Cost-effectiveness of risk-based low-dose computed tomography screening for lung cancer in Switzerland.

Throughout Europe, computed tomography (CT) screening for lung cancer is in a phase of clinical implementation or reimbursement evaluation. To efficiently select individuals for screening, the use of lung cancer risk models has been suggested, but their incremental (cost-)effectiveness relative to eligibility based on pack-year criteria has not been thoroughly evaluated for a European setting. We evaluate the cost-effectiveness of pack-year and risk-based screening (PLCOm2012 model-based) strategies for Switzerland, which aided in informing the recommendations of the Swiss Cancer Screening Committee (CSC). We use the MISCAN (MIcrosimulation SCreening ANalysis)-Lung model to estimate benefits and harms of screening among individuals born 1940 to 1979 in Switzerland. We evaluate 1512 strategies, differing in the age ranges employed for screening, the screening interval and the strictness of the smoking requirements. We estimate risk-based strategies to be more cost-effective than pack-year-based screening strategies. The most efficient strategy compliant with CSC recommendations is biennial screening for ever-smokers aged 55 to 80 with a 1.6% PLCOm2012 risk. Relative to no screening this strategy is estimated to reduce lung cancer mortality by 11.0%, with estimated costs per Quality-Adjusted Life-Year (QALY) gained of €19 341, and a €1.990 billion 15-year budget impact. Biennial screening ages 55 to 80 for those with 20 pack-years shows a lower mortality reduction (10.5%) and higher cost per QALY gained (€20 869). Despite model uncertainties, our estimates suggest there may be cost-effective screening policies for Switzerland. Risk-based biennial screening ages 55 to 80 for those with ≥1.6% PLCOm2012 risk conforms to CSC recommendations and is estimated to be more efficient than pack-year-based alternatives.

Survival modelling and cost-effectiveness analysis of treatments for newly diagnosed metastatic hormone-sensitive prostate cancer.

BACKGROUND: In metastatic hormone-sensitive prostate cancer (mHSPC) treatment, survival benefits have been shown by adding docetaxel or recent androgen receptor axis-targeted therapies (ARATs) abiraterone, apalutamide, or enzalutamide to androgen deprivation therapy (ADT). However, the optimal treatment strategy in terms of costs and effects is unclear, not least due to high ARAT costs. METHODS: To assess treatment cost-effectiveness, we developed a Markov cohort model with health states of progression-free disease, progressive disease and death for men with newly diagnosed mHSPC, with a 30-year time horizon. Survival data, adverse events and utilities were informed by randomized controlled trial results, our meta-analysis of re-created individual patient survival data, and publicly available sources of unit costs. We applied a Swiss healthcare payer perspective and discounted costs and effects by 3%. RESULTS: We found a significant overall survival benefit for ADT+abiraterone versus ADT+docetaxel. The corresponding incremental cost-effectiveness ratio (ICER) was predicted to be EUR 39,814 per quality-adjusted life-year (QALY) gained. ADT+apalutamide and ADT+enzalutamide incurred higher costs and lower QALYs compared to ADT+abiraterone. For all ARATs, drug costs constituted the most substantial cost component. Results were stable except for a large univariable reduction in the pre-progression utility under ADT+abiraterone and very large variations in drug prices. CONCLUSIONS: Our model projected ADT+abiraterone to be cost-effective compared to ADT+docetaxel at a willingness-to-pay threshold of EUR 70,400/QALY (CHF 100,000 applying purchasing power parities). Given lower estimated QALYs for ADT+apalutamide and ADT+enzalutamide compared to ADT+abiraterone, the former only became cost-effective (the preferred) treatment option(s) at substantial 75-80% (80-90%) price reductions.

Effectiveness of a Long-term Home-Based Exercise Training Program in Patients With COPD After Pulmonary Rehabilitation: A Multicenter Randomized Controlled Trial.

BACKGROUND: Most patients with COPD do not maintain exercise training after pulmonary rehabilitation (PR). RESEARCH QUESTION: Does a 12-month home-based, minimal-equipment strength training program after PR have an effect on dyspnea, exercise capacity, and patient-reported outcomes in patients with COPD? STUDY DESIGN AND METHODS: In a parallel-arm multicenter study across four Swiss PR clinics, patients with COPD were allocated randomly (1:1 ratio) into an intervention group (IG; home-based strength training program) or control group (CG; usual care). The primary outcome was change in Chronic Respiratory Questionnaire (CRQ) dyspnea scale score from baseline to 12 months. Secondary outcomes were change in exercise capacity (1-min sit-to-stand-test [1MSTST], 6-min walk test [6MWT]), health-related quality of life, exacerbations, and symptoms. We assessed the IG's experience by interviews at study end. Main analyses were based on the intention-to-treat approach, and adjusted linear regression models were used. RESULTS: One hundred twenty-three patients with COPD (IG, n = 61; CG, n = 62) were randomized, 61 of whom were women and whose mean ± SD age was 66.8 ± 8.1 years and mean ± SD FEV1 was 39.3 ± 15.3% predicted. One hundred four participants completed 12 months of follow-up (IG, n= 53; CG, n= 51). Of the 53 IG participants, 37 participants (70%) conducted the training until study end. We found no difference in change in CRQ dyspnea scale score over 12 months (adjusted mean difference, 0.28; 95% CI, -0.23 to 0.80; P = .27). We found moderate evidence for a difference in 1MSTST repetitions favoring the IG (adjusted mean difference, 2.6; 95% CI, 0.22-5.03; P = .033), but no evidence for an effect in other outcomes. Seventy-nine percent of the IG reported positive effects that they attributed to the training. INTERPRETATION: The home exercise program had no effect on dyspnea, but improved 1MSTST performance and patient-perceived fitness. The supported program was well accepted by patients with COPD and may facilitate continued exercise training at home. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03461887; URL: www. CLINICALTRIALS: gov.

Reporting quality of clinical trial protocols: a repeated cross-sectional study about the Adherence to SPIrit Recommendations in Switzerland, CAnada and GErmany (ASPIRE-SCAGE).

OBJECTIVES: Comprehensive protocols are key for the planning and conduct of randomised clinical trials (RCTs). Evidence of low reporting quality of RCT protocols led to the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist in 2013. We aimed to examine the quality of reporting of RCT protocols from three countries before and after the publication of the SPIRIT checklist. DESIGN: Repeated cross sectional study. SETTING: Swiss, German and Canadian research ethics committees (RECs). PARTICIPANTS: RCT protocols approved by RECs in 2012 (n=257) and 2016 (n=292). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes were the proportion of reported SPIRIT items per protocol and the proportion of trial protocols reporting individual SPIRIT items. We compared these outcomes in protocols approved in 2012 and 2016, and built regression models to explore factors associated with adherence to SPIRIT. For each protocol, we also extracted information on general trial characteristics and assessed whether individual SPIRIT items were reported RESULTS: The median proportion of reported SPIRIT items among RCT protocols showed a non-significant increase from 72% (IQR, 63%-79%) in 2012 to 77% (IQR, 68%-82%) in 2016. However, in a preplanned subgroup analysis, we detected a significant improvement in investigator-sponsored protocols: the median proportion increased from 64% (IQR, 55%-72%) in 2012 to 76% (IQR, 64%-83%) in 2016, while for industry-sponsored protocols median adherence was 77% (IQR 72%-80%) for both years. The following trial characteristics were independently associated with lower adherence to SPIRIT: single-centre trial, no support from a clinical trials unit or contract research organisation, and investigator-sponsorship. CONCLUSIONS: In 2012, industry-sponsored RCT protocols were reported more comprehensively than investigator-sponsored protocols. After publication of the SPIRIT checklist, investigator-sponsored protocols improved to the level of industry-sponsored protocols, which did not improve.

Treatments for Metastatic Hormone-sensitive Prostate Cancer: Systematic Review, Network Meta-analysis, and Benefit-harm assessment.

CONTEXT: Multiple treatments for metastatic, hormone-sensitive prostate cancer (mHSPC) are available, but their effects on health-related quality of life (HRQoL) and benefit-harm balance remain unclear. OBJECTIVE: To assess clinical effectiveness regarding survival and HRQoL, safety, and benefit-harm balance of mHSPC treatments. EVIDENCE ACQUISITION: We searched MEDLINE, EMBASE, CENTRAL, and ClinicalTrials.gov until March 1, 2022. Randomized controlled trials (RCTs) comparing docetaxel, abiraterone, enzalutamide, apalutamide, darolutamide, and radiotherapy combined with androgen deprivation therapy (ADT) mutually or with ADT alone were eligible. Three reviewers independently performed screening, data extraction, and risk of bias assessment in duplicate. EVIDENCE SYNTHESIS: Across ten RCTs, we found relevant survival benefits for ADT + docetaxel (high certainty according to the Grading of Recommendations, Assessment, Development and Evaluation [GRADE]), ADT + abiraterone (moderate certainty), ADT + enzalutamide (low certainty), ADT + apalutamide (high certainty), and ADT + docetaxel + darolutamide (high certainty) compared with ADT alone. ADT + radiotherapy appeared effective only in low-volume de novo mHSPC. We found a short-term HRQoL decrease lasting 3-6 mo for ADT + docetaxel (moderate certainty) and a potential HRQoL benefit for ADT + abiraterone up to 24 mo of follow-up (moderate certainty) compared with ADT alone. There was no difference in HRQoL for ADT + enzalutamide, ADT + apalutamide, or ADT + radiotherapy over ADT alone (low-high certainty). Grade 3-5 adverse effect rates were increased with all systemic combination treatments. A benefit-harm assessment showed high probabilities (>60%) for a net clinical benefit with ADT + abiraterone, ADT + enzalutamide, and ADT + apalutamide, while ADT + docetaxel and ADT + docetaxel + darolutamide appeared unlikely (<40%) to be beneficial. CONCLUSIONS: Despite substantial survival benefits, no systemic combination treatment showed a clear HRQoL improvement compared with ADT alone. We found evidence for a short-term HRQoL decline with ADT + docetaxel and a higher net clinical benefit with ADT + abiraterone, ADT + apalutamide and ADT + enzalutamide. While individualized decision-making remains important and economic factors need to be considered, the evidence may support a general preference for the combination of ADT with androgen receptor axis-targeted therapies over docetaxel-containing strategies. PATIENT SUMMARY: We assessed different combination treatments for metastatic hormone-sensitive prostate cancer. While survival was better with all systemic combination treatments, there was no clear improvement in health-related quality of life compared with androgen deprivation therapy alone. Novel hormonal combination treatments had a more favorable benefit-harm balance than combination treatments that include chemotherapy.

The Swiss Approach - feasibility of a national low-dose CT lung cancer screening program.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths in Switzerland. Despite this, there is no lung cancer screening program in the country. In the United States, low-dose computed tomography (LDCT) lung cancer screening is partially established and endorsed by guidelines. Moreover, evidence is growing that screening reduces lung cancer-related mortality and this was recently shown in a large European randomized controlled trial. Implementation of a lung cancer screening program, however, is challenging and depends on many country-specific factors. The goal of this article is to outline a potential Swiss lung cancer screening program. FRAMEWORK: An exhaustive literature review on international screening models as well as interviews and site visits with international experts were initiated. Furthermore, workshops and interviews with national experts and stakeholders were conducted to share experiences and to establish the basis for a national Swiss lung cancer screening program. SCREENING APPROACH: General practitioners, pulmonologists and the media should be part of the recruitment process. Decentralisation of the screening might lead to a higher adherence rate. To reduce stigmatisation, the screening should be integrated in a "lung health check". Standardisation and a common quality level are mandatory. The PLCOm2012 risk calculation model with a threshold of 1.5% risk for developing cancer in the next six years should be used in addition to established inclusion criteria. Biennial screening is preferred. LUNG RADS and NELSON+ are applied as classification models for lung nodules. CONCLUSION: Based on data from recent studies, literature research, a health technology assessment, the information gained from this project and a pilot study the Swiss Interest Group for lung cancer screening (CH-LSIG) recommends the timely introduction of a systematic lung cancer screening program in Switzerland. The final decision is for the Swiss Cancer Screening Committee to make.

Nonregistration, discontinuation, and nonpublication of randomized trials: A repeated metaresearch analysis.

BACKGROUND: We previously found that 25% of 1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up. We aimed to assess a decade later (1) whether rates of completion and publication have increased; (2) the extent to which nonpublished RCTs can be identified in trial registries; and (3) the association between reporting quality of protocols and premature discontinuation or nonpublication of RCTs. METHODS AND FINDINGS: We included 326 RCT protocols approved in 2012 by research ethics committees in Switzerland, the United Kingdom, Germany, and Canada in this metaresearch study. Pilot, feasibility, and phase 1 studies were excluded. We extracted trial characteristics from each study protocol and systematically searched for corresponding trial registration (if not reported in the protocol) and full text publications until February 2022. For trial registrations, we searched the (i) World Health Organization: International Clinical Trial Registry Platform (ICTRP); (ii) US National Library of Medicine (ClinicalTrials.gov); (iii) European Union Drug Regulating Authorities Clinical Trials Database (EUCTR); (iv) ISRCTN registry; and (v) Google. For full text publications, we searched PubMed, Google Scholar, and Scopus. We recorded whether RCTs were registered, discontinued (including reason for discontinuation), and published. The reporting quality of RCT protocols was assessed with the 33-item SPIRIT checklist. We used multivariable logistic regression to examine the association between the independent variables protocol reporting quality, planned sample size, type of control (placebo versus other), reporting of any recruitment projection, single-center versus multicenter trials, and industry versus investigator sponsoring, with the 2 dependent variables: (1) publication of RCT results; and (2) trial discontinuation due to poor recruitment. Of the 326 included trials, 19 (6%) were unregistered. Ninety-eight trials (30%) were discontinued prematurely, most often due to poor recruitment (37%; 36/98). One in 5 trials (21%; 70/326) remained unpublished at 10 years follow-up, and 21% of unpublished trials (15/70) were unregistered. Twenty-three of 147 investigator-sponsored trials (16%) reported their results in a trial registry in contrast to 150 of 179 industry-sponsored trials (84%). The median proportion of reported SPIRIT items in included RCT protocols was 69% (interquartile range 61% to 77%). We found no variables associated with trial discontinuation; however, lower reporting quality of trial protocols was associated with nonpublication (odds ratio, 0.71 for each 10% increment in the proportion of SPIRIT items met; 95% confidence interval, 0.55 to 0.92; p = 0.009). Study limitations include that the moderate sample size may have limited the ability of our regression models to identify significant associations. CONCLUSIONS: We have observed that rates of premature trial discontinuation have not changed in the past decade. Nonpublication of RCTs has declined but remains common; 21% of unpublished trials could not be identified in registries. Only 16% of investigator-sponsored trials reported results in a trial registry. Higher reporting quality of RCT protocols was associated with publication of results. Further efforts from all stakeholders are needed to improve efficiency and transparency of clinical research.

Early mobilisation and rehabilitation in Swiss intensive care units: a cross-sectional survey.

BACKGROUND: Patients in intensive care units (ICUs) are at high risk of developing physical, functional, cognitive, and mental impairments. Early mobilisation aims to improve patient outcomes and is increasingly considered the standard of care. This survey aimed to investigate the characteristics, current use and variations of early mobilisation and rehabilitation in Swiss ICUs. METHODS: We conducted a cross-sectional survey among all ICU lead physicians, who provided data on their institutional characteristics, early mobilisation and rehabilitation practices, and their perceptions of the use and variation of early rehabilitation practices in Switzerland. RESULTS: The survey response rate was 44% (37/84). Among ICUs caring for adults (34/37), 26 were in the German-speaking region, five in the French-speaking region, and three in the Italian-speaking region. All ICUs regularly involved physiotherapy in the rehabilitation process and 50% reported having a specialised physiotherapy team. All ICUs reported performing early mobilisation, starting within the first 7 days after ICU admission. About half reported the use of a rehabilitation (45%) or early mobilisation protocol (50%). Regular, structured, interdisciplinary rounds or meetings of the ICU care team to discuss rehabilitation measures and goals for patients were stated to be held by 53%. The respondents stated that 82% of their patients received early mobilisation measures during their ICU stay. Most frequently provided mobilisation measures included passive range of motion (97%), passive chair position in bed (97%), active range of motion muscle activation and training (88%), active side to side turning (91%), sitting on the edge of the bed (94%), transfer from bed to a chair (97%), and ambulation (94%). The proportion of ICUs providing a specific early mobilisation measure, the proportion of patients receiving it, and the time dedicated to it varied across language regions, hospital types, ICU types, and ICU sizes. Almost one third of the ICU lead physicians considered early rehabilitation to be underused in their own ICU and about half considered it to be underused in Switzerland more generally. ICU lead physicians stressed lack of personnel, financial resources, and time as key causes for underuse. Moreover, they highlighted the importance of early and systematic or protocol-based rehabilitation and interprofessional approaches that are adaptive to the patients' rehabilitation needs and potential. CONCLUSION: This survey suggests that almost all ICUs in Switzerland practice some form of early mobilisation with the aim of early rehabilitation. However, the described approaches, as well as the reported use of early mobilisation measures were heterogenous across Swiss ICUs.

Productivity losses due to influenza and influenza-like illness in Switzerland: results of the Swiss Sentinel Surveillance Network in a non-pandemic era.

BACKGROUND: The incidence of influenza and influenza-like illnesses in Switzerland is generally high. Although related direct medical costs can be substantial, especially if hospitalisations occur, several studies suggested that indirect costs due to the loss of productivity may represent an even higher economic burden. The aim of this study was to assess the costs arising from lost productivity due to influenza and influenza-like illnesses in Switzerland. METHODS: Analyses were based on data collected in 2016 and 2017 by the Swiss Sentinel Surveillance Network of the Swiss Federal Office of Public Health (SFOPH). The available information covered details on the physicians collecting the data, patients' characteristics, symptoms, treatments, and inability to work (in terms of physician-recorded workdays lost for own sickness or caregiving). The cost of lost productivity, estimated using the human capital approach, was calculated as the number of workdays lost due to influenza-like illnesses multiplied by the mean salary for one working day. Salary differences across sex, age and region were considered. Extrapolation to the national level was performed by adjusting for the size of the Swiss population, the age and sex distribution, the regional distribution, the number of Sentinel general physician contacts and the specialisation of the physician. RESULTS: At the Swiss national level, the estimated total yearly number of cases of inability to work due to influenza and influenza-like illnesses was 101,287 in 2016 and 86,373 in 2017. In subgroups defined by year, gender, region and age class, numbers of cases per 100,000 inhabitants ranged from 12 to 2396. The total number of workdays lost in Switzerland, considering degree of employment and visit day, were estimated to be 324,118 in 2016 and 278,121 in 2017. The number of workdays lost was generally higher in men (53.7% of the total in 2016 and 55.6% of the total in 2017) than women. The estimated total costs due to inability to work, calculated using a human capital approach and including the caregiving costs, were CHF 115 million in 2016 and CHF 103 million in 2017, equivalent to CHF 1.4 million per 100,000 inhabitants. CONCLUSION: The costs of lost productivity due to influenza and influenza-like illnesses in Switzerland are substantial and may vary considerably between different years, regions and age classes. As the present analyses could not consider all causes of lost productivity (e.g., short-term inability to work not requiring a physician consultation, hospitalisations, early retirement, premature death), the total indirect costs due to influenza or influenza-like illnesses can be expected to be higher than the presented estimates.

Reporting quality of trial protocols improved for non-regulated interventions but not regulated interventions: A repeated cross-sectional study.

OBJECTIVES: To investigate the adherence of randomised controlled trial (RCT) protocols evaluating non-regulated interventions (including dietary interventions, surgical procedures, behavioural and lifestyle interventions, and exercise programmes) in comparison with regulated interventions to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement. METHODS: We conducted a repeated cross-sectional investigation in a random sample of RCT protocols approved in 2012 (n = 257) or 2016 (n = 292) by research ethics committees in Switzerland, Germany, or Canada. We investigated the proportion of accurately reported SPIRIT checklist items in protocols of trials with non-regulated as compared to regulated interventions. RESULTS: Overall, 131 (24%) of trial protocols tested non-regulated interventions. In 2012, the median proportion of SPIRIT items reported in these protocols (59%, interquartile range [IQR], 53%-69%) was lower than in protocols with regulated interventions (median, 74%, IQR, 66%-80%). In 2016, the reporting quality of protocols with non-regulated interventions (median, 75%, IQR, 62%-83%) improved to the level of regulated intervention protocols, which had not changed on average. CONCLUSIONS: Reporting of RCT protocols evaluating non-regulated interventions improved between 2012 and 2016, although remained suboptimal. SPIRIT recommendations need to be further endorsed by researchers, ethics committees, funding agencies, and journals to optimize reporting of RCT protocols.

Systematic early versus late mobilization or standard early mobilization in mechanically ventilated adult ICU patients: systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aimed to determine the effectiveness of systematic early mobilization in improving muscle strength and physical function in mechanically ventilated intensive care unit (ICU) patients. METHODS: We conducted a two-stage systematic literature search in MEDLINE, EMBASE and the Cochrane Library until January 2019 for randomized controlled trials (RCTs) examining the effects of early mobilization initiated within 7 days after ICU admission compared with late mobilization, standard early mobilization or no mobilization. Priority outcomes were Medical Research Council Sum Score (MRC-SS), incidence of ICU-acquired weakness (ICUAW), 6-min walk test (6MWT), proportion of patients reaching independence, time needed until walking, SF-36 Physical Function Domain Score (PFS) and SF-36 Physical Health Component Score (PCS). Meta-analysis was conducted where sufficient comparable evidence was available. We evaluated the certainty of evidence according to the GRADE approach. RESULTS: We identified 12 eligible RCTs contributing data from 1304 participants. Two RCTs were categorized as comparing systematic early with late mobilization, nine with standard early mobilization and one with no mobilization. We found evidence for a benefit of systematic early mobilization compared to late mobilization for SF-36 PFS (MD 12.3; 95% CI 3.9-20.8) and PCS (MD 3.4; 95% CI 0.01-6.8), as well as on the proportion of patients reaching independence and the time needed to walking, but not for incidence of ICUAW (RR 0.62; 95% CI 0.38-1.03) or MRC-SS. For systematic early compared to standard early mobilization, we found no statistically significant benefit on MRC-SS (MD 5.8; 95% CI - 1.4 to 13.0), incidence of ICUAW (RR 0.90; 95% CI 0.63-1.27), SF-36 PFS (MD 8.1; 95% CI - 15.3 to 31.4) or PCS (MD - 2.4; 95% CI - 6.1 to 1.3) or other priority outcomes except for change in 6MWT from baseline. Generally, effects appeared stronger for systematic early compared to late mobilization than to standard early mobilization. We judged the certainty of evidence for all outcomes as very low to low. CONCLUSION: The evidence regarding a benefit of systematic early mobilization remained inconclusive. However, our findings indicate that the larger the difference in the timing between the intervention and the comparator, the more likely an RCT is to find a benefit for early mobilization. STUDY REGISTRATION: PROSPERO (CRD42019122555).

Rationale and design of repeated cross-sectional studies to evaluate the reporting quality of trial protocols: the Adherence to SPIrit REcommendations (ASPIRE) study and associated projects.

BACKGROUND: Clearly structured and comprehensive protocols are an essential component to ensure safety of participants, data validity, successful conduct, and credibility of results of randomized clinical trials (RCTs). Funding agencies, research ethics committees (RECs), regulatory agencies, medical journals, systematic reviewers, and other stakeholders rely on protocols to appraise the conduct and reporting of RCTs. In response to evidence of poor protocol quality, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline was published in 2013 to improve the accuracy and completeness of clinical trial protocols. The impact of these recommendations on protocol completeness and associations between protocol completeness and successful RCT conduct and publication remain uncertain. OBJECTIVES AND METHODS: Aims of the Adherence to SPIrit REcommendations (ASPIRE) study are to investigate adherence to SPIRIT checklist items of RCT protocols approved by RECs in the UK, Switzerland, Germany, and Canada before (2012) and after (2016) the publication of the SPIRIT guidelines; determine protocol features associated with non-adherence to SPIRIT checklist items; and assess potential differences in adherence across countries. We assembled an international cohort of RCTs based on 450 protocols approved in 2012 and 402 protocols approved in 2016 by RECs in Switzerland, the UK, Germany, and Canada. We will extract data on RCT characteristics and adherence to SPIRIT for all included protocols. We will use multivariable regression models to investigate temporal changes in SPIRIT adherence, differences across countries, and associations between SPIRIT adherence of protocols with RCT registration, completion, and publication of results. We plan substudies to examine the registration, premature discontinuation, and non-publication of RCTs; the use of patient-reported outcomes in RCT protocols; SPIRIT adherence of RCT protocols with non-regulated interventions; the planning of RCT subgroup analyses; and the use of routinely collected data for RCTs. DISCUSSION: The ASPIRE study and associated substudies will provide important information on the impact of measures to improve the reporting of RCT protocols and on multiple aspects of RCT design, trial registration, premature discontinuation, and non-publication of RCTs observing potential changes over time.

Acetylcholinesterase inhibitors combined with memantine for moderate to severe Alzheimer's disease: a meta-analysis.

BACKGROUND: The clinical efficacy and safety of combination therapy with acetylcholinesterase inhibitor (AChEI) and memantine compared to AChEI or memantine alone in patients with Alzheimer’s disease is inconclusive. AIMS OF THE STUDY: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing the clinical efficacy and safety of combination therapy of AChEI and memantine to monotherapy with either substance in patients with moderate to severe Alzheimer's disease (Mini-Mental State Examination score is <20). METHODS: We systematically searched EMBASE, Medline and CENTRAL until February 2018 for eligible RCTs. We pooled the outcome data using inverse variance weighting models assuming random effects, and assessed the quality of evidence (QoE) according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We included nine RCTs (2604 patients). At short-term follow-up (closest to 6 months), combination therapy compared to AChEI monotherapy had a significantly greater effect on cognition than AChEI monotherapy (standardised mean difference [SMD] 0.20, 95% confidence interval [CI] 0.05 to 0.35, 7 RCTs, low QoE) and clinical global impression (SMD −0.15, 95% CI −0.28 to −0.01, 4 RCTs, moderate QoE), but not on activities of daily living (SMD 0.09, 95% CI −0.01 to 0.18, 5 RCTs, moderate QoE) or behavioural and psychological symptoms of dementia (mean difference −3.07, 95% CI −6.53 to 0.38, 6 RCT, low QoE). There was no significant difference in adverse events (relative risk ratio 1.05, 95% CI 0.98 to 1.12, 4 RCTs, low QoE). Evidence for long-term follow-up (≥ 9 months) or nursing home placement was sparse. Only two studies compared combination therapy with memantine monotherapy. CONCLUSIONS: Combination therapy had statistically significant effects on cognition and clinical global impression. The clinical relevance of these effects is uncertain. The overall QoE was very low. With the current evidence, it remains unclear whether combination therapy adds any benefit. Large pragmatic RCTs with long-term follow-up and focus on functional outcomes, delay in nursing home placement and adverse events are needed.  .

Economic burden of symptomatic iron deficiency - a survey among Swiss women.

BACKGROUND: Symptomatic iron deficiency (ID) is a disorder affecting 10-20% of menstruating women. ID is diagnosed by measuring serum ferritin, a protein helping to store iron in the body. A deeper understanding of the association between ID and its societal and economic burden is relevant for patients, physicians, health care decision makers. METHODS: An online household survey was carried out among Swiss women aged 18-50 years suffering from debilitating symptoms due to ID. The data was population-weighted for age and region. The costs of misdiagnosis and the ID-related economic burden (i.e. days of sick leave) from productivity losses on the labor market were determined and extrapolated to the Swiss population. Furthermore, the patient burden was assessed based on quality of life daily measurements. RESULTS: The total sample included 1010 women who received an ID diagnosis with a blood test in the last 2 years (mean age: 33.5 years). Most named symptoms were "being tired or exhausted" (96.4%) and reduced physical energy level (41.0%). In total, 354 (35.0% of the total sample) patients received an initial diagnosis other than ID. Of those, 46.8% were treated prior to the ID diagnosis with a pharmacological medical therapy or psychotherapy. Extrapolating these numbers to the Swiss female population aged 18-50 years, the direct medical costs would be CHF 78 million (assuming an annual ID incidence of ID diagnosis of 9.5%). On average, 28.5% of participants in the work-force had to take sick leave due to ID symptoms within a period of 2 years (mean: 5.2 days, i.e. 2.6 days/year). The estimated annual indirect costs in Switzerland would be CHF 33 million (human capital approach) or CHF 26 million (friction cost method), respectively. Being exhausted and impaired concentration appear to be the most important factors negatively impacting daily living and hence quality of life. CONCLUSION: The societal and economic burden among women due to debilitating symptoms of ID in Switzerland is substantial. Timely, correct diagnosis and treatment of ID may contribute to reducing this burden. Further studies are needed in this area to validate our results.

Resource use, costs, and approval times for planning and preparing a randomized clinical trial before and after the implementation of the new Swiss human research legislation.

BACKGROUND: The preparation of a randomized controlled trial (RCT) requires substantial resources and the administrative processes can be burdensome. To facilitate the conduct of RCTs it is important to better understand cost drivers. In January 2014 the enactment of the new Swiss Legislation on Human Research (LHR) considerably changed the regulatory framework in Switzerland. We assess if the new LHR was associated with change in (i) resource use and costs to prepare an RCT, and (ii) approval times with research ethics committees (RECs) and the regulatory authority Swissmedic. METHODS: We surveyed investigators of RCTs which were approved by RECs in 2012 or in 2016 and asked for RCT preparation costs using a pre-specified item list. Additionally, we collected approval times from RECs and Swissmedic. RESULTS: The response rates of the investigator survey were 8.3% (19/228) for 2012 and 16.5% (47/285) in 2016. The median preparation cost of an RCT was USD 72,400 (interquartile range [IQR]: USD 59,500-87,700; n = 18) in 2012 and USD 72,600 (IQR: USD 42,800-169,600; n = 35) in 2016. For single centre RCTs a median REC approval time of 82 (IQR: 49-107; n = 38) days in 2012 and 92 (IQR: 65-131; n = 63) days in 2016 was observed. The median Swissmedic approval time for any clinical trial was 27 (IQR: 19-51; n = 213) days in 2012 and 49 (IQR: 36-67; n = 179) days in 2016. The total duration for achieving RCT approval from both authorities (REC and Swissmedic) in the parallel submission procedure applied in 2016 could not be assessed. CONCLUSION: Based on limited data the costs to plan and prepare RCTs in Switzerland were approximately USD 72,000 in 2012 and 2016. For effective and valid research on costs and approval times of RCTs a greater willingness to share cost information among investigators and more collaboration between stakeholders with data linkage is necessary.

Cost-effectiveness of low-dose CT screening for lung cancer in a European country with high prevalence of smoking-A modelling study.

OBJECTIVES: In Europe, there is uncertainty about the potential effects and cost-effectiveness of low dose computed tomography screening for lung cancer and about the applicability of results of North American studies. We aimed to estimate the effects and cost-effectiveness of lung cancer screening in a population-based setting in Switzerland where the smoking prevalence is high. MATERIALS AND METHODS: The MIcrosimulation Screening ANalysis-Lung (MISCAN) model was adapted using country specific input parameters regarding lung cancer epidemiology, smoking behaviours, and treatment costs. The effects and costs of 648 screening scenarios with different screening start and stop ages, smoking eligibility criteria, and screening intervals were examined from a public healthcare system perspective across a lifetime horizon in a cohort born between 1935 and 1965. RESULTS: All screening scenarios showed an increase in the total number of detected lung cancer cases and a decrease in lung cancer mortality. On the efficiency frontier, 15 of 27 scenarios showed incremental cost-effectiveness ratios below € 50,000 per life year gained. These scenarios reduced lung cancer mortality by 6-15% while increasing incidence of lung cancer diagnoses by 2-6%. CONCLUSION: These results suggest that lung cancer screening may be cost-effective in Switzerland, a high-income, European country with high smoking prevalence.

Adaptation of cost-effectiveness analyses to a single country: the case of bariatric surgery for obesity and overweight.

OBJECTIVES: The aims of this study were to (a) identify and assess the quality of reporting of published cost-effectiveness studies of bariatric surgery, (b) assess their transferability to Switzerland, and (c) adapt transferable cost-effectiveness results to Switzerland. METHODS: A systematic literature search was performed in Medline, Embase and other databases. Two reviewers independently undertook screening, extraction, assessment of reporting quality utilising the Consolidated Health Economic Evaluation Reporting Standards, transferability, adaptation of cost data and recalculation of cost-effectiveness results. Cost data were adapted in three steps: correction for different levels of resource utilisation, for different prices of healthcare services and for change in costs over time. RESULTS: Fifteen studies fulfilled criteria for adaptation of cost data to Switzerland. Four out of fifteen adapted studies with a long time-horizon for patients with a body mass index (BMI) >35kg/m2 indicated bariatric surgery to be a cost-saving (dominant) approach compared with conventional treatment. Other studies for patients with BMI >35kg/m2 showed cost-effective results, with incremental cost-effectiveness ratios (ICERs) below CHF 50,000 per quality adjusted life-year (QALY) gained. Two studies assessed cost-effectiveness for patients with BMI <35kg/m2, and revealed ICERs below 50,000 per QALY gained for bariatric surgery versus conventional treatment. Between-study differences were related to approaches for the modelling effectiveness and costs, time horizon, population, type of intervention and possibly other unidentified reasons. Gastric bypass appeared to be superior to gastric banding, but was more expensive. CONCLUSIONS: Nearly all studies found bariatric surgery to be a cost saving or cost-effective compared with conventional treatment. The adaptation of existing cost-effectiveness analyses cannot be considered to give accurate ICERs for Switzerland, but may have achieved an approximation of cost-effectiveness levels to be expected for Switzerland. It has made the results of international cost-effectiveness studies reported for different countries and in different currencies more comparable, and may be useful for individual countries in which financing or capacity for economic analyses is scarce.

Premature Discontinuation of Pediatric Randomized Controlled Trials: A Retrospective Cohort Study.

OBJECTIVES: To determine the proportion of pediatric randomized controlled trials (RCTs) that are prematurely discontinued, examine the reasons for discontinuation, and compare the risk for recruitment failure in pediatric and adult RCTs. STUDY DESIGN: A retrospective cohort study of RCTs approved by 1 of 6 Research Ethics Committees (RECs) in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics, trial discontinuation, and reasons for discontinuation from protocols, corresponding publications, REC files, and a survey of trialists. RESULTS: We included 894 RCTs, of which 86 enrolled children and 808 enrolled adults. Forty percent of the pediatric RCTs and 29% of the adult RCTs were discontinued. Slow recruitment accounted for 56% of pediatric RCT discontinuations and 43% of adult RCT discontinuations. Multivariable logistic regression analyses suggested that pediatric RCT was not an independent risk factor for recruitment failure after adjustment for other potential risk factors (aOR, 1.22; 95% CI, 0.57-2.63). Independent risk factors were acute care setting (aOR, 4.00; 95% CI, 1.72-9.31), nonindustry sponsorship (aOR, 4.45; 95% CI, 2.59-7.65), and smaller planned sample size (aOR, 1.05; 95% CI 1.01-1.09, in decrements of 100 participants). CONCLUSION: Forty percent of pediatric RCTs were discontinued prematurely, owing predominately to slow recruitment. Enrollment of children was not an independent risk factor for recruitment failure.

Therapeutic Efficacy and Cost Effectiveness of High Cut-Off Dialyzers Compared to Conventional Dialysis in Patients with Cast Nephropathy.

BACKGROUND: High Cut-Off (HCO) dialysis membranes efficiently reduce serum free light chain (FLC) concentrations and may improve renal recovery and survival from multiple myeloma (MM) associated renal failure with cast nephropathy. However, clinical trials comparing dialysis with HCO versus conventional filters are lacking. The aim of this study was to assess clinical outcomes and economic impact of HCO dialyzers compared to conventional hemodialysis membranes in cast nephropathy. METHODS: Multicenter retrospective analysis of 19 patients treated for renal failure from FLC associated cast nephropathy with standard induction chemotherapy (bortezomib/dexamethasone). We compared hemodialysis treatment with High Cut-Off (n = 12) versus conventional dialyzers (n = 7). Primary endpoint was survival; secondary endpoints were renal recovery, renal function and treatment costs. RESULTS: At 12 months, patient survival was 25% in the HCO group versus 0% in controls (p = NS). A tendency towards faster renal recovery (p = 0.066) and better renal function at 3, 6 and 12 months (p = 0.109) after diagnosis of MM was noted in the HCO group. Complete renal response rate was achieved in 10.5 and 0% of HCO and control patients, respectively, partial renal response in 15.8 and 5.3%, and minor renal response in 26.3 and 15.8%, respectively. Both patient survival and renal recovery were significantly correlated with the extent of free light chain (FLC) reduction in serum. Median treatment costs were CHF 230'000 and 223'000 (p = NS) in the HCO and control group, respectively. CONCLUSIONS: Hemodialysis treatment with HCO membranes for cast nephropathy tended towards better survival as well as faster and better recovery of renal function versus conventional dialyzers. Moreover, total medical costs were comparable between groups. In the absence of results from randomized prospective trials on this topic, the use of HCO dialyzers in patients with renal failure from cast nephropathy may be recommended. Prospective randomized trials are required.

Agreements between Industry and Academia on Publication Rights: A Retrospective Study of Protocols and Publications of Randomized Clinical Trials.

BACKGROUND: Little is known about publication agreements between industry and academic investigators in trial protocols and the consistency of these agreements with corresponding statements in publications. We aimed to investigate (i) the existence and types of publication agreements in trial protocols, (ii) the completeness and consistency of the reporting of these agreements in subsequent publications, and (iii) the frequency of co-authorship by industry employees. METHODS AND FINDINGS: We used a retrospective cohort of randomized clinical trials (RCTs) based on archived protocols approved by six research ethics committees between 13 January 2000 and 25 November 2003. Only RCTs with industry involvement were eligible. We investigated the documentation of publication agreements in RCT protocols and statements in corresponding journal publications. Of 647 eligible RCT protocols, 456 (70.5%) mentioned an agreement regarding publication of results. Of these 456, 393 (86.2%) documented an industry partner's right to disapprove or at least review proposed manuscripts; 39 (8.6%) agreements were without constraints of publication. The remaining 24 (5.3%) protocols referred to separate agreement documents not accessible to us. Of those 432 protocols with an accessible publication agreement, 268 (62.0%) trials were published. Most agreements documented in the protocol were not reported in the subsequent publication (197/268 [73.5%]). Of 71 agreements reported in publications, 52 (73.2%) were concordant with those documented in the protocol. In 14 of 37 (37.8%) publications in which statements suggested unrestricted publication rights, at least one co-author was an industry employee. In 25 protocol-publication pairs, author statements in publications suggested no constraints, but 18 corresponding protocols documented restricting agreements. CONCLUSIONS: Publication agreements constraining academic authors' independence are common. Journal articles seldom report on publication agreements, and, if they do, statements can be discrepant with the trial protocol.