Obinutuzumab in Combination with Chemotherapy for the First-Line Treatment of Patients with Advanced Follicular Lymphoma: An Evidence Review Group Evaluation of the NICE Single Technology Appraisal

The National Institute for Health and Care Excellence (NICE), as part of the institute’s single technology appraisal (STA) process, invited the company that makes obinutuzumab (Roche Products Limited) to submit evidence of the clinical and cost effectiveness of the drug in combination with chemotherapy, with or without obinutuzumab as maintenance therapy for adult patients with untreated, advanced follicular lymphoma (FL) in the UK. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company’s submission, the ERG review, and NICE’s subsequent decisions. The clinical evidence was derived from two phase III, company-sponsored, randomised, open-label studies. Most evidence on obinutuzumab was based on the GALLIUM trial that compared obinutuzumab in combination with chemotherapy as induction followed by obinutuzumab maintenance monotherapy with rituximab in combination with chemotherapy as induction followed by rituximab maintenance monotherapy in previously untreated patients with FL (grades 1–3a). Long-term clinical evidence was based on the PRIMA trial, studying the benefit of two years of rituximab maintenance after first-line treatment in patients with FL. The cost-effectiveness evidence submitted by the company relied on a partitioned survival cost-utility model, implemented in Microsoft® Excel. The base-case incremental cost-effectiveness ratio (ICER) presented in the company submission was <£20,000 per quality-adjusted life-year (QALY) gained. Although the ERG concluded that the economic model met the NICE reference case to a reasonable extent, some errors were identified and several assumptions made by the company were challenged. A new base-case scenario produced by the ERG suggested an ICER that was higher than the company base case, but still below £30,000 per QALY gained. However, some ERG scenario analyses were close to or even above the threshold. This was the case in particular for assuming a treatment effect that did not extend beyond trial follow-up. These results led to an initial negative recommendation by the appraisal committee. Subsequently, the company submitted a revised base case focu

Can incontinence be cured? A systematic review of cure rates

Background Incontinence constitutes a major health problem affecting millions of people worldwide. The present study aims to assess cure rates from treating urinary (UI) or fecal incontinence (FI) and the number of people who may remain dependent on containment strategies. Methods Medline, Embase, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, and PEDro were searched from January 2005 to June 2015. Supplementary searches included conference abstracts and trials registers (2013–2015). Included studies had patients ≥ 18 years with UI or FI, reported treatment cure or success rates, had ≥ 50 patients treated with any intervention recognized in international guideline algorithms, a follow-up ≥ 3 months, and were published from 2005 onwards. Title and abstract screening, full paper screening, data extraction and risk-of-bias assessment were performed independently by two reviewers. Disagreements were resolved through discussion or referral to a third reviewer where necessary. A narrative summary of included studies is presented. Results Most evidence was found for UI: Surgical interventions for stress UI showed a median cure rate of 82.3% (interquartile range (IQR), 72–89.5%); people with urgency UI were mostly treated using medications (median cure rate for antimuscarinics = 49%; IQR, 35.6–58%). Pelvic floor muscle training and bulking agents showed lower cure rates for UI. Sacral neuromodulation for FI had a median cure rate of 38.6% (IQR, 35.6–40.6%). Conclusions Many individuals were not cured and hence may continue to rely on containment. No studies were found assessing success of containment strategies. There was a lack of data in the disabled and in those with neurological diseases, in the elderly and those with cognitive impairment. Surgical interventions were effective for stress UI. Other interventions for UI and FI showed lower cure rates. Many individuals are likely to be reliant on containment strategies

Systematic review of the accuracy of dual-source cardiac CT for detection of Arterial Stenosis in difficult to image patient groups

__Purpose:__ To assess the diagnostic performance of dual-source cardiac (DSC) computed tomography (CT) newer-generation CT instruments for identifying anatomically significant coronary artery disease (CAD) in patients who are difficult to image by using 64-section CT. __Materials and Methods:__ A literature search comprised bibliographic databases (January 1, 2000, to March 22, 2011, with a pragmatic update on September 6, 2012), trial registries, and conference proceedings. Only studies using invasive coronary angiography as reference standard were included. Risk of bias was assessed (QUADAS-2). Results were stratified according to patient group on the basis of clinical characteristics. Summary estimates of sensitivity and specificity of DSC CT for detecting 50% or greater arterial stenosis were calculated by using a bivariate summary receiver operating characteristic or random-effects model. __Results:__ Twenty-five studies reported accuracy of DSC CT for diagnosing CAD in difficult to image patients; in 22 studies, one of two CT units of the same manufacturer (Somatom Definition or Somatom Definition Flash) was used, and in the remaining three, a different CT unit of another manufacturer (Aquilion One) was used. The pooled, per-patient estimates of sensitivity were 97.7% (95% confidence interval [CI]: 88.0%, 99.9%) and 97.7% (95% CI: 93.2%, 99.3%) for patients with arrhythmias and high heart rates, respectively. The corresponding pooled estimates of specificity were 81.7% (95% CI: 71.6%, 89.4%) and 86.3% (95% CI: 80.2%, 90.7%), respectively. All data were acquired by using Somatom Definition. In two studies with Somatom and one study with Aquilion One, sensitivity estimates of 90% or greater were reported in patients with previous stent implantations; specificities were 81.7% and 89.5% for Somatom and 81.0% for Aquilion One. In patients with high coronary calcium scores, previous bypass grafts, or obesity, only per-segment or per-artery data were available. Sensitivity estimates remained high (.90% in all but one study), and specificities ranged from 79.1% to 100%. All data were acquired by using Somatom Definition. __Conclusion:__ DSC CT may be sufficiently accurate to diagnose clinically significant CAD in some or all difficult to image patients

Epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation testing in adults with locally advanced or metastatic non-small cell lung cancer: A systematic review and cost-effectiveness analysis

__Abstract__ Background: Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Some epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutations make tumours responsive to treatment with EGFR-TK inhibitors (EGFR-TKIs) but less responsive to treatment with standard chemotherapy. Patients with NSCLC are therefore tested for EGFR-TK tumour gene mutations to inform treatment decisions. There are a variety of tests available to detect these mutations. The different tests vary in the specific mutations that they attempt to detect, the amount of tumour cells needed for the test to work, the time that it takes to give a result, the error rate of the test, and the cost of the test. Objective: To compare the performance and cost-effectiveness of EGFR-TK mutation tests used to identify previously untreated adults with locally advanced or metastatic NSCLC, who may benefit from first-line treatment with TKIs. Data sources: Twelve databases to August 2012 [including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations and Daily Update (OvidSP), EMBASE, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment database (HTA), Science Citation Index (SCI), Latin American and Caribbean Health Sciences Literature (LILACS), BIOSIS Previews, NIHR Health Technology Assessment programme, PROSPERO (International Prospective Register of Systematic Reviews)], research registers and conference proceedings. A web-based survey gathered data on technical performance of EGFR-TK mutation tests. Methods: Randomised controlled trials were assessed for methodological quality using the Cochrane risk of bias tool. Diagnostic accuracy studies were assessed using QUADAS-2. There were insufficient data for m

Viscoelastic point-of-care testing to assist with the diagnosis, management and monitoring of haemostasis: A systematic review and cost-effectiveness analysis

Background: Patients with substantive bleeding usually require transfusion and/or (re-)operation. Red blood cell (RBC) transfusion is independently associated with a greater risk of infection, morbidity, increased hospital stay and mortality. ROTEM (ROTEM® Delta, TEM International GmbH, Munich, Germany; www.rotem.de), TEG (TEG® 5000 analyser, Haemonetics Corporation, Niles, IL, USA; www.haemonetics.com) and Sonoclot (Sonoclot® coagulation and platelet function analyser, Sienco Inc., Arvada, CO) are point-of-care viscoelastic (VE) devices that use thromboelastometry to test for haemostasis in whole blood. They have a number of proposed advantages over standard laboratory tests (SLTs): they provide a result much quicker, are able to identify what part of the clotting process is disrupted, and provide information on clot formation over time and fibrinolysis. Objectives: This assessment aimed to assess the clinical effectiveness and cost-effectiveness of VE devices to assist with the diagnosis, management and monitoring of haemostasis disorders during and after cardiac surgery, trauma-induced coagulopathy and post-partum haemorrhage (PPH). Methods: Sixteen databases were searched to December 2013: MEDLINE (OvidSP), MEDLINE In-Process and Other Non-Indexed Citations and Daily Update (OvidSP), EMBASE (OvidSP), BIOSIS Previews (Web of Knowledge), Science Citation Index (SCI) (Web of Science), Conference Proceedings Citation Index (CPCI-S) (Web of Science), Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA) database, Latin American and Caribbean Health Sciences Literature (LILACS), International Network of Agencies for Health Technology Assessment (INAHTA), National Institute for Health Research (NIHR) HTA programme, Aggressive Research Intelligence Facility (ARIF), Medion, and the International Prospective Register of Systematic Reviews (PROSPERO). Randomised controlled trials (RCTs) were assessed for quality using the Cochrane Risk of Bias tool. Prediction studies were assessed using QUADAS-2. For RCTs, summary relative risks (RRs) were estimated using random-effects models. Continuous data were summarised narratively. For prediction studies, the

Exercise recommendations for women with polycystic ovary syndrome : Is the evidence enough?

In this opinion piece, we summarize, discuss implications of implementation, and critically evaluate our 2018 evidence-based guideline recommendations for exercise and physical activity in women with polycystic ovary syndrome (PCOS). We developed recommendations as part of a larger international guideline development project. The overall guideline scope and priorities were informed by extensive health professional and consumer engagement. The lifestyle guideline development group responsible for the exercise recommendations included experts in endocrinology, exercise physiology, gynecology, dietetics, and obstetrics, alongside consumers. Extensive online communications and two face-to-face meetings addressed five prioritized clinical questions related to lifestyle, including the role of exercise as therapy for women with PCOS. The guideline recommendations were formulated based on one narrative and two evidence-based reviews, before consensus voting within the guideline panel. The development process was in accordance with the Appraisal of Guidelines for Research and Evaluation (AGREE) II, and used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework to assess evidence quality, desirable and undesirable consequences, feasibility, acceptability, cost, implementation, and recommendation strength. Given the evidence for exercise as therapy in PCOS being of low quality, a consensus recommendation was made based on current exercise guidelines for the general population. Women with PCOS and clinicians are forced to adopt generic approaches when recommending exercise therapy that perpetuates clinical management with pharmacological solutions. The current status of evidence highlights the need for greater international co-operation between researchers and funding agencies to address key clinical knowledge gaps around exercise therapy in PCOS to generate evidence for appropriate, scalable, and sustainable best practice approaches

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field