Data flow within global clinical trials: a scoping review.

OBJECTIVE: To document clinical trial data flow in global clinical trials published in major journals between 2013 and 2021 from Global South to Global North. DESIGN: Scoping analysis METHODS: We performed a search in Cochrane Central Register of Controlled Trials (CENTRAL) to retrieve randomised clinical trials published between 2013 and 2021 from The BMJ, BMJ Global Health, the Journal of the American Medical Association, the Lancet, Lancet Global Health and the New England Journal of Medicine. Studies were included if they involved recruitment and author affiliation across different country income groupings using World Bank definitions. The direction of data flow was extracted with a data collection tool using sites of trial recruitment as the starting point and the location of authors conducting statistical analysis as the ending point. RESULTS: Of 1993 records initially retrieved, 517 studies underwent abstract screening, 348 studies underwent full-text screening and 305 studies were included. Funders from high-income countries were the sole funders of the majority (82%) of clinical trials that recruited across income groupings. In 224 (73.4%) of all assessable studies, data flowed exclusively to authors affiliated with high-income countries or to a majority of authors affiliated with high-income countries for statistical analysis. Only six (3.2%) studies demonstrated data flow to lower middle-income countries and upper middle-income countries for analysis, with only one with data flow to a lower middle-income country. CONCLUSIONS: Global clinical trial data flow demonstrates a Global South to Global North trajectory. Policies should be re-examined to assess how data sharing across country income groupings can move towards a more equitable model.

Factors Modifying the Associations of Single or Combination Programmed Cell Death 1 and Programmed Cell Death Ligand 1 Inhibitor Therapies With Survival Outcomes in Patients With Metastatic Clear Cell Renal Cell Carcinoma: A Systematic Review and Meta-analysis.

Importance: Programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors are immune checkpoint inhibitors widely used in the treatment of metastatic clear cell renal cell carcinoma (ccRCC) and other cancers. There is a lack of understanding regarding which factors are associated with therapeutic response. Objectives: To conduct a systematic literature review of trials reporting on factors associated with differential response to PD-1/PD-L1 inhibitors among patients diagnosed with metastatic ccRCC and quantitatively synthesize the magnitude to which each factor modified the response to PD-1/PD-L1 inhibitors. Data Sources: The MEDLINE and Cochrane Register of Trials databases were searched for studies published in English from 2006 onward. Searches were last run on September 3, 2019. Study Selection: This systematic review and meta-analysis assessed 662 phase 2/3 randomized clinical trials that provided subgroup analyses of any baseline characteristics regarding the treatment response to PD-1/PD-L1 inhibitors, alone or as part of a combination therapy, with respect to overall survival (OS) or progression-free survival (PFS) among patients with metastatic ccRCC. Data Extraction and Synthesis: A novel quantitative approach was used to synthesize subgroup findings across trials. The ratio of the subgroup-specific hazard ratios (HRs) from each study were pooled using a random-effects meta-analysis whereby ratios of 1.00 would indicate that the subgroup-specific HRs were equal in magnitude. Main Outcomes and Measures: Main outcomes were OS and PFS. Results: From an initial 662 reports, 7 trials were considered eligible for inclusion. Meta-analyses suggested the treatment response to PD-1/PD-L1 inhibitors in patients with metastatic ccRCC was significantly associated with age (OS: ratio of HR for age ≥75 years to HR for age <65 years, 1.51; 95% CI, 1.01-2.26), PD-L1 expression (PFS: ratio of HR for PD-L1 < 1% to HR for PD-L1 ≥ 10%, 2.21; 95% CI, 1.14-4.27; ratio of HR for PD-L1 < 1% to HR for PD-L1 ≥ 1%, 1.36; 95% CI, 1.10-1.68), Memorial Sloan Kettering Cancer Center risk score (PFS: ratio of HR for immediate risk score to HR for poor risk score, 1.62; 95% CI, 1.14-2.29; ratio of HR for favorable risk score to HR for poor risk score, 1.53; 95% CI, 1.00-2.34; ratio of HR for favorable risk score to HR for intermediate risk score, 0.96; 95% CI, 0.70-1.30), and sarcomatoid tumor presence (PFS: ratio of HR for no sarcomatoid differentiation to HR for sarcomatoid differentiation, 1.54; 95% CI, 1.07-2.21). Conclusions and Relevance: This analysis suggests that older age, low levels of PD-L1 expression, and the absence of sarcomatoid tumor differentiation are associated with a diminished response to anti-PD-1/PD-L1 immunotherapies with respect to survival outcomes among patients with metastatic ccRCC.

Characteristics and methods of incorporating randomized and nonrandomized evidence in network meta-analyses: a scoping review.

OBJECTIVES: The objective of the study was to conduct a scoping review of the published literature on methods used to combine randomized and nonrandomized evidence (NRE) in network meta-analyses (NMAs) and their respective characteristics. STUDY DESIGN AND SETTING: We conducted a scoping review using a list of NMAs which incorporated NRE that were identified from a previous review. All NMAs that included NRE in the analysis of main outcomes or sensitivity analyses were eligible for inclusion. Two reviewers independently screened studies for inclusion and performed data abstraction. Data analysis involved quantitative (frequencies and percentages) and qualitative (narrative synthesis) methods. RESULTS: A total of 23 NMAs met the predefined inclusion criteria, of which 74% (n = 17) used naïve pooling, 0% used NRE as informative priors, 9% (n = 2) used the 3-level Bayesian hierarchical model, 9% (n = 2) used all methods, and 9% (n = 2) used other methods. Most NMAs were supplemented with additional analyses to investigate the effect estimates when only randomized evidence was included. CONCLUSION: Although most studies provided justification for the inclusion of NRE, transparent reporting of the method used to combine randomized evidence and NRE was unclear in most published networks. Most NMAs used naïve pooling for combining randomized evidence and NRE.