively, of total referrals. The proportion of referrals for elevated IOP increased from 10.9% pre-NICE to 28.0% post-NICE for OSIs, and from 19% to 45.1% for non-OSIs.
In terms of ‘demand management’, OSIs can reduce FVDR of patients reviewed in secondary care; however, in terms of ‘patient safety’ this study also shows that overemphasis on IOP as a criterion for referral is having an adverse effect on both the non-OSIs and indeed the OSIs ability to detect glaucomatous optic nerve features. It is recommended that referral letters from non-OSIs be stratified for risk, directing high-risk patients straight to secondary care, and low-risk patients to OSIs.
PMCID: PMC3717451  PMID: 23878172
23.  Comparing specialist medical care with specialist medical care plus the Lightning Process® for chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME): study protocol for a randomised controlled trial (SMILE Trial) 
Trials  2013;14:444.
Chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a relatively common and potentially serious condition with a limited evidence base for treatment. Specialist treatment for paediatric CFS/ME uses interventions recommended by National Institute for Health and Clinical Excellence (NICE) including cognitive behavioural therapy, graded exercise therapy and activity management. The Lightning Process® (LP) is a trademarked intervention derived from osteopathy, life-coaching and neuro-linguistic programming, delivered over three consecutive days as group sessions. Although over 250 children with CFS/ME attend LP courses each year, there are no reported studies on the effectiveness or cost-effectiveness.
This pragmatic randomised controlled trial is set within a specialist paediatric CFS/ME service in the south west of England. Children and young people with CFS/ME (n = 80 to 112), aged 12 to 18 years old will be randomised to specialist medical care (SMC) or SMC plus the LP. The primary outcome will be physical function (SF-36 physical function short form) and fatigue (Chalder Fatigue Scale).
This study will tell us whether adding the LP to SMC is effective and cost-effective compared to SMC alone. This study will also provide detailed information on the implementation of the LP and SMC.
Trial registration
Current Controlled Trials ISRCTN81456207 (31 July 2012).
PMCID: PMC3879423  PMID: 24370208
Fatigue; Paediatrics; Chronic fatigue syndrome; Myalgic encephalomyelitis
24.  The views of patients and the general public about expensive anti-cancer drugs in the NHS: a questionnaire-based study 
JRSM Short Reports  2011;2(9):69.
To determine the views of patients and members of the public about who should pay for expensive new cancer drugs not recommended by the National Institute for Health and Clinical Excellence (NICE).
A study-specific questionnaire was used to elicit the views of patients and the general public between April and June 2010. It examined whether participants thought patients should be told about all possible cancer treatments, if the NHS should always fund non-NICE recommended drugs and attitudes towards self-funding/co-payments. The influence of sociodemographic factors on responses was also examined.
Oncology clinics in Sussex and various locations including old persons' lunch clubs, parks, sports venues and support groups.
Two hundred and 10 patients with common solid tumours, and 416 members of the general public
Main outcome measures
Frequencies of responses to items regarding payments for expensive anti-cancer drugs stratified by sociodemographic factors and comparison of responses between patients and members of the public.
Most respondents (70% [147/210] of patients and 64% [266/416] of the general public) had heard of NICE. Both groups believed that doctors should tell patients about all available cancer treatments even if the NHS cannot pay (94%, 196/208; 93%, 388/415). However, only 49% (101/207) of patients and 36% (146/409) of the public believed that the NHS should always fund all new cancer drugs that have failed health technology assessments. Strong predictors of willingness to purchase expensive new cancer drugs included younger age (<45 years), sex (female) and higher educational level.
The general population appear realistic about the difficulties of providing funding for expensive new drugs. A communication skills training course has been developed to help clinicians with these difficult consultations.
PMCID: PMC3184012  PMID: 21969880
25.  Impact of ethnic-specific guidelines for anti-hypertensive prescribing in primary care in England: a longitudinal study 
In England, the National Institute for Health and Care Excellence (NICE) produces guidelines for the management of hypertension. In 2006, the NICE guidelines introduced an ethnic-age group algorithm based on the 2004 British Hypertension Society guidelines to guide antihypertensive drug prescription.
A longitudinal retrospective study with 15933 hypertensive patients aged 18 years or over and registered with 28 general practices in Wandsworth, London in 2007 was conducted to assess variations in antihypertensive prescribing. Logistic models were used to measure variations in the odds of being prescribed the 2006 NICE first line recommended monotherapy among NICE patient groups over the period.
From 2000 to 2007, the percentage of patients prescribed the recommended monotherapy increased from 54.2% to 61.4% (p < 0.0001 for annual trend). Over the study period, black patients were more likely to be prescribed the recommended monotherapy than younger non-black patients (OR 0.16, 95% CI 0.12 – 0.21) and older non-black patients (OR 0.49, 95% CI 0.37 – 0.65). After the introduction of the NICE guidelines there was an increase in the NICE recommended monotherapy (OR 1.44, 95% CI 1.19 – 1.75) compared with the underlying trend. Compared to black patients, an increase in the use of recommended monotherapy was observed in younger non-black patients (OR 1.49, 95% CI 1.17 – 1.91) but not in older non-black patients (OR 0.58, 95% CI 0.46 – 0.74).
The introduction of the 2006 NICE guideline had the greatest impact on prescribing for younger non-black patients. Lower associated increases among black patients may be due to their higher levels of recommended prescribing at baseline. The analysis suggests that guidelines did not impact equally on all patient groups.
PMCID: PMC3943578  PMID: 24568655
Hypertension; Hypertension guidelines; Primary care; Antihypertensive drugs; Trend analysis; Antihypertensive prescribing

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