Gait function assessed using 3D gait analysis in patients with cervical spinal myelopathy before and after surgical decompression: a systematic review and meta-analysis.

BACKGROUND: Degenerative cervical myelopathy (DCM) is the most common cause of cervical spinal cord dysfunction in adults and the result of chronic degenerative changes of the cervical spine. The compression of the spinal cord can lead to ischemia, inflammation, and neuronal apoptosis with a consequent impairment of the neurological function. Gait impairment is one of the most frequent signs of DCM. PURPOSE: To investigate the changes in spatio-temporal gait parameters assessed using 3D gait analysis in patients affected by DCM compared with healthy controls and the effect of surgical decompression on these parameters. STUDY DESIGN/SETTING: Systematic review and meta-analysis. PATIENT SAMPLE: The meta-analysis included 267 patients with DCM and 276 healthy controls. OUTCOME MEASURES: Spatio-temporal parameters of gait were assessed. The primary outcome was gait speed; the secondary outcomes were cadence, stride length, step width, stride time, single-limb support time, and double-limb support time. METHODS: Studies reporting spatial and/or temporal gait parameters measured using 3D gait analysis in patients with DCM were included. Data sources were Embase, Medline, and the Core Collection of Web of Science. Meta-analyses were performed to investigate the influence of surgical decompression in patients measured before and after surgery as well as to compare gait parameters of patients with DCM with controls. RESULTS: Thirteen studies reporting on 267 patients with DCM and 276 healthy controls met the inclusion criteria. Seven studies compared patients with DCM with healthy controls, three studies compared gait in patients with DCM before and after surgical decompression, and three studies performed both comparisons. Compared with healthy controls, patients with DCM had slower gait speed (Standardized Mean Difference (SMD), -1.49; 95% confidence interval (CI) [-1.86; -1.13]; p<.001), lower cadence (SMD, -0.78; 95%CI [-1.00; -0.56]; p<.001), shorter stride length (SMD, -1.27; 95%CI [-1.53, -1.01]; p<.001), greater step width (SMD, 0.98; 95%CI [0.42, 1.54]; p=.003), longer stride time (SMD, 0.77; 95%CI [0.37, 1.16]; p=.009), single-limb support phase (SMD, -0.68; 95%CI [-1.06; -0.29]; p=.011), and double-limb support phase (SMD 0.84; 95%CI [0.35, 1.32]; p=.012). After surgical decompression, patients with DCM showed an improvement in gait speed (SMD, 0.57 (95%CI [0.29; 0.85]; p=.003) and no significant differences in other spatio-temporal parameters. CONCLUSIONS: Patients with DCM have clearly different spatio-temporal gait parameters than healthy controls. Gait speed is the only spatio-temporal gait parameter that improves significantly after surgical decompression suggesting that gait speed may be an important clinical outcome parameter in patients with DCM.

Ex vivo experimental strategies for assessing unconstrained shoulder biomechanics: A scoping review.

BACKGROUND: Biomechanical studies of the shoulder often choose an ex vivo approach, especially when investigating the active and passive contribution of individual muscles. Although various simulators of the glenohumeral joint and its muscles have been developed, to date a testing standard has not been established. The objective of this scoping review was to present an overview of methodological and experimental studies describing ex vivo simulators that assess unconstrained, muscular driven shoulder biomechanics. METHODS: All studies with ex vivo or mechanical simulation experiments using an unconstrained glenohumeral joint simulator and active components mimicking the muscles were included in this scoping review. Static experiments and humeral motion imposed through an external guide, e.g., a robotic device, were excluded. RESULTS: Nine different glenohumeral simulators were identified in 51 studies after the screening process. We identified four control strategies characterized by: (a) using a primary loader to determine the secondary loaders with constant force ratios; (b) using variable muscle force ratios according to electromyography; (c) calibrating the muscle path profile and control each motor according to this profile; or (d) using muscle optimization. CONCLUSION: The simulators with the control strategy (b) (n = 1) or (d) (n = 2) appear most promising due to its capability to mimic physiological muscle loads.

Citation tracking for systematic literature searching: A scoping review.

Citation tracking (CT) collects references with citation relationships to pertinent references that are already known. This scoping review maps the benefit of and the tools and terminology used for CT in health-related systematic literature searching. We included methodological studies on evidence retrieval by CT in health-related literature searching without restrictions on study design, language, or publication date. We searched MEDLINE/Ovid, Web of Science Core Collection, CINAHL/EBSCOhost, LLISFT/EBSCOhost, LISTA/EBSCOhost, conducted web searching via Google Scholar, backward/forward CT of included studies and pertinent reviews, and contacting of experts. Two reviewers independently assessed eligibility. Data extraction and analysis were performed by one reviewer and checked by another. We screened 11,861 references and included 47 studies published between 1985 and 2021. Most studies (96%) assessed the benefit of CT either as supplementary or primary/stand-alone search method. Added value of CT for evidence retrieval was found by 96% of them. Science Citation Index and Social Sciences Citation Index were the most common citation indexes used. Application of multiple citation indexes in parallel, co-citing or co-cited references, CT iterations, or software tools was rare. CT terminology was heterogeneous and frequently ambiguous. The use of CT showed an added value in most of the identified studies; however, the benefit of CT in health-related systematic literature searching likely depends on multiple factors that could not be assessed with certainty. Application, terminology, and reporting are heterogeneous. Based on our results, we plan a Delphi study to develop recommendations for the use and reporting of CT.

Introducing the Library of Guidance for Health Scientists (LIGHTS): A Living Database for Methods Guidance.

Importance: Improving methodological quality is a priority in the health research community. Finding appropriate methods guidance can be challenging due to heterogeneous terminology, poor indexing in medical databases, and variation in formats. The Library of Guidance for Health Scientists (LIGHTS) is a new searchable database for methods guidance articles. Observations: Journal articles that aim to provide guidance for performing (including planning, design, conduct, analysis, and interpretation), reporting, and assessing the quality of health-related research involving humans or human populations (ie, excluding basic and animal research) are eligible for LIGHTS. A team of health researchers, information specialists, and methodologists continuously identifies and manually indexes eligible guidance documents. The search strategy includes focused searches of specific journals, specialized databases, and suggestions from researchers. A current limitation is that a keyword-based search of MEDLINE (and other general databases) and manual screening of records were not feasible because of the large number of hits (n = 915 523). As of September 20, 2022, LIGHTS included 1246 articles (336 reporting guidelines, 80 quality assessment tools, and 830 other methods guidance articles). The LIGHTS website provides a user-oriented search interface including filters for study type, specific methodological topic, research context, guidance type, and development process of the guidance. Automated matching of alternative methodological expressions (eg, enter loss to follow-up and find articles indexed with missing data) enhances search queries. Conclusions and Relevance: LIGHTS is a peer-supported initiative that is intended to increase access to and use of methods guidance relevant to health researchers, statisticians, methods consultants, methods developers, ethics boards, peer reviewers, journal editors, and funding bodies.

Searching two or more databases decreased the risk of missing relevant studies: a metaresearch study.

BACKGROUND AND OBJECTIVES: Assessing changes in coverage, recall, review, conclusions and references not found when searching fewer databases. METHODS: In randomly selected 60 Cochrane reviews, we checked included study publications' coverage (indexation) and recall (findability) using different search approaches with MEDLINE, Embase, and CENTRAL and related them to authors' conclusions and certainty. We assessed characteristics of unfound references. RESULTS: Overall 1989/2080 included references, were indexed in ≥1 database (coverage = 96%). In reviews where using one of our search approaches would not change conclusions and certainty (n = 44-54), median coverage and recall were highest (range 87.9%-100.0% and 78.2%-93.3%, respectively). Here, searching ≥2 databases reached >95% coverage and ≥87.9% recall. In reviews with unchanged conclusions but less certainty (n = 2-8): 63.3%-79.3% coverage and 45.0%-75.0% recall. In reviews with opposite conclusions (n = 1-3): 63.3%-96.6% and 52.1%-78.7%. In reviews where a conclusion was no longer possible (n = 3-7): 60.6%-86.0% and 20.0%-53.8%. The 265 references that were indexed but unfound were more often abstractless (30% vs. 11%) and older (28% vs. 17% published before 1991) than found references. CONCLUSION: Searching ≥2 databases improves coverage and recall and decreases the risk of missing eligible studies. If researchers suspect that relevant articles are difficult to find, supplementary search methods should be used.

A systematic survey of methods guidance suggests areas for improvement regarding access, development, and transparency.

BACKGROUND: To assess the current practice of developing and presenting methods guidance and explore opportunities for improvement. STUDY DESIGN AND SETTING: We systematically surveyed methods guidance published in high-impact general and methodology-focused medical journals indexed in MEDLINE in 2020. We included articles that explicitly stated the objective to provide methods guidance for health research. We extracted characteristics related to findability, methods used for development, presentation, and transparency. RESULTS: We included 105 methods guidance articles published in 12 different journals. Less than half had a structured abstract (42%) or was indexed with medical subject headings (38%) or author keywords (17%) related to guidance. Methods for development, reported in 42%, differed between reporting guidelines (n = 13, 100% reported methods) and other guidance articles (n = 92, 34% reported methods). Frequent methods for presentation were illustrative case studies (45%), research checklists (34%), and step-by-step guides (10%). Most articles did not describe the authors' expertise (22%). Conflicts of interest, reported in 34%, were often unclear. CONCLUSION: Potential areas for improving methods guidance include better findability through more consistent labeling and indexing and standards for development and reporting.

Subclinical giant cell arteritis in new onset polymyalgia rheumatica A systematic review and meta-analysis of individual patient data.

OBJECTIVES: To determine the prevalence and predictors of subclinical giant cell arteritis (GCA) in patients with newly diagnosed polymyalgia rheumatica (PMR). METHODS: PubMed, Embase, and Web of Science Core Collection were systematically searched (date of last search July 14, 2021) for any published information on any consecutively recruited cohort reporting the prevalence of GCA in steroid-naïve patients with PMR without cranial or ischemic symptoms. We combined prevalences across populations in a random-effect meta-analysis. Potential predictors of subclinical GCA were identified by mixed-effect logistic regression using individual patient data (IPD) from cohorts screened with PET/(CT). RESULTS: We included 13 cohorts with 566 patients from studies published between 1965 to 2020. Subclinical GCA was diagnosed by temporal artery biopsy in three studies, ultrasound in three studies, and PET/(CT) in seven studies. The pooled prevalence of subclinical GCA across all studies was 23% (95% CI 14%-36%, I2=84%) for any screening method and 29% in the studies using PET/(CT) (95% CI 13%-53%, I2=85%) (n=266 patients). For seven cohorts we obtained IPD for 243 patients screened with PET/(CT). Inflammatory back pain (OR 2.73, 1.32-5.64), absence of lower limb pain (OR 2.35, 1.05-5.26), female sex (OR 2.31, 1.17-4.58), temperature >37° (OR 1.83, 0.90-3.71), weight loss (OR 1.83, 0.96-3.51), thrombocyte count (OR 1.51, 1.05-2.18), and haemoglobin level (OR 0.80, 0.64-1.00) were most strongly associated with subclinical GCA in the univariable analysis but not C-reactive protein (OR 1.00, 1.00-1.01) or erythrocyte sedimentation rate (OR 1.01, 1.00-1.02). A prediction model calculated from these variables had an area under the curve of 0.66 (95% CI 0.55-0.75). CONCLUSION: More than a quarter of patients with PMR may have subclinical GCA. The prediction model from the most extensive IPD set has only modest diagnostic accuracy. Hence, a paradigm shift in the assessment of PMR patients in favour of implementing imaging studies should be discussed.

Ex-vivo experimental strategies for assessing unconstrained shoulder biomechanics: a scoping review protocol.

Background: Shoulder biomechanics cannot be measured directly in living persons. While different glenohumeral joint simulators have been developed to investigate the role of the glenohumeral muscles in shoulder biomechanics, a standard for these simulators has not been defined. With this scoping review we want to describe available ex-vivo experimental strategies for assessing unconstrained shoulder biomechanics. Objective: The scoping review aims at identifying methodological and/or experimental studies describing or involving ex-vivo simulators that assess unconstrained shoulder biomechanics and synthesizing their strengths and limitations. Inclusion criteria: All unconstrained glenohumeral joint simulators published in connection with ex-vivo or mechanical simulation experiments will be included. Studies on glenohumeral simulators with active components to mimic the muscles will be included. We will exclude studies where the experiment is static or the motion is induced through an external guide, e.g., a robotic device. Methods: We will perform database searching in PubMed, Embase via Elsevier and Web of Science. Two reviewers will independently assess full texts of selected abstracts. Direct backward and forward citation tracking on included articles will be conducted. We will narratively synthesize the results and derive recommendations for designing ex-vivo simulators for assessing unconstrained shoulder biomechanics.

Monitoring strategies for clinical intervention studies.

BACKGROUND: Trial monitoring is an important component of good clinical practice to ensure the safety and rights of study participants, confidentiality of personal information, and quality of data. However, the effectiveness of various existing monitoring approaches is unclear. Information to guide the choice of monitoring methods in clinical intervention studies may help trialists, support units, and monitors to effectively adjust their approaches to current knowledge and evidence. OBJECTIVES: To evaluate the advantages and disadvantages of different monitoring strategies (including risk-based strategies and others) for clinical intervention studies examined in prospective comparative studies of monitoring interventions. SEARCH METHODS: We systematically searched CENTRAL, PubMed, and Embase via Ovid for relevant published literature up to March 2021. We searched the online 'Studies within A Trial' (SWAT) repository, grey literature, and trial registries for ongoing or unpublished studies. SELECTION CRITERIA: We included randomized or non-randomized prospective, empirical evaluation studies of different monitoring strategies in one or more clinical intervention studies. We applied no restrictions for language or date of publication. DATA COLLECTION AND ANALYSIS: We extracted data on the evaluated monitoring methods, countries involved, study population, study setting, randomization method, and numbers and proportions in each intervention group. Our primary outcome was critical and major monitoring findings in prospective intervention studies. Monitoring findings were classified according to different error domains (e.g. major eligibility violations) and the primary outcome measure was a composite of these domains. Secondary outcomes were individual error domains, participant recruitment and follow-up, and resource use. If we identified more than one study for a comparison and outcome definitions were similar across identified studies, we quantitatively summarized effects in a meta-analysis using a random-effects model. Otherwise, we qualitatively summarized the results of eligible studies stratified by different comparisons of monitoring strategies. We used the GRADE approach to assess the certainty of the evidence for different groups of comparisons. MAIN RESULTS: We identified eight eligible studies, which we grouped into five comparisons. 1. Risk-based versus extensive on-site monitoring: based on two large studies, we found moderate certainty of evidence for the combined primary outcome of major or critical findings that risk-based monitoring is not inferior to extensive on-site monitoring. Although the risk ratio was close to 'no difference' (1.03 with a 95% confidence interval [CI] of 0.81 to 1.33, below 1.0 in favor of the risk-based strategy), the high imprecision in one study and the small number of eligible studies resulted in a wide CI of the summary estimate. Low certainty of evidence suggested that monitoring strategies with extensive on-site monitoring were associated with considerably higher resource use and costs (up to a factor of 3.4). Data on recruitment or retention of trial participants were not available. 2. Central monitoring with triggered on-site visits versus regular on-site visits: combining the results of two eligible studies yielded low certainty of evidence with a risk ratio of 1.83 (95% CI 0.51 to 6.55) in favor of triggered monitoring intervention. Data on recruitment, retention, and resource use were not available. 3. Central statistical monitoring and local monitoring performed by site staff with annual on-site visits versus central statistical monitoring and local monitoring only: based on one study, there was moderate certainty of evidence that a small number of major and critical findings were missed with the central monitoring approach without on-site visits: 3.8% of participants in the group without on-site visits and 6.4% in the group with on-site visits had a major or critical monitoring finding (odds ratio 1.7, 95% CI 1.1 to 2.7; P = 0.03). The absolute number of monitoring findings was very low, probably because defined major and critical findings were very study specific and central monitoring was present in both intervention groups. Very low certainty of evidence did not suggest a relevant effect on participant retention, and very low certainty evidence indicated an extra cost for on-site visits of USD 2,035,392. There were no data on recruitment. 4. Traditional 100% source data verification (SDV) versus targeted or remote SDV: the two studies assessing targeted and remote SDV reported findings only related to source documents. Compared to the final database obtained using the full SDV monitoring process, only a small proportion of remaining errors on overall data were identified using the targeted SDV process in the MONITORING study (absolute difference 1.47%, 95% CI 1.41% to 1.53%). Targeted SDV was effective in the verification of source documents, but increased the workload on data management. The other included study was a pilot study, which compared traditional on-site SDV versus remote SDV and found little difference in monitoring findings and the ability to locate data values despite marked differences in remote access in two clinical trial networks. There were no data on recruitment or retention. 5. Systematic on-site initiation visit versus on-site initiation visit upon request: very low certainty of evidence suggested no difference in retention and recruitment between the two approaches. There were no data on critical and major findings or on resource use. AUTHORS' CONCLUSIONS: The evidence base is limited in terms of quantity and quality. Ideally, for each of the five identified comparisons, more prospective, comparative monitoring studies nested in clinical trials and measuring effects on all outcomes specified in this review are necessary to draw more reliable conclusions. However, the results suggesting risk-based, targeted, and mainly central monitoring as an efficient strategy are promising. The development of reliable triggers for on-site visits is ongoing; different triggers might be used in different settings. More evidence on risk indicators that identify sites with problems or the prognostic value of triggers is needed to further optimize central monitoring strategies. In particular, approaches with an initial assessment of trial-specific risks that need to be closely monitored centrally during trial conduct with triggered on-site visits should be evaluated in future research.

Methodological approaches for conducting follow-up research with clinical trial participants: a scoping review and expert interviews.

BACKGROUND: Evidence-based establishment and implementation of best principles, laws and ordinances that regulate clinical research depend on the consultation and involvement of trial participants. Yet, guidance on methodological approaches to obtain trial participants' perspectives is currently missing. This scoping review therefore aimed at identifying, describing and evaluating research approaches to obtain trial participants' feedback on their views and experiences. METHODS: We searched the electronic databases Medline and PsycInfo via Ovid and the Web of Science Core Collection. Clinical trials were included that involved adult participants that were conducted in selected high-income countries and that were published in peer-reviewed journals between 1985 and 2018. In addition, 29 expert interviews were conducted between March and May 2019. RESULTS: Out of 5994 identified records, 23 articles were included in this review. Twelve studies used a qualitative approach, 10 were quantitative and one study used a mixed-method design. More than 75% of all work was conducted in the USA and the UK. The scoping review and the expert interviews highlighted that recruitment of participants was generally done through direct contact by principal investigators and/or study nurses or through searches in de-identified patient databases. Authors used surveys, interviews or focus group discussions. The tools used were either based on existing validated ones or developed and verified de novo with the support of experts and/or patient representatives. CONCLUSIONS: To our knowledge, this is the first methodological literature review of approaches to researching experiences of clinical trial participants where findings were triangulated with expert interviews. Covering a range of indications, trial phases and study settings, it demonstrates that clinical trial participant perspectives and experience is heavily under-researched. This casts doubt on the overall robustness of available insight into trial participants' views and experiences. Our results demonstrate that the methodology for studying participant opinion, perception and experience should be adapted to the measure of interest and conform to the study population. Using valid patient experience data is the basis to evaluate existing legal and regulatory human subject research frameworks for their appropriateness from a patient perspective. Such an evaluation will be critical to empower research participants.

Treatment effects in randomised trials using routinely collected data for outcome assessment versus traditional trials: meta-research study.

OBJECTIVE: To compare effect estimates of randomised clinical trials that use routinely collected data (RCD-RCT) for outcome ascertainment with traditional trials not using routinely collected data. DESIGN: Meta-research study. DATA SOURCE: Studies included in the same meta-analysis in a Cochrane review. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised clinical trials using any type of routinely collected data for outcome ascertainment, including from registries, electronic health records, and administrative databases, that were included in a meta-analysis of a Cochrane review on any clinical question and any health outcome together with traditional trials not using routinely collected data for outcome measurement. REVIEW METHODS: Effect estimates from trials using or not using routinely collected data were summarised in random effects meta-analyses. Agreement of (summary) treatment effect estimates from trials using routinely collected data and those not using such data was expressed as the ratio of odds ratios. Subgroup analyses explored effects in trials based on different types of routinely collected data. Two investigators independently assessed the quality of each data source. RESULTS: 84 RCD-RCTs and 463 traditional trials on 22 clinical questions were included. Trials using routinely collected data for outcome ascertainment showed 20% less favourable treatment effect estimates than traditional trials (ratio of odds ratios 0.80, 95% confidence interval 0.70 to 0.91, I2=14%). Results were similar across various types of outcomes (mortality outcomes: 0.92, 0.74 to 1.15, I2=12%; non-mortality outcomes: 0.71, 0.60 to 0.84, I2=8%), data sources (electronic health records: 0.81, 0.59 to 1.11, I2=28%; registries: 0.86, 0.75 to 0.99, I2=20%; administrative data: 0.84, 0.72 to 0.99, I2=0%), and data quality (high data quality: 0.82, 0.72 to 0.93, I2=0%). CONCLUSIONS: Randomised clinical trials using routinely collected data for outcome ascertainment show smaller treatment benefits than traditional trials not using routinely collected data. These differences could have implications for healthcare decision making and the application of real world evidence.

Association of Supporting Trial Evidence and Reimbursement for Off-Label Use of Cancer Drugs.

Importance: In many health systems, access to off-label drug use is controlled through reimbursement restrictions by health insurers, especially for expensive cancer drugs. Objective: To determine whether evidence from randomized clinical trials is associated with reimbursement decisions for requested off-label use of anticancer drugs in the Swiss health system. Design, Setting, and Participants: This cross-sectional study used reimbursement requests from routinely collected health records of 5809 patients with drug treatment for cancer between January 2015 and July 2018 in 3 major cancer centers, covering cancer care of approximately 5% of the Swiss population, to identify off-label drug use. For each off-label use indication with 3 or more requests, randomized clinical trial evidence on treatment benefits was systematically identified for overall survival (OS) or progression-free survival (PFS). Data were analyzed from August 2018 to December 2020. Exposures: Available randomized clinical trial evidence on benefits for OS or PFS for requested off-label use indications. Main Outcomes and Measures: The main outcome was the association between evidence for treatment benefit (expressed as improved OS or PFS) and reimbursement in multivariable regression models. Results: Among 3046 patients with cancer, 695 off-label use reimbursement requests in 303 different indications were made for 598 patients (median [interquartile range] age, 64 [53-73] years; 420 [60%] men). Off-label use was intended as first-line treatment in 311 requests (45%). Reimbursement was accepted in 446 requests (64%). For 71 indications, including 431 requests for 376 patients, there were 3 or more requests. Of these, 246 requests (57%) had no supporting evidence for OS or PFS benefit. Reimbursement was granted in 162 of 246 requests without supporting evidence (66%). Of 117 requests supported by OS benefit, 79 (67%) were reimbursed, and of 68 requests supported by PFS benefit alone, 54 (79%) were reimbursed. Evidence of OS benefit from randomized clinical trials was not associated with a higher chance of reimbursement (odds ratio, 0.76, 95% CI, 0.45-1.27). Conclusions and Relevance: These findings suggest that in a health care system enabling access to off-label use, it was frequently intended as a first-line treatment in cancer care. Availability of randomized clinical trial evidence showing survival benefit was not associated with reimbursement decisions for off-label anticancer drug treatment in Switzerland. A transparent process with criteria considering clinical evidence is needed for evidence-based reimbursement decisions to ensure fair access to cancer treatments.

Antimicrobial Prophylaxis for Postoperative Urinary Tract Infections in Transurethral Resection of Bladder Tumors: A Systematic Review and Meta-Analysis.

PURPOSE: The administration of antimicrobial prophylaxis for postoperative urinary tract infections following transurethral resection of bladder tumors is controversial. We aimed to systematically review evidence on the potential effect of antimicrobial prophylaxis on postoperative urinary tract infections and asymptomatic bacteriuria. MATERIALS AND METHODS: We conducted a systematic search in Embase®, Medline® and the Cochrane Central Register of Controlled Trials. Randomized controlled trials and nonrandomized controlled trials assessing the effect of any form of antimicrobial prophylaxis in patients with transurethral resection of bladder tumors on postoperative urinary tract infections or asymptomatic bacteriuria were included. Risk of bias was assessed using RoB 2.0 or the Newcastle-Ottawa Scale. Fixed and random effects meta-analyses were conducted. As a potential basis for a scoping review, we exploratorily searched Medline for risk factors for urinary tract infections after transurethral resection of bladder tumors. The protocol was registered on PROSPERO (CRD42019131733). RESULTS: Of 986 screened publications, 7 studies with 1,725 participants were included; the reported effect sizes varied considerably. We found no significant effect of antimicrobial prophylaxis on urinary tract infections: the pooled odds ratio of the random effects model was 1.55 (95% CI 0.73-3.31). The random effects meta-analysis examining the effect of antimicrobial prophylaxis on asymptomatic bacteriuria showed an OR of 0.43 (0.18-1.04). Risk of bias was moderate. Our exploratory search identified 3 studies reporting age, preoperative pelvic radiation, preoperative hospital stay, duration of operation, tumor size, preoperative asymptomatic bacteriuria and pyuria as risk factors for urinary tract infections following transurethral resection of bladder tumors. CONCLUSIONS: We observed insufficient evidence supporting routine antimicrobial prophylaxis in patients undergoing transurethral resection of bladder tumors for the prevention of postoperative urinary tract infections; our findings may inform harmonization of international guidelines.

Clinical Trial Evidence Supporting US Food and Drug Administration Approval of Novel Cancer Therapies Between 2000 and 2016.

Importance: Clinical trial evidence used to support drug approval is typically the only information on benefits and harms that patients and clinicians can use for decision-making when novel cancer therapies become available. Various evaluations have raised concern about the uncertainty surrounding these data, and a systematic investigation of the available information on treatment outcomes for cancer drugs approved by the US Food and Drug Administration (FDA) is warranted. Objective: To describe the clinical trial data available on treatment outcomes at the time of FDA approval of all novel cancer drugs approved for the first time between 2000 and 2016. Design, Setting, and Participants: This comparative effectiveness study analyzed randomized clinical trials and single-arm clinical trials of novel drugs approved for the first time to treat any type of cancer. Approval packages were obtained from drugs@FDA, a publicly available database containing information on drug and biologic products approved for human use in the US. Data from January 2000 to December 2016 were included in this study. Main Outcomes and Measures: Regulatory and clinical trial characteristics were described. For randomized clinical trials, summary treatment outcomes for overall survival, progression-free survival, and tumor response across all therapies were calculated, and median absolute survival increases were estimated. Tumor types and regulatory characteristics were assessed separately. Results: Between 2000 and 2016, 92 novel cancer drugs were approved by the FDA for 100 indications based on data from 127 clinical trials. The 127 clinical trials included a median of 191 participants (interquartile range [IQR], 106-448 participants). Overall, 65 clinical trials (51.2%) were randomized, and 95 clinical trials (74.8%) were open label. Of 100 indications, 44 indications underwent accelerated approval, 42 indications were for hematological cancers, and 58 indications were for solid tumors. Novel drugs had mean hazard ratios of 0.77 (95% CI, 0.73-0.81; I2 = 46%) for overall survival and 0.52 (95% CI, 0.47-0.57; I2 = 88%) for progression-free survival. The median tumor response, expressed as relative risk, was 2.37 (95% CI, 2.00-2.80; I2 = 91%). The median absolute survival benefit was 2.40 months (IQR, 1.25-3.89 months). Conclusions and Relevance: In this study, data available at the time of FDA drug approval indicated that novel cancer therapies were associated with substantial tumor responses but with prolonging median overall survival by only 2.40 months. Approval data from 17 years of clinical trials suggested that patients and clinicians typically had limited information available regarding the benefits of novel cancer treatments at market entry.

The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days.

Background: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Methods: Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Results: Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). Conclusions: The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats.

Development of a patient-reported outcome questionnaire for aplastic anemia and paroxysmal nocturnal hemoglobinuria (PRO-AA/PNH).

BACKGROUND: The introduction of new therapy modalities has significantly improved the outcome of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) patients. However, relatively little is known about the exact disease burden of AA/PNH since standardized assessments of symptoms including health-related quality of life (HRQoL) are frequently missing or inadequately designed for this rare patient group. We aimed to develop AA/PNH-specific questionnaires for self-reporting of symptoms, which could be included in electronic platforms for data collection and patient care. METHODS: By scoping review, we extracted any reported symptoms in AA/PNH and their prevalence from the literature (Phase I). Consensus rounds with patients and medical experts were conducted to identify core symptoms reported in the literature and to add missing items (Phase II). Ultimately, AA/PNH-specific patient-reported outcome (PRO) questionnaires including the selected measures were designed (Phase III). RESULTS: AA symptoms from 62 and PNH symptoms from 45 observational studies were extracted from the literature. Twenty-four patients and seven medical experts identified 11 core symptoms including HRQoL issues after three consensus rounds. Significant differences in the symptom ranking of patients versus medical experts could be observed. Therefore, patient- as well as expert-centered PRO questionnaires in AA and PNH were created following the concepts of validated instruments. CONCLUSION: The development of symptom self-reporting questionnaires for AA and PNH was feasible and the disease-specific PRO questionnaires can now be validated within a web-based workflow in a subsequent feasibility study.