The quality of COVID-19 systematic reviews during the coronavirus 2019 pandemic: an exploratory comparison.

BACKGROUND: The unprecedented volume and speed at which COVID-19-related systematic reviews (SRs) may have been produced has raised questions regarding the quality of this evidence. It is feasible that pandemic-related factors may have led to an impairment in quality (reduced internal validity, increased risk of bias [RoB]). This may have serious implications for decision-making related to public health and individual healthcare. OBJECTIVE: The primary objective was to compare the quality of SRs published during the pandemic that were related to COVID-19 with SRs published during the pandemic that were unrelated to COVID-19 (all of which were fully appraised in the KSR Evidence database of SRs in healthcare). Our secondary objective was to compare the quality of SRs published during the pandemic (regardless of research topic), with SRs published pre-pandemic. METHODS: We compared all SRs related to COVID-19 to all SRs unrelated to COVID-19 that (i) were published during the pandemic (between 1st March 2020 and September 14, 2022), (ii) were included in KSR Evidence, and (iii) had been appraised using the ROBIS tool. We then compared all SRs published during the pandemic (regardless of research topic) with a pre-pandemic sample of SRs. RESULTS: For SRs published during the pandemic, we found there was no statistically significant difference in quality between those SRs tagged as being related to COVID-19 and those that were not [relative risk (RR) of low RoB for COVID-19 versus COVID-19-unrelated reviews: 0.94; 95% confidence interval (CI): 0.66 to 1.34]. Generally, COVID-19 SRs and COVID-19-unrelated SRs were both of low quality with only 10% of COVID-19 reviews and 11% of COVID-19-unrelated reviews rated as low RoB. However, SRs (regardless of topic) published during the pandemic were of lower quality than those published pre-pandemic (RR for low RoB for 'during pandemic' versus 'pre-pandemic': 0.30; 95% CI: 0.26 to 0.34) with 11% of pandemic and 36% of pre-pandemic SRs rated as low RoB. CONCLUSION: These results suggest COVID-19 and COVID-19-unrelated SRs published during the pandemic are equally of low quality. SRs published during the pandemic were generally lower quality compared with SRs published pre-pandemic irrespective of COVID-19 focus. Moreover, SR quality in general is seriously lacking, and considerable efforts need to be made to substantially improve the quality and rigour of the SR process.

Effectiveness, safety and cost-effectiveness of sacral neuromodulation for idiopathic slow-transit constipation: a systematic review.

AIM: Sacral neuromodulation (SNM) is a minimally invasive treatment option for functional constipation. Evidence regarding its effectiveness is contradictory, driven by heterogeneous study populations and designs. The aim of this study was to assess the effectiveness, safety and cost-effectiveness of SNM in children and adults with refractory idiopathic slow-transit constipation (STC). METHOD: OVID Medline, OVID Embase, Cochrane Library, the KSR Evidence Database, the NHS Economic Evaluation Database and the International HTA Database were searched up to 25 May 2023. For effectiveness outcomes, randomized controlled trials (RCTs) were selected. For safety outcomes, all study designs were selected. For cost-effectiveness outcomes, trial- and model-based economic evaluations were selected for review. Study selection, risk of bias and quality assessment, and data extraction were independently performed by two reviewers. For the intervention 'sacral neuromodulation' effectiveness outcomes included defaecation frequency and constipation severity. Safety and cost-effectiveness outcomes were, respectively, adverse events and incremental cost-effectiveness ratios. RESULTS: Of 1390 records reviewed, 67 studies were selected for full-text screening. For effectiveness, one cross-over and one parallel-group RCT was included, showing contradictory results. Eleven studies on safety were included (four RCTs, three prospective cohort studies and four retrospective cohort studies). Overall infection rates varied between 0% and 22%, whereas reoperation rates varied between 0% and 29%. One trial-based economic evaluation was included, which concluded that SNM was not cost-effective compared with personalized conservative treatment at a time horizon of 6 months. The review findings are limited by the small number of available studies and the heterogeneity in terms of study populations, definitions of refractory idiopathic STC and study designs. CONCLUSION: Evidence for the (cost-)effectiveness of SNM in children and adults with refractory idiopathic STC is inconclusive. Reoperation rates of up to 29% were reported.

European Society of Coloproctology: Guidelines for diagnosis and treatment of cryptoglandular anal fistula.

AIM: The primary aim of the European Society of Coloproctology (ESCP) Guideline Development Group (GDG) was to produce high-quality, evidence-based guidelines for the management of cryptoglandular anal fistula with input from a multidisciplinary group and using transparent, reproducible methodology. METHODS: Previously published methodology in guideline development by the ESCP has been replicated in this project. The guideline development process followed the requirements of the AGREE-S tool kit. Six phases can be identified in the methodology. Phase one sets the scope of the guideline, which addresses the diagnostic and therapeutic management of perianal abscess and cryptoglandular anal fistula in adult patients presenting to secondary care. The target population for this guideline are healthcare practitioners in secondary care and patients interested in understanding the clinical evidence available for various surgical interventions for anal fistula. Phase two involved formulation of the GDG. The GDG consisted of 21 coloproctologists, three research fellows, a radiologist and a methodologist. Stakeholders were chosen for their clinical and academic involvement in the management of anal fistula as well as being representative of the geographical variation among the ESCP membership. Five patients were recruited from patient groups to review the draft guideline. These patients attended two virtual meetings to discuss the evidence and suggest amendments. In phase three, patient/population, intervention, comparison and outcomes questions were formulated by the GDG. The GDG ratified 250 questions and chose 45 for inclusion in the guideline. In phase four, critical and important outcomes were confirmed for inclusion. Important outcomes were pain and wound healing. Critical outcomes were fistula healing, fistula recurrence and incontinence. These outcomes formed part of the inclusion criteria for the literature search. In phase five, a literature search was performed of MEDLINE (Ovid), PubMed, Embase (Ovid) and the Cochrane Database of Systematic Reviews by eight teams of the GDG. Data were extracted and submitted for review by the GDG in a draft guideline. The most recent systematic reviews were prioritized for inclusion. Studies published since the most recent systematic review were included in our analysis by conducting a new meta-analysis using Review manager. In phase six, recommendations were formulated, using grading of recommendations, assessment, development, and evaluations, in three virtual meetings of the GDG. RESULTS: In seven sections covering the diagnostic and therapeutic management of perianal abscess and cryptoglandular anal fistula, there are 42 recommendations. CONCLUSION: This is an up-to-date international guideline on the management of cryptoglandular anal fistula using methodology prescribed by the AGREE enterprise.

The Role of Nonmetastatic Lymph Nodes in the Survival of Colorectal Cancer: A Systematic Review.

Objective: In this review, we aim to provide an overview of literature on lymph node (LN) histomorphological features and their relationship with the prognosis in colorectal cancer (CRC). Background: Lymph nodes play a crucial role in the treatment and prognosis of CRC. The presence of LN metastases considerably worsens the prognosis in CRC patients. Literature has shown that the total number of LNs and the number negative LNs (LNnegs) has prognostic value in CRC patients. In esophageal carcinoma, LN size seems to be surrogate of the host antitumor response and a potentially clinically useful new prognostic biomarker for (y)pN0 esophageal carcinoma. Methods: A comprehensive search was performed in Pubmed, Embase, Medline, CINAHL, and the Cochrane library in March 2021. The PRISMA guidelines were followed. Only studies focusing on histomorphological features and LN size and their relation to overall survival were selected. Results: A total of 9 unique articles met all inclusion criteria and were therefore included in this systematic review. Six of these studies investigated HMF (eg, paracortical hyperplasia, germinal center predominance, and sinus histiocytosis) and 4 studies LNneg size and their relationship with overall survival. The presence of paracortical hyperplasia and an increased number of large LNnegs is related to a more favorable prognosis in CRC. Conclusion: The results of this systematic review seem to support the hypothesis that there is a relationship between the host antitumor response reflected in different histomorphological reaction patterns visible in LNnegs and LNneg size related to survival in CRC patients.

The Association of Coloproctology of Great Britain and Ireland guideline on the management of anal fissure.

AIM: The management of anal fissure: ACPGBI position statement was written 15 years ago. [KLR Cross et al., Colorectal Dis, 2008]. Our aim was to update the guideline and provide recommendations on the most effective treatment for patients with anal fissures utilising a multidisciplinary, rigorous guideline methodology. METHODS: The development process consisted of six phases. In phase 1 we defined the scope of the guideline. The patient population included patients with acute and chronic anal fissure. The target group was all practitioners (primary and secondary care) treating patients with fissures and, in addition, healthcare workers and patients who desired information regarding fissure management. In phase 2 we formed a guideline development group (GDG) including a methodologist. In phase 3 review questions were formulated, using a reversed PICO process, starting with possible recommendations based on the GDG's knowledge. In phase 4 a comprehensive literature search focused on existing systematic reviews addressing each review question, supplemented by more recent studies if appropriate. In phase 5 data were extracted from the included papers and checked by the GDG. If indicated, meta-analysis of systematic review data was updated by the GDG. During phase 6 the GDG members decided what recommendations could be made based on the evidence in the literature and strength of the recommendation was assessed using 'grade'. RESULTS: This guideline is divided into two sections: Primary care which includes (i) diagnosis; (ii) basic treatment; (iii) topical treatment; and secondary care which includes (iv) botulinum toxin therapy; (v) surgical intervention and (vi) special situations (including pregnancy and breast-feeding patients, children, receptive anal intercourse and low-pressure fissures). A total of 23 recommendations were formulated. A new term clinically healed was described by the GDG. CONCLUSION: This guideline provides an up-to-date evidence-based summary of the current knowledge of the management of anal fissure and may serve as a useful guide for clinicians as well as a potential reference for patients.

Digital interventions to moderate physical inactivity and/or nutrition in young people: a Cancer Prevention Europe overview of systematic reviews.

Background: Strategies to increase physical activity (PA) and improve nutrition would contribute to substantial health benefits in the population, including reducing the risk of several types of cancers. The increasing accessibility of digital technologies mean that these tools could potentially facilitate the improvement of health behaviours among young people. Objective: We conducted a review of systematic reviews to assess the available evidence on digital interventions aimed at increasing physical activity and good nutrition in sub-populations of young people (school-aged children, college/university students, young adults only (over 18 years) and both adolescent and young adults (<25 years)). Methods: Searches for systematic reviews were conducted across relevant databases including KSR Evidence (www.ksrevidence.com), Cochrane Database of Systematic Reviews (CDSR) and Database of Abstracts of Reviews of Effects (DARE; CRD). Records were independently screened by title and abstract by two reviewers and those deemed eligible were obtained for full text screening. Risk of bias (RoB) was assessed with the Risk of Bias Assessment Tool for Systematic Reviews (ROBIS) tool. We employed a narrative analysis and developed evidence gap maps. Results: Twenty-four reviews were included with at least one for each sub-population and employing a range of digital interventions. The quality of evidence was limited with only one of the 24 of reviews overall judged as low RoB. Definitions of "digital intervention" greatly varied across systematic reviews with some reported interventions fitting into more than one category (i.e., an internet intervention could also be a mobile phone or computer intervention), however definitions as reported in the relevant reviews were used. No reviews reported cancer incidence or related outcomes. Available evidence was limited both by sub-population and type of intervention, but evidence was most pronounced in school-aged children. In school-aged children eHealth interventions, defined as school-based programmes delivered by the internet, computers, tablets, mobile technology, or tele-health methods, improved outcomes. Accelerometer-measured (Standardised Mean Difference [SMD] 0.33, 95% Confidence Interval [CI]: 0.05 to 0.61) and self-reported (SMD: 0.14, 95% CI: 0.05 to 0.23) PA increased, as did fruit and vegetable intake (SMD: 0.11, 95% CI: 0.03 to 0.19) (review rated as low RoB, minimal to considerable heterogeneity across results). No difference was reported for consumption of fat post-intervention (SMD: -0.06, 95% CI: -0.15 to 0.03) or sugar sweetened beverages(SSB) and snack consumption combined post-intervention (SMD: -0.02, 95% CI:-0.10 to 0.06),or at the follow up (studies reported 2 weeks to 36 months follow-up) after the intervention (SMD:-0.06, 95% CI: -0.15 to 0.03) (review rated low ROB, minimal to substantial heterogeneity across results). Smartphone based interventions utilising Short Messaging Service (SMS), app or combined approaches also improved PA measured using objective and subjective methods (SMD: 0.44, 95% CI: 0.11 to 0.77) when compared to controls, with increases in total PA [weighted mean difference (WMD) 32.35 min per day, 95% CI: 10.36 to 54.33] and in daily steps (WMD: 1,185, 95% CI: 303 to 2,068) (review rated as high RoB, moderate to substantial heterogeneity across results). For all results, interpretation has limitations in terms of RoB and presence of unexplained heterogeneity. Conclusions: This review of reviews has identified limited evidence that suggests some potential for digital interventions to increase PA and, to lesser extent, improve nutrition in school-aged children. However, effects can be small and based on less robust evidence. The body of evidence is characterised by a considerable level of heterogeneity, unclear/overlapping populations and intervention definitions, and a low methodological quality of systematic reviews. The heterogeneity across studies is further complicated when the age (older vs. more recent), interactivity (feedback/survey vs. no/less feedback/surveys), and accessibility (type of device) of the digital intervention is considered. This underscores the difficulty in synthesising evidence in a field with rapidly evolving technology and the resulting challenges in recommending the use of digital technology in public health. There is an urgent need for further research using contemporary technology and appropriate methods.

Digital interventions to moderate alcohol consumption in young people: a Cancer Prevention Europe overview of systematic reviews.

Background: Strategies to reduce alcohol consumption would contribute to substantial health benefits in the population, including reducing cancer risk. The increasing accessibility and applicability of digital technologies make these powerful tools suitable to facilitate changes in behaviour in young people which could then translate into both immediate and long-term improvements to public health. Objective: We conducted a review of systematic reviews to assess the available evidence on digital interventions aimed at reducing alcohol consumption in sub-populations of young people [school-aged children, college/university students, young adults only (over 18 years) and both adolescent and young adults (<25 years)]. Methods: Searches were conducted across relevant databases including KSR Evidence, Cochrane Database of Systematic Reviews (CDSR) and Database of Abstracts of Reviews of Effects (DARE). Records were independently screened by title and abstract and those that met inclusion criteria were obtained for full text screening by two reviewers. Risk of bias (RoB) was assessed with the ROBIS checklist. We employed a narrative analysis. Results: Twenty-seven systematic reviews were included that addressed relevant interventions in one or more of the sub-populations, but those reviews were mostly assessed as low quality. Definitions of "digital intervention" greatly varied across systematic reviews. Available evidence was limited both by sub-population and type of intervention. No reviews reported cancer incidence or influence on cancer related outcomes. In school-aged children eHealth multiple health behaviour change interventions delivered through a variety of digital methods were not effective in preventing or reducing alcohol consumption with no effect on the prevalence of alcohol use [Odds Ratio (OR) = 1.13, 95% CI: 0.95-1.36, review rated low RoB, minimal heterogeneity]. While in adolescents and/or young adults who were identified as risky drinkers, the use of computer or mobile device-based interventions resulted in reduced alcohol consumption when comparing the digital intervention with no/minimal intervention (-13.4 g/week, 95% CI: -19.3 to -7.6, review rated low RoB, moderate to substantial heterogeneity).In University/College students, a range of E-interventions reduced the number of drinks consumed per week compared to assessment only controls although the overall effect was small [standardised mean difference (SMD): -0.15, 95% CI: -0.21 to -0.09]. Web-based personalised feedback interventions demonstrated a small to medium effect on alcohol consumption (SMD: -0.19, 95% CI: -0.27 to -0.11) (review rated high RoB, minimal heterogeneity). In risky drinkers, stand-alone Computerized interventions reduced short (SMD: -0.17, 95% CI: -0.27 to -0.08) and long term (SMD: -0.17, 95% CI: -0.30 to -0.04) alcohol consumption compared to no intervention, while a small effect (SMD: -0.15, 95% CI: -0.25 to -0.06) in favour of computerised assessment and feedback vs. assessment only was observed. No short-term (SMD: -0.10, 95% CI: -0.30 to 0.11) or long-term effect (SMD: -0.11, 95% CI: -0.53 to 0.32) was demonstrated for computerised brief interventions when compared to counsellor based interventions (review rated low RoB, minimal to considerable heterogeneity). In young adults and adolescents, SMS-based interventions did not significantly reduce the quantity of drinks per occasion from baseline (SMD: 0.28, 95% CI: -0.02 to 0.58) or the average number of standard glasses per week (SMD: -0.05, 95% CI: -0.15 to 0.05) but increased the risk of binge drinking episodes (OR = 2.45, 95% CI: 1.32-4.53, review rated high RoB; minimal to substantial heterogeneity). For all results, interpretation has limitations in terms of risk of bias and heterogeneity. Conclusions: Limited evidence suggests some potential for digital interventions, particularly those with feedback, in reducing alcohol consumption in certain sub-populations of younger people. However, this effect is often small, inconsistent or diminishes when only methodologically robust evidence is considered. There is no systematic review evidence that digital interventions reduce cancer incidence through alcohol moderation in young people. To reduce alcohol consumption, a major cancer risk factor, further methodologically robust research is warranted to explore the full potential of digital interventions and to form the basis of evidence based public health initiatives.

Abemaciclib in Combination with Endocrine Therapy for Adjuvant Treatment of Hormone Receptor-Positive, HER2-Negative, Node-Positive Early Breast Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Eli Lilly) of abemaciclib (Verzenios) to submit evidence for the clinical and cost effectiveness of this drug in combination with endocrine therapy (ET) for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive early breast cancer at high risk of recurrence, as part of the Institute's Single Technology Appraisal (STA) process. Kleijnen Systematic Reviews Ltd, in combination with Newcastle University, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarised the Company Submission (CS), presents the ERG's critical review of the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the Appraisal Committee. The ERG produced a critical review of the evidence for the clinical and cost-effectiveness evidence in the CS and also independently searched for relevant evidence and modified the manufacturer decision analytic model to examine the impact of altering some of the key assumptions. A systematic literature review identified the MonarchE trial, an ongoing, open-label, randomised, double blind trial involving 5637 people comparing abemaciclib in combination with ET versus ET alone. The trial included two cohorts that used different inclusion criteria to define high risk of recurrence. The ERG considered Cohort 1 as an adequate representation of this population and the AC concluded that Cohort 1 was generalisable to National Health Service clinical practice. Trial results showed improvements in invasive disease-free survival for the abemaciclib arm, which was considered an appropriate surrogate outcome. The ERG believed that the modelling structure presented in the de novo economic model by the company was appropriate but highlighted several areas of uncertainty that had the potential to have a significant impact on the resulting incremental cost-effectiveness ratio (ICER). Areas of uncertainty included the extrapolation of long-term survival curves, the duration of treatment effect and treatment waning, and the proportion of patients who receive other CDK4/6 treatments for metastatic disease after receiving abemaciclib. ICER estimates were £9164 per quality-adjusted life-year gained for the company's base-case and £17,810 for the ERG's base-case. NICE recommended abemaciclib with ET as an option for the adjuvant treatment of HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence.

Fenfluramine for Treating Dravet Syndrome: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Fenfluramine, tradename Fintepla®, was appraised within the National Institute for Health and Care Excellence (NICE) single technology appraisal (STA) process as Technology Appraisal 808. Within the STA process, the company (Zogenix International) provided NICE with a written submission and a mathematical health economic model, summarising the company's estimates of the clinical effectiveness and cost-effectiveness of fenfluramine for patients with Dravet syndrome (DS). This company submission (CS) was reviewed by an evidence review group (ERG) independent of NICE. The ERG, Kleijnen Systematic Reviews in collaboration with Maastricht University Medical Centre, produced an ERG report. This paper presents a summary of the ERG report and the development of the NICE guidance. The CS included a systematic review of the evidence for fenfluramine. From this review the company identified and presented evidence from two randomised trials (Study 1 and Study 1504), an open-label extension study (Study 1503) and 'real world evidence' from a prospective and retrospective study. Both randomised trials were conducted in patients up to 18 years of age with DS, whose seizures were incompletely controlled with previous anti-epileptic drugs. A Bayesian network meta-analysis was performed to compare fenfluramine with cannabidiol plus clobazam. There was no evidence of a difference between any doses of fenfluramine and cannabidiol in the mean convulsive seizure frequency (CSF) rate during treatment. However, fenfluramine increased the number of patients achieving ≥ 50% reduction in CSF frequency from baseline compared to cannabidiol. The company used an individual-patient state-transition model (R version 3.5.2) to model cost-effectiveness of fenfluramine. The CSF and convulsive seizure-free days were estimated using patient-level data from the placebo arm of the fenfluramine registration studies. Subsequently, a treatment effect of either fenfluramine or cannabidiol was applied. Utility values for the economic model were obtained by mapping Pediatric Quality of Life Inventory data from the registration studies to EuroQol-5D-3L Youth (EQ-5D-Y-3L). The company included caregiver utilities in their base-case, as the severe needs of patients with DS have a major impact on parents and caregivers. There were several key issues. First, the company included caregiver utilities in the model in a way that when patients in the economic model died, the corresponding caregiver utility was also set to zero. Second, the model was built in R statistical software, resulting in transparency issues. Third, the company assumed the same percentage reduction for convulsive seizure days as was estimated for CSF. Fourth, during the final appraisal committee meeting, influential changes were made to the model that were not in line with the ERG's preferences (but were accepted by the appraisal committee). The company's revised and final incremental cost effectiveness ratio (ICER) in line with committee preferences resulted in fenfluramine dominating cannabidiol. Fenfluramine was recommended as an add-on to other antiepileptic medicines for treating seizures associated with DS in people aged 2 years and older in the National Health Service (NHS).

Role of the faecal immunochemical test in patients with risk-stratified suspected colorectal cancer symptoms: A systematic review and meta-analysis to inform the ACPGBI/BSG guidelines.

Background: The UK National Institute for Health and Care Excellence (NICE), recommended in 2017 the use of the faecal immunochemical test (FIT) to guide investigations in patients presenting with NICE-defined low-risk symptoms suspicious for colorectal cancer (CRC). At that time, NICE did not recommend FIT use for high-risk symptoms. This is the first systematic review to evaluate the diagnostic accuracy of FIT in NICE-defined high and low-risk symptoms and was designed to inform the joint ACPGBI/BSG guidelines. Methods: We performed a systematic literature review and meta-analysis. PROSPERO registration number CRD42021224674. Medline and EMBASE databases were searched from inception to 31st March 2022. We included studies recruiting adult patients presenting with suspected CRC symptoms in whom FIT was performed and diagnostic accuracy data for CRC detection could be derived at a limit of detection (LoD) and/or 10 µg haemoglobin/gram faeces threshold in four commonly used analysers. FIT performance was assessed for high-risk, low-risk and individual symptoms where possible. Bivariate meta-analysis was performed where study numbers allowed. Findings: Thirty-one studies (79566 patients) met inclusion criteria. At 10 µg/g, for "all symptoms" (n = 35,945) sensitivity and specificity were 91.0% (95% CI: 88.9, 92.7) and 75.2% (95% CI: 69.6, 80.1); for "high-risk" symptoms (n = 18,264), 88.7% (95% CI: 84.4, 92.0) and 78.5% (95% CI: 73.0, 83.2); and for "low-risk" symptoms (n = 2161), 88.7% (95% CI: 78.1, 95.3) and 88.5% (95% CI: 87.1, 89.9), respectively. At LoD, for "all symptoms" (n = 26,056) sensitivity and specificity were 94.7% (95% CI: 90.5, 97.1) and 66.5% (95% CI: 58.7, 73.6); for "high-risk" symptoms (n = 16,768), 92.8% (95% CI: 86.4, 96.3) and 70.3% (95% CI: 66.5, 73.8); and for "low-risk" symptoms (n = 2082), 94.7% (95% CI: 85.4, 98.9) and 71.9% (95% CI: 69.9, 73.9), respectively. Summary estimates were similar across different analysers. Interpretation: FIT sensitivity for CRC detection is maximised at the LoD; its performance is similar in high and low-risk symptoms, and across different analysers where a common threshold is used. FIT performance for CRC detection is adequate and transferrable to clinical diagnostic pathways. Funding: This review was part-funded by NHS England awarded to RM Partners. RB and RC were funded by research fellowships awarded by Croydon University Hospital.

Belimumab for Treating Active Autoantibody-Positive Systemic Lupus Erythematosus: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (GlaxoSmithKline [GSK]) of Benlysta (belimumab) to submit evidence regarding its clinical and cost effectiveness, for the review and possible extension of a previously conditionally approved intravenous formulation of belimumab for the treatment of active autoantibody-positive systemic lupus erythematosus (SLE). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review of the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the NICE Appraisal Committee.This appraisal is different to the previous appraisal in three ways: (1). This appraisal expands its definition of 'high disease activity'. (2). In TA397, belimumab was approved, with a managed access arrangement (MAA), for adults only. This appraisal includes subjects aged 5 years or older. (3). The original appraisal included an intravenous formulation only, but the current appraisal also includes a new subcutaneous formulation in the form of a prefilled pen.The company was required to collect real-world data from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR), including data on the efficacy, safety, and effect on health-related quality of life of belimumab versus rituximab. This appraisal considers these data as well as additional clinical trial evidence presented in the company's updated submission to address uncertainties identified during the original appraisal. The ERG identified three major concerns with the evidence presented on the clinical effectiveness in the current submission; namely, short follow-up in the main comparative trials (BLISS-SC, BLISS-52 and BLISS-76); using the propensity score-matching (PSM) analysis in calibrating the cost-effectiveness model can severely bias the results in favour of belimumab; and BILAG-BR data are not suitable for a comparison of belimumab with rituximab.The main issue in the economic analysis was the uncertainty about long-term disease activity progression and resulting organ damage. The company's approach of calibrating modelled organ damage to longer-term data analysed using the PSM analysis was methodologically inappropriate. The final analysis comparing belimumab with standard treatment for the intravenous formulation resulted in an incremental cost-effectiveness ratio of £12,335 per quality-adjusted life-year (QALY) gained and £30,278 per QALY gained in the company's and ERG's base-case analyses, respectively. For the subcutaneous formulation, the final analysis resulted in £8480 per QALY gained and £29,313 per QALY gained in the company's and ERG's base-case analyses, respectively. NICE recommended belimumab in both intravenous and subcutaneous formulations as an add-on treatment option for active autoantibody-positive SLE in the HDA-2 subgroup.

Duration of Protection After Vaccination Against Yellow Fever: A Systematic Review and Meta-Analysis.

The duration of protection after a single dose of yellow fever vaccine is a matter of debate. To summarize the current knowledge, we performed a systematic literature review and meta-analysis. Studies on the duration of protection after 1 and ≥2 vaccine doses were reviewed. Data were stratified by time since vaccination. In our meta-analysis, we used random-effects models. We identified 36 studies from 20 countries, comprising more than 17 000 participants aged 6 months to 85 years. Among healthy adults and children, pooled seroprotection rates after single vaccination dose were close to 100% by 3 months and remained high in adults for 5 to 10 years. In children vaccinated before age 2 years, the seroprotection rate was 52% within 5 years after primary vaccination. For immunodeficient persons, data indicate relevant waning. The extent of waning of seroprotection after yellow fever vaccination depends on age and immune status at primary vaccination.

Faecal immunochemical testing (FIT) in patients with signs or symptoms of suspected colorectal cancer (CRC): a joint guideline from the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and the British Society of Gastroenterology (BSG).

Faecal immunochemical testing (FIT) has a high sensitivity for the detection of colorectal cancer (CRC). In a symptomatic population FIT may identify those patients who require colorectal investigation with the highest priority. FIT offers considerable advantages over the use of symptoms alone, as an objective measure of risk with a vastly superior positive predictive value for CRC, while conversely identifying a truly low risk cohort of patients. The aim of this guideline was to provide a clear strategy for the use of FIT in the diagnostic pathway of people with signs or symptoms of a suspected diagnosis of CRC. The guideline was jointly developed by the Association of Coloproctology of Great Britain and Ireland/British Society of Gastroenterology, specifically by a 21-member multidisciplinary guideline development group (GDG). A systematic review of 13 535 publications was undertaken to develop 23 evidence and expert opinion-based recommendations for the triage of people with symptoms of a suspected CRC diagnosis in primary care. In order to achieve consensus among a broad group of key stakeholders, we completed an extended Delphi of the GDG, and also 61 other individuals across the UK and Ireland, including by members of the public, charities and primary and secondary care. Seventeen research recommendations were also prioritised to inform clinical management.

Comparison of Patients With Head and Neck Cancer in Randomized Clinical Trials and Clinical Practice: A Systematic Review.

Importance: When patient populations in randomized clinical trials deviate too much from the general population, it undermines the relevance for daily practice. Objective: To investigate if patients with head and neck cancer in randomized clinical trials are representative of the clinically treated population. Evidence Review: A systematic literature search was performed for randomized clinical trials on head and neck cancer evaluating an intervention to improve outcome with total sample size of 100 patients or greater and published between 2009 and 2019. Outcome measures were age, performance status, and recruitment rate. National cancer registries provided reference data. Databases that were searched included MEDLINE and Epub Ahead of Print; Embase; Cochrane Central Register of Controlled Trials; and ClinicalTrials.gov. Abstracts of search results were retrieved to assess selection criteria by 2 reviewers independently. After the selection procedure was completed by both reviewers, the results were compared and reviewed once more to reach consensus. Full articles were downloaded to retrieve general study information and outcome data. Findings: A total of 16 927 publications were identified, resulting in 87 compliant randomized clinical trials with a total of 34 241 patients. Half of the trials included all major head and neck sites, and one-third were exclusively for nasopharynx cancers. The experimental intervention was systemic treatment in 47 (54%) studies, radiotherapy in 23 (26%), and other in 17 (20%). Median sample size was 332, and median duration of accrual was 4.6 years. Median accrual per center per year for head and neck and nasopharynx trials was 5.4 and 39.7 patients, respectively. Median age of patients in head and neck trials was 57 years, which was 7 years younger than in cancer registries. More than 70% of patients had a World Health Organization performance score of 0 to 1 or a Karnofsky performance status of 90 to 100. Conclusions and Relevance: In this systematic review, patients in head and neck randomized clinical trials had a very good performance status, and half of them were younger than 57 years, while half of the clinical population was older than 64 years. In more than 50% of the head and neck trials, the yearly accrual per center was less than 6 patients, suggesting overly restrictive recruitment. Critical appraisal of trial population characteristics is recommended before results are implemented in clinical guidelines and general practice.

Most healthcare interventions tested in Cochrane Reviews are not effective according to high quality evidence: a systematic review and meta-analysis.

OBJECTIVE: To estimate the proportion of healthcare interventions tested within Cochrane Reviews that are effective according to high-quality evidence. METHODS: We selected a random sample of 2,428 (35%) of all Cochrane Reviews published between 1 January 2008 and 5 March 2021. We extracted data about interventions within these reviews that were compared with placebo, or no treatment, and whose outcome quality was rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. We calculated the proportion of interventions whose benefits were based on high-quality evidence (defined as having high quality GRADE rating for at least one primary outcome, statistically significant positive results, and being judged by review authors as effective. We also calculated the proportion of interventions that suggested harm. RESULTS: Of 1,567 eligible interventions, 87 (5.6%) had high-quality evidence supporting their benefits. Harms were measured for 577 (36.8%) interventions. There was statistically significant evidence for harm in 127 (8.1%) of these. Our dependence on the reliability of Cochrane author assessments (including their GRADE assessments) was the main potential limitation of our study. CONCLUSION: More than 9 in 10 healthcare interventions studied within recent Cochrane Reviews are not supported by high-quality evidence, and harms are under-reported.

Guideline for the diagnosis and treatment of Faecal Incontinence-A UEG/ESCP/ESNM/ESPCG collaboration.

INTRODUCTION: The goal of this project was to create an up-to-date joint European clinical practice guideline for the diagnosis and treatment of faecal incontinence (FI), using the best available evidence. These guidelines are intended to help guide all medical professionals treating adult patients with FI (e.g., general practitioners, surgeons, gastroenterologists, other healthcare workers) and any patients who are interested in information regarding the diagnosis and management of FI. METHODS: These guidelines have been created in cooperation with members from the United European Gastroenterology (UEG), European Society of Coloproctology (ESCP), European Society of Neurogastroenterology and Motility (ESNM) and the European Society for Primary Care Gastroenterology (ESPCG). These members made up the guideline development group (GDG). Additionally, a patient advisory board (PAB) was created to reflect and comment on the draft guidelines from a patient perspective. Relevant review questions were established by the GDG along with a set of outcomes most important for decision making. A systematic literature search was performed using these review questions and outcomes as a framework. For each predefined review question, the study or studies with the highest level of study design were included. If evidence of a higher-level study design was available, no lower level of evidence was sought or included. Data from the studies were extracted by two reviewers for each predefined important outcome within each review question. Where possible, forest plots were created. After summarising the results for each review question, a systematic quality assessment using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach was performed. For each review question, we assessed the quality of evidence for every predetermined important outcome. After evidence review and quality assessment were completed, recommendations could be formulated. The wording used for each recommendation was dependent on the level of quality of evidence. Lower levels of evidence resulted in weaker recommendations and higher levels of evidence resulted in stronger recommendations. Recommendations were discussed within the GDG to reach consensus. RESULTS: These guidelines contain 45 recommendations on the classification, diagnosis and management of FI in adult patients. CONCLUSION: These multidisciplinary European guidelines provide an up-to-date comprehensive evidence-based framework with recommendations on the diagnosis and management of adult patients who suffer from FI.