Exploring reasons for recruitment failure in clinical trials: a qualitative study with clinical trial stakeholders in Switzerland, Germany, and Canada

Background Poor participant recruitment is the most frequent reason for premature discontinuation of randomized clinical trials (RCTs), particularly if they are investigator-initiated. The aims of this qualitative study were to investigate (1) the views of clinical trial stakeholders from three different countries regarding reasons for recruitment failure in RCTs and (2) how these compare and contrast with the causes identified in a previous systematic review of RCT publications. Methods From August 2015 to November 2016, we conducted 49 semi-structured interviews with a purposive sample of clinical trial stakeholders. This included investigators based in Germany (n = 9), Switzerland (n = 6) and Canada (n = 1) with personal experience of a discontinued RCT and 33 other stakeholders (e.g., representatives of ethics committees, clinical trial units, pharmaceutical industry) in Switzerland. Individual semi-structured qualitative interviews were conducted and analyzed using thematic analysis. Results Interviewees identified a total of 29 different reasons for recruitment failure. Overoptimistic recruitment estimates, too narrow eligibility criteria, lack of engagement of recruiters/trial team, lack of competence/training/experience of recruiters, insufficient initial funding, and high burden for trial participants were mentioned most frequently. The interview findings largely confirm the previous systematic review on published reasons for recruitment failure. However, eight new reasons for recruitment failure were identified in the interviews, which led to the checklist of reasons for recruitment failure being revised and a new category describing research environment-related factors being added. Conclusions This study highlights the diversity of often interlinked reasons for recruitment failure in RCTs. Integrating the findings of this interview study with a previous systematic review of RCT publications led to a comprehensive, structured checklist of empirically-informed reasons for recruitment failure. The checklist may be useful to guide further research on interventions to improve participant recruitment in RCTs and helpful for trial investigators, research ethics committees, and funding agencies when assessing trial feasibility with respect to recruitment.

Revisiting the anger/sadistic typology of sexual homicide

PurposeThe anger/sadistic model is one of several typologies proposed for sexual homicide events. This paper aims to empirically test this model by examining sexual homicide cases. Empirically validating these typologies provides greater validity and reliability toward the sexual homicide classification systems that are useful in police investigations. Design/methodology/approachSecondary data analysis was conducted using police data on 249 solved sexual homicide cases in Canada from 1948 to 2010. Through a robust classifying method, latent class analysis was used to examine variables from the anger/sadistic typology. Additionally, variables from the pre-crime, crime and post-crime phases were examined in relation to the classes’ external validity. FindingsThree classes emerged, namely, expressive, methodical and instrumental. Expressive and methodical were similar to the anger/sadistic model in terms of the presence of premeditation, victim-offender relationship and body disposal location. Instrumental was characterized by the absence of mutilation on the victim’s body, targeted acquaintances and the use of physical restraints. The three-class typology resembled evidence found in a previous systematic review and also reinforced the notion of heterogeneity in sexual homicide offenses. Originality/valueThis is the first study to empirically test the anger/sadistic typology. Such validation is important given that sexual homicide classification systems can aid in police investigations (e.g. narrowing down the list of potential suspects). Replication of studies is needed to lend credibility to research processes, which, in turn, allows practitioners and policymakers to integrate the results into policies effectively.

The Role of Denosumab for Surgical Outcomes in Patients with Giant Cell Tumour of Bone: A Systematic Review

Background: The role of denosumab in patients with resectable giant cell tumour of bone remains unclear. We asked the following research question: for patients (aged ≥ 12 years) with resectable giant cell tumour of bone, what are the benefits and harms of denosumab compared with no denosumab in terms of (1) facilitation of surgery (operative time, blood loss), (2) disease recurrence, (3) pain control, (4) disease stability, and (5) adverse effects (e.g., malignant transformation, osteonecrosis of jaw, atypical femur fracture)? One previous systematic review addressed only one outcome—disease recurrence. Therefore, we undertook this new systematic review to address the above five outcomes. Methods: MEDLINE, EMBASE, PubMed, and Cochrane Database of Systematic Reviews databases were searched on June 30, 2020. Results: This systematic review included one previous systematic review and five comparative studies. Due to poor quality, non-randomized studies fraught with selection bias, it is difficult to determine if a significant difference exists in the outcomes for surgical giant cell tumour of bone with perioperative denosumab. There were no reported cases of adverse effects from denosumab. Conclusion: To date, there is insufficient evidence to understand the value of denosumab in the perioperative setting in patients with giant cell tumour of bone.

Is the evidence on the effectiveness of pay for performance schemes in healthcare changing? Evidence from a meta-regression analysis

Background This study investigated if the evidence on the success of the Pay for Performance (P4P) schemes in healthcare is changing as the schemes continue to evolve by updating a previous systematic review. Methods A meta-regression analysis using 116 studies evaluating P4P schemes published between January 2010 to February 2018. The effects of the research design, incentive schemes, use of incentives, and the size of the payment to revenue ratio on the proportion of statically significant effects in each study were examined. Results There was evidence of an increase in the range of countries adopting P4P schemes and weak evidence that the proportion of studies with statistically significant effects have increased. Factors hypothesized to influence the success of schemes have not changed. Studies evaluating P4P schemes which made payments for improvement over time, were associated with a lower proportion of statistically significant effects. There was weak evidence of a positive association between the incentives’ size and the proportion of statistically significant effects. Conclusion The evidence on the effectiveness of P4P schemes is evolving slowly, with little evidence that lessons are being learned concerning the design and evaluation of P4P schemes.

Role of Blood-Based Biomarkers in Ischemic Stroke Prognosis

Background and Purpose: Outcome prognostication in ischemic stroke patients remains challenging due to limited predictive properties of existing models. Blood-based biomarkers might provide additional information to established prognostic factors. We intended to identify the most promising prognostic biomarkers in ischemic stroke, their incremental prognostic value, and whether their predictive value differs among etiologies. Methods: We searched MEDLINE (Ovid) and Institute for Scientific Information Web of Knowledge for articles reporting the predictive performance of blood-based biomarkers measured up to 7 days after ischemic stroke and reporting functional outcome or death at least 7 days after stroke. This work updates a previous systematic review (up to January 2007), follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and was registered (International Prospective Register of Systematic Reviews PROSPERO 2018; https://www.crd.york.ac.uk/PROSPERO /; Unique identifier: CRD42018094671). Results: Two hundred ninety-one articles published between January 2007 and August 2018 comprising 257 different biomarkers met inclusion criteria. Median sample size was 232 (interquartile range, 110–455); 260 (89%) articles reported regression analyses with 78% adjusting for stroke severity, 82% for age, 67% for both, and 9% for none of them; 37% investigated discrimination, 5% calibration, and 11% reclassification. Including publications from a previous systematic review (1960–January 2007), natriuretic peptides, copeptin, procalcitonin, mannose-binding lectin, adipocyte fatty acid–binding protein, and cortisol were the biomarkers most consistently associated with poor outcome in higher-quality studies showing an incremental value over established prognostic factors. Other biomarkers were less consistently associated with poor outcome or were reported in lower quality studies. High heterogeneity among studies precluded the performance of a meta-analysis. Conclusions: The number of reports on prognostic blood-based biomarkers in ischemic stroke increased 3.5-fold in the period January 2007 to August 2018. Although sample size increased, methodological flaws are still common. Natriuretic peptides and markers of inflammation, atherogenesis, and stress response are the most promising prognostic biomarkers among identified studies.

Prevalence of Brazilian children and adolescents who met health criteria for aerobic fitness: systematic review update for Report Card Brazil Project

abstract The aim of the study was to update Brazilian evidence on the prevalence of children and adolescents who met health criteria for aerobic fitness. This systematic review is part of the Report Card Brazil Project and the search was restricted to studies published during the period from January 2018 to December 2019 in nine electronic databases. Studies with different designs, which allowed extracting information about the prevalence of children and adolescents who met health criteria for aerobic fitness (age up to 19 years or average age up to 19 years) were included. Studies published from 2020 were not included due to the possible effect of the pandemic on this indicator and because there is no certainty as to when the pandemic will end. Of the 694 studies initially identified, 13 studies with information of 14,673 children and adolescents were included after reading titles, abstracts, full texts and references. The prevalence of children and adolescents who met health criteria for aerobic fitness was 26.9% (29.7% for girls; 44.6% for boys). In this search, eight different cutoff points were used to determine adequate aerobic fitness levels and five tests were used to determine aerobic fitness. Analyzing data from the present review with the previous systematic review of this project, one third of children and adolescents in Brazil meet health criteria for aerobic fitness.

Candidate proteomic biomarkers in systemic sclerosis discovered using mass-spectrometry: an update of a systematic review (2014-2020)

Background: Systemic sclerosis (Ssc) is an autoimmune disease characterized by graduate cutaneous and tissue fibrosis development and irreversible fibroproliferative vascular changes. The aim of the current systematic review was to update the list of proteomic candidate biomarkers identified from Ssc samples with mass spectrometry techniques.Methods: Medline and Scopus databases were searched on 1st September 2020. Relevant articles were searched from March 2014 until September 2020. Two independent reviewers evaluated the retrieved articles.Results: From a total of 97 articles, 9 articles were included in the final analysis summarizing 539 candidate proteomic biomarkers from various samples from Ssc patients (a larger number compared to the previous systematic review). Most biomarkers were identified from cutaneous biopsies. Only 5 articles included a validation step of the findings with only 13 biomarkers being validated.Conclusions: Although many candidate biomarkers were additionally identified, independent validation studies are needed in order to evaluate the importance of these biomarkers for Ssc patients.

Revisiting the Natural History of Pulmonary Tuberculosis: A Bayesian Estimation of Natural Recovery and Mortality Rates

Background Tuberculosis (TB) natural history remains poorly characterized, and new investigations are impossible as it would be unethical to follow up TB patients without treatment. Methods We considered the reports identified in a previous systematic review of studies from the prechemotherapy era, and extracted detailed data on mortality over time. We used a Bayesian framework to estimate the rates of TB-induced mortality and self-cure. A hierarchical model was employed to allow estimates to vary by cohort. Inference was performed separately for smear-positive TB (SP-TB) and smear-negative TB (SN-TB). Results We included 41 cohorts of SP-TB patients and 19 cohorts of pulmonary SN-TB patients in the analysis. The median estimates of the TB-specific mortality rates were 0.389 year−1 (95% credible interval [CrI], .335–.449) and 0.025 year−1 (95% CrI, .017–.035) for SP-TB and SN-TB patients, respectively. The estimates for self-recovery rates were 0.231 year−1 (95% CrI, .177–.288) and 0.130 year−1 (95% CrI, .073–.209) for SP-TB and SN-TB patients, respectively. These rates correspond to average durations of untreated TB of 1.57 years (95% CrI, 1.37–1.81) and 5.35 years (95% CrI, 3.42–8.23) for SP-TB and SN-TB, respectively, when assuming a non-TB-related mortality rate of 0.014 year−1 (ie, a 70-year life expectancy). Conclusions TB-specific mortality rates are around 15 times higher for SP-TB than for SN-TB patients. This difference was underestimated dramatically in previous TB modeling studies, raising concerns about the accuracy of the associated predictions. Despite being less infectious, SN-TB may be responsible for equivalent numbers of secondary infections as SP-TB due to its much longer duration.

DPP4 inhibitors and respiratory infection, a systematic review and meta-analysis of the CardioVascular Outcomes Trials conducted before the pandemic and implications for the management of diabetes during COVID-19

Background Association between DPP4 inhibitors and respiratory infection remains unclear. CardioVascular Outcomes Trials (CVOTs) conducted before the COVID-19 pandemic are available. We aimed to estimate the effect of DPP4 inhibitors on the risk of respiratory infections. Methods We updated a previous systematic review and meta-analysis, searching for CVOTs assessing a DPP4 inhibitor in patients with type 2 diabetes mellitus. We focused on placebo-controlled CVOTs. Our primary outcome was 'any respiratory infection'. We added a sensitivity analysis integrating non-CVOTs and active-controlled CVOTs. Findings We included 47 714 patients in five placebo-controlled CVOTs. Median follow-up ranged from 1.5 years to 3 years. 4 369 events of overall respiratory infection were reported (rate of 9.2%). DPP4 inhibitors were not associated with a different risk compared to placebo (RR = 0.99 [95%CI: 0.93; 1.04]). The sensitivity analysis integrating the non-CVOTs studies and the active-controlled CVOT reached 11 349 events among 82 644 participants (rate of 13.7%). DPP4 inhibitors were not associated with a different risk of overall respiratory infection (RR = 1.00 [95% CI: 0.97; 1.03]). Interpretation Our up-dated meta-analysis provides the most powerful and least biased estimation of the association of DPP4 inhibitors and the risk of overall (non COVID-19) respiratory infection. We did not find any effect of the DPP4 inhibitors on the risk of respiratory infection. Our results support the recently published practical recommendations for the management of diabetes in patients with COVID-19, suggesting that DPP4 inhibitors should not be discontinued regarding the COVID-19 pandemic.