The effectiveness and acceptability of evidence synthesis summary formats for clinical guideline development groups: a mixed-methods systematic review.

INTRODUCTION: Clinical guideline development often involves a rigorous synthesis of evidence involving multidisciplinary stakeholders with different priorities and knowledge of evidence synthesis; this makes communicating findings complex. Summary formats are typically used to communicate the results of evidence syntheses; however, there is little consensus on which formats are most effective and acceptable for different stakeholders. METHODS: This mixed-methods systematic review (MMSR) aimed to evaluate the effectiveness and acceptability (e.g. preferences and attitudes and preferences towards) of evidence synthesis summary formats for GDG members. We followed the PRISMA 2020 guideline and Joanna Briggs Institute Manual for Evidence Synthesis for MMSRs. We searched six databases (inception to April 20, 2021) for randomised controlled trials (RCTs), RCTs with a qualitative component, and qualitative studies. Screening, data extraction, and quality appraisal were performed in duplicate. Qualitative findings were synthesised using meta-aggregation, and quantitative findings are described narratively. RESULTS: We identified 17,240 citations and screened 54 full-text articles, resulting in 22 eligible articles (20 unique studies): 4 articles reported the results of 5 RCTs, one of which also had a qualitative component. The other 18 articles discussed the results of 16 qualitative studies. Therefore, we had 5 trials and 17 qualitative studies to extract data from. Studies were geographically heterogeneous and included a variety of stakeholders and summary formats. All 5 RCTs assessed knowledge or understanding with 3 reporting improvement with newer formats. The qualitative analysis identified 6 categories of recommendations: 'presenting information', 'tailoring information' for end users, 'trust in producers and summary', 'knowledge required' to understand findings, 'quality of evidence', and properly 'contextualising information'. Across these categories, the synthesis resulted in 126 recommendations for practice. Nine recommendations were supported by both quantitative and qualitative evidence and 116 by only qualitative. A majority focused on how to present information (n = 64) and tailor content for different end users (n = 24). CONCLUSIONS: This MMSR provides guidance on how to improve evidence summary structure and layout. This can be used by synthesis producers to better communicate to GDGs. Study findings will inform the co-creation of evidence summary format prototypes based on GDG member's needs. Trial registration The protocol for this project was previously published, and the project was preregistered on Open Science Framework (Clyne and Sharp, Evidence synthesis and translation of findings for national clinical guideline development: addressing the needs and preferences of guideline development groups, 2021; Sharp and Clyne, Evidence synthesis summary formats for decision-makers and Clinical Guideline Development Groups: A mixed-methods systematic review protocol, 2021).

Efficacy and safety of electronic cigarettes as a smoking cessation intervention: A systematic review and network meta-analysis.

INTRODUCTION: This systematic review of randomized controlled trials (RCTs) evaluated the efficacy and safety of electronic cigarettes (e-cigarettes, ENDS) in helping people who smoke to achieve abstinence compared with electronic non-nicotine delivery systems (ENNDS, no nicotine) or any smoking cessation comparator treatment or combination of treatments at 24-26 weeks and at 52 weeks. METHODS: Systematic review techniques involved searches of three databases in February 2020 with update searches run on 14 May 2021, two-person independent screening, two-person independent assessment of bias, formal extraction of data with verification by a second person, a feasibility assessment to decide if meta-analysis was appropriate, and network meta-analysis (NMA) of data at 24-26 weeks. Data at 52 weeks were narratively summarized. RESULTS: Ten RCTs met the inclusion criteria, eight for efficacy and ten for safety. Eight of the nine RCTs were assessed as at high risk of bias. The sample sizes of the RCTs were 30-2012. Using nicotine replacement therapy (NRT) as the reference treatment, the incidences of smoking cessation at 24-26 weeks were comparable between ENDS and NRT groups (RR=1.17; 95% CrI: 0.66-1.86). Three sensitivity analyses were carried out indicating the main findings for 24-26 weeks were robust to assumptions. The findings at 52 weeks were inconclusive. CONCLUSIONS: This systematic review and NMA indicates that there is no clear evidence of a difference in effect between nicotine containing e-cigarettes and NRT on incidences of smoking cessation at 24-26 weeks, and substantial uncertainty remains.

Association between electronic cigarette use and tobacco cigarette smoking initiation in adolescents: a systematic review and meta-analysis.

BACKGROUND: This systematic review of prospective longitudinal primary studies sought to determine whether electronic cigarette (e-cigarette) use by teenagers who had never smoked conventional tobacco cigarettes (tobacco cigarettes) at baseline was associated with subsequently commencing tobacco cigarette smoking. METHODS: The review followed the principles of a systematic review and meta-analysis. A key word search identified peer-reviewed articles published between 1 January 2005 and 2 October 2019 from seven bibliographic databases and one search engine. Using pre-prepared inclusion/exclusion criteria two researchers independently screened abstracts, and subsequently, full text papers. Selected articles were quality assessed in duplicate. Data on study participants characteristics, exposure and outcome measures were recorded in an adapted Cochrane Data Extraction Form. Feasibility assessment was done to detect clinical heterogeneity and choose an approach to meta-analysis. Analysis comprised pairwise random effects meta-analyses, and sensitivity and subgroup analyses. RESULTS: From the 6619 studies identified, 14 one-off primary studies in 21 articles were suitable for inclusion. The participants ages ranged from 13 to 19 years and comprised teenagers based in Europe and North America. Nine of the 14 one-off studies, with follow-up periods between 4 and 24 months, met the criteria for inclusion in a meta-analysis of the association between ever use of e-cigarettes and subsequent initiation of tobacco cigarette use. Based on primary study adjusted odds ratios, our meta-analysis calculated a 4.06 (95% confidence interval (CI): 3.00-5.48, I2 68%, 9 primary studies) times higher odds of commencing tobacco cigarette smoking for teenagers who had ever used e-cigarettes at baseline, though the odds ratio were marginally lower (to 3.71 times odds, 95%CI: 2.83-4. 86, I2 35%, 4 primary studies) when only the four high-quality studies were analysed. CONCLUSION: The systematic review found that e-cigarette use was associated with commencement of tobacco cigarette smoking among teenagers in Europe and North America, identifying an important health-related harm. Given the availability and usage of e-cigarettes, this study provides added support for urgent response by policymakers to stop their use by teenagers to decrease direct harms in this susceptible population group, as well as to conserve achievements in diminishing tobacco cigarette initiation.

Clinical efficacy and safety of first-line treatments in patients with mantle cell lymphoma: A systematic literature review.

Mantle cell lymphoma (MCL) is a rare form of non-Hodgkin's lymphoma (NHL) with a median overall survival (OS) of approximately 3-5 years. Systematic literature reviews (SLRs) identified efficacy and safety data for first-line therapies, reported in randomised controlled trials (RCTs) and non-randomised interventional studies (NRISs). Nine and 20 independent studies were included in the RCT and NRISs SLRs, respectively. Differences in the regimens and patient outcomes varied according to patient age and suitability for autologous stem cell transplantation (ASCT). In elderly patients ineligible for transplant, OS ranged from 40 months to 69.6 months. In young transplant-eligible patients, OS ranged from 53 months to 152.4 months. Despite the paucity of directly comparable evidence on the efficacy and safety of MCL therapies, these SLRs highlight that MCL remains a difficult NHL subtype to treat, with short survival highlighting the unmet need for newer treatments that improve patient outcomes.

Cost-Effectiveness Analyses, Costs and Resource Use, and Health-Related Quality of Life in Patients with Follicular or Marginal Zone Lymphoma: Systematic Reviews.

BACKGROUND: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are types of indolent non-Hodgkin lymphoma (NHL) that develop in the B lymphocytes (also known as B cells). OBJECTIVE: The aim of this study was to conduct a comprehensive review of studies relating to cost effectiveness, costs and resource use, and health-related quality of life (HRQoL) in patients with FL or MZL. METHODS: Three separate systematic reviews were conducted to identify all published evidence on cost effectiveness, costs and resource use, and HRQoL between 2007 and March 2017 using the MEDLINE®, MEDLINE in-process, E-pubs ahead of print (Ovid SP®), Embase (Ovid SP®), NHS EED, and EconLit databases. Select congress proceedings were also searched. Two systematic reviewers independently reviewed titles, abstracts, and full papers against eligibility criteria. Relevant data were extracted into bespoke data extraction templates (DETs) by a single systematic reviewer; these data were then validated for accuracy by a second reviewer against clean copies of the relevant publications. RESULTS: A total of 25 cost-effectiveness studies (24 in FL; 1 in FL and MZL) met the eligibility criteria. Markov models were the most utilised cost-effectiveness model. US FL studies reported an incremental cost-effectiveness ratio (ICER) of $28,565/QALY for first-line rituximab-cyclophosphamide, vincristine, and prednisone (R-CVP) versus CVP, and $43,000/QALY for second-line obinutuzumab plus bendamustine (G + B) followed by G maintenance versus B. In the UK, ICERs were £1529-10,834/quality-adjusted life-year (QALY) for first-line rituximab + chemotherapy versus chemotherapy, £27,988/QALY for second-line G + B + G-maintenance versus B, and £62,653/QALY for second-line idelalisib versus chemotherapy and/or rituximab. Five costs/resource use and four HRQoL studies were identified in FL, and none in MZL. US mean lifetime costs in first-line patients ranged from $108,000 (rituximab) to $130,300 (rituximab-cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisolone [CHOP]), and from £2185 (watch-and-wait) to £17,054 (chemotherapy) in the UK. In a multinational study, more rituximab-refractory patients receiving G + B + G-maintenance reported a meaningful improvement in total FACT-Lym scores compared with patients receiving B. In the UK, total FACT-Lym scores were meaningfully higher for newly diagnosed patients compared with patients with progression (136.04 vs. 109.7). CONCLUSIONS AND RELEVANCE: We found a small body of evidence of quality of life, and potentially cost-effective treatment options for FL; however, no evidence was reported on MZL specifically. The significant data gaps in knowledge in these diseases demonstrate a marked need for further studies.

Systematic literature review of the global burden of illness of mantle cell lymphoma.

Background: Mantle cell lymphoma (MCL), a rare and aggressive disease, accounts for approximately 5% of all B-cell non-Hodgkin's lymphomas. Evidence on the burden of this disease, for patients and healthcare providers, is scarce.Methods: Four systematic literature reviews were developed to identify epidemiological, real-world clinical, economic and humanistic burden data on patients with MCL. Electronic databases searched included MEDLINE and Embase, NHS EED and Econlit.Results: Eight epidemiological studies, 19 clinical burden, 2 economic impact and 0 quality of life studies were identified. The range of standardized MCL incidence rates was 0.1-1.27/100,000. Overall survival rates of patients at 3 years differed by age at diagnosis (≤65 years: 76-81%, >65 years: 46-64%) and disease stage (stage I: 73-80%, stage IV: 48-53%). Outcomes were poorer in previously treated patients, and those with later stage or blastoid disease, and improved with more recent diagnosis/treatment. Hospitalization is a major contributor to healthcare cost and differs by therapy toxicity.Conclusions: We identified significant data gaps for many G20 countries for epidemiology, real-world clinical, economic and humanistic burden. These literature reviews demonstrate the ongoing unmet need for MCL patients globally. Future research to further understand the real-world impact of MCL is needed along with new therapeutic options to improve patient outcomes.

Critical appraisal of nonrandomized studies-A review of recommended and commonly used tools.

RATIONALE, AIMS, AND OBJECTIVES: When randomized controlled trial data are limited or unavailable, or to supplement randomized controlled trial evidence, health technology assessment (HTA) agencies may rely on systematic reviews of nonrandomized studies (NRSs) for evidence of the effectiveness of health care interventions. NRS designs may introduce considerable bias into systematic reviews, and several methodologies by which to evaluate this risk of bias are available. This study aimed to identify tools commonly used to assess bias in NRS and determine those recommended by HTA bodies. METHODS: Appraisal tools used in NRS were identified through a targeted search of systematic reviews (January 2013-March 2017; MEDLINE and EMBASE [OVID SP]). Recommendations for the critical appraisal of NRS by expert review groups and HTA bodies were reviewed. RESULTS: From the 686 studies included in the narrative synthesis, 48 critical appraisal tools were identified. Commonly used tools included the Newcastle-Ottawa Scale, the methodological index for NRS, and bespoke appraisal tools. Neither the Cochrane Handbook nor the Centre for Reviews and Dissemination recommends a particular instrument for the assessment of risk of bias in NRS, although Cochrane has recently developed their own NRS critical appraisal tool. Among HTA bodies, only the Canadian Agency for Drugs and Technologies in Health recommends use of a specific critical appraisal tool-SIGN 50 (for cohort or case-control studies). Several criteria including reporting, external validity, confounding, and power were examined. CONCLUSION: There is no consensus between HTA groups on the preferred appraisal tool. Reviewers should select from a suite of tools on the basis of the design of studies included in their review.

Burden of illness of follicular lymphoma and marginal zone lymphoma.

Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are two subtypes of indolent B cell non-Hodgkin lymphoma (NHL) that account for approximately 20% and 12% of all NHLs, respectively. FL and MZL are rare conditions with orphan disease designations. We conducted a comprehensive review of the burden of FL and MZL that encompasses the epidemiological, real world clinical, economic, and humanistic impact of these diseases globally. A targeted literature search identified 31 eligible studies for review. Epidemiological coverage was poor, with data obtained for studies from only seven countries. The incidences of both subtypes were low: age-standardized incidence rates of FL ranged from 2.1/100,000 in France to 4.3/100,000 in the USA, while for MZL it varied geographically from 0.5/100,000 in Australia to 2.6/100,000 in the UK. The cumulative total direct healthcare costs for FL were higher for patients with progressive disease compared to those without ($30,890 vs. $8704 at 12 months, respectively) and main driver of costs related to the use of chemotherapy. Five-year overall survival was improved in patients with FL compared with MZL (e.g., 76.5% vs 60.7% in one study that reported on both subtypes). Mortality rates were particularly lower in female patients with FL aged < 60 years. However, limited outcome data for MZL patients were identified. FL and MZL contribute significant burden on healthcare systems and on patients globally, with delays in progression potentially leading to cost savings. More rigorous characterization of these two NHL subtypes, new and more effective treatments, and standardization of reporting would lead to a more robust understanding of future data in this disease area.

A practical approach to predict expansion of evidence networks: a case study in treatment-naive advanced melanoma.

Network meta-analysis (NMA) is a statistical method used to produce comparable estimates of efficacy across a range of treatments that may not be compared directly within any single trial. NMA feasibility is determined by the comparability of the data and presence of a connected network. In rapidly evolving treatment landscapes, evidence networks can change substantially in a short period of time. We investigate methods to determine the optimum time to conduct or update a NMA based on anticipated available evidence. We report the results of a systematic review conducted in treatment-naive advanced melanoma and compare networks of evidence available at retrospective, current, and prospective time points. For included publications, we compared the primary completion date of trials from clinical trials registries (CTRs) with the date of their first available publication to provide an estimate of publication lag. Using CTRs we were able to produce anticipated networks for future time points based on projected study completion dates and average publication lags which illustrated expansion and strengthening of the initial network. We found that over a snapshot of periods between 2015 and 2018, evidence networks in melanoma changed substantively, adding new comparators and increasing network connectedness. Searching CTRs for ongoing trials demonstrates it is possible to anticipate future networks at a certain time point. Armed with this information, sensible decisions can be made over when best to conduct or update a NMA. Incorporating new and upcoming interventions in a NMA enables presentation of a complete, up-to-date and evolving picture of the evidence.

Value and usability of unpublished data sources for systematic reviews and network meta-analyses.

Peer-reviewed publications and conference proceedings are the mainstay of data sources for systematic reviews and network meta-analyses (NMA), but access to informative unpublished data is now becoming commonplace. To explore the usefulness of three types of 'grey' literature-clinical trials registries, clinical study reports and data from regulatory authorities-we conducted four case studies. The reporting of outcome data in peer-reviewed publications, the clinical trials registries and the clinical study reports for two clinical trials-one in melanoma, one in juvenile idiopathic arthritis (JIA)-was examined. In addition, we assessed the value of including unpublished data from the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) in evidence syntheses of hepatitis C virus (HCV) and chronic obstructive pulmonary disease (COPD), respectively. For the clinical trials in melanoma and JIA, we identified outcome parameters on ClinicalTrials.gov additional to those reported in the peer-reviewed publications: subgroup data and additional efficacy end points/extended follow-up, respectively. The clinical study report also provided results for several subgroups unavailable elsewhere. For HCV and COPD, additional outcome data were obtained from the EMA European Public Assessment Report (EPAR) and the FDA, respectively, including data on subgroups and mortality. We conclude that data from these grey literature sources have the potential to influence results of systematic reviews and NMAs, and may thus have implications for healthcare decisions. However, it is important to consider carefully the availability, reliability and consequent usability of these data sources in systematic reviews and NMAs.

Relative efficacy and safety of simeprevir and telaprevir in treatment-naïve hepatitis C-infected patients in a Japanese population: A Bayesian network meta-analysis.

AIM: Simeprevir (SMV) is an oral, once-daily protease inhibitor for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. In phase II/III randomized controlled trials (RCT) conducted in Japan, SMV, in combination with peginterferon-α and ribavirin (PEG IFN/RBV), demonstrated potent efficacy in HCV genotype 1-infected patients relative to PEG IFN/RBV and was generally well tolerated. Telaprevir (TVR) in combination with PEG IFN/RBV is licensed for the treatment of HCV in Japan. In the absence of head-to-head comparisons of TVR and SMV in a Japanese population, we undertook a network meta-analysis (NMA) to examine the relative efficacy and safety of SMV and TVR in combination with PEG IFN/RBV. METHODS: A systematic review identified SMV and TVR RCT in Japanese treatment-naïve patients. Bayesian NMA was performed assuming fixed study effects. RESULTS: Three studies met our inclusion criteria: two SMV and one TVR. SMV showed a higher mean odds ratio (OR) of achieving SVR versus TVR (OR, 1.68 (95% credible interval 0.66-4.26)). SMV showed a lower mean OR of discontinuation: overall, 0.35 (0.12-1.00); and due to AE, 0.87 (0.23-3.34) versus TVR. SMV showed a lower mean OR of experiencing anemia 0.20 (0.07-0.56) and rash 0.41 (0.17-0.99) but a higher mean OR of experiencing pruritus 1.26 (0.46-3.47) versus TVR. CONCLUSION: In this indirect treatment comparison, SMV, in combination with PEG IFN/RBV, showed a favorable risk-benefit profile compared with TVR with PEG IFN/RBV in Japanese treatment-naïve HCV patients.