Systematic review of outcomes and patient heterogeneity in relapsed or refractory diffuse large B-cell lymphoma.

Aim: To evaluate trials of systemic therapies in transplant-ineligible or -experienced, relapsed/refractory diffuse large-B cell lymphoma and the impact of patient characteristics on overall response rate (ORR). Patients & methods: Systematically reviewed multiple databases through 22 July 2021. Analyzed variations in patient characteristics and their relationship with ORR across trials. Results: Among 17 included trials, key patient characteristics varied substantially: primary refractory (0-69%), refractory to last line of therapy (LOT) (12-100%), ≥2 prior LOTs (14-100%), ≥3 prior LOTs (0-64%), IPI ≥3 (23-73%), tumor stage III/IV (50-90%) and median age (56-74 years). ORRs varied substantially (25-83%), correlating with these characteristics. Conclusion: Differences in patient characteristics significantly contribute to the variability in ORR across these trials and should be considered when contextualizing efficacy data.

The use of nonrandomized evidence to estimate treatment effects in health technology assessment.

Health technology assessment (HTA) is increasingly informed by nonrandomized studies, but there is limited guidance from HTA bodies on expectations around evidence quality and study conduct. We developed recommendations to support the appropriate use of such evidence based on a pragmatic literature review and a workshop involving 16 experts from eight countries as part of the EU's Horizon-2020 IMPACT-HTA program (work package six). To ensure HTA processes remain rigorous and robust, HTA bodies should demand clear, extensive and structured reporting of nonrandomized studies, including an in-depth assessment of the risk of bias. In recognition of the additional uncertainty imparted by nonrandomized designs in estimates of treatment effects, HTA bodies should strengthen early scientific advice and engage in collaborative efforts to improve use of real-world data.

Single-arm oncology trials and the nature of external controls arms.

Aim: Single-arm trials with external control arms (ECAs) have gained popularity in oncology. ECAs may consist of primary data from previous trials, electronic health records (EHRs) or aggregate data from the literature. We sought to provide a description of how such studies achieve similarity of patients, comparability of data quality and outcome assessment. Materials & methods: In a stratified convenience sample of 15 studies, five used primary data from trials as ECAs, five used secondary data from EHRs and five used aggregate data from the literature. Data were collected from the published literature and public web resources, blinded to the eventual approval decision. Results: Studies using ECAs from primary data and EHR data displayed methods to achieve comparability of information, including matched baseline characteristics. Aggregate data from published studies did not attempt to match covariates. The EHR controls often showed calendar time overlap for collecting information while trial data were mostly historic. Outcome data were not consistently reported across studies. US FDA approval was only seen when primary data from trials or EHR data were used as the ECA, however no ECA in this sample directly contributed to approval. Discussion: In this nonsystematic review of ECAs for single-arm trials, the ECAs derived from primary data collected by other trials or EHRs show patterns of patient comparability, time overlap, and realistic methodological approaches to achieving balance between treatment arms. They are often submitted to regulators while literature-derived aggregate findings as ECA may serve as benchmarks for pipeline decisions.

The terminology conflict on efficacy and effectiveness in healthcare.

Designers and architects created the rule 'form follows function (FFF)' for their own profession. Our paper demonstrates that this FFF rule applies equally well to the designers of clinical studies. Four examples present are as follows: disregarding this FFF rule causes an inconsistent terminology to differentiate between efficacy and effectiveness, inconsistent differentiation of efficacy and effectiveness interferes with the consistent interpretation of the results of clinical studies, inconsistent interpretation of clinical studies results in an unexpectedly variance of recommendations in clinical guidelines and the fusion of the FFF designer rule and of the demands of Cochrane and Bradford Hill ('can it work?', 'does it work?' and 'is it worth it?') avoids the terminology problem and its misleading consequences. This strategy is presented.

A scoping review and survey provides the rationale, perceptions, and preferences for the integration of randomized and nonrandomized studies in evidence syntheses and GRADE assessments.

OBJECTIVES: To review the literature and obtain preferences and perceptions from experts regarding the role of randomized studies (RSs) and nonrandomized studies (NRSs) in systematic reviews of intervention effects. STUDY DESIGN AND SETTING: Scoping review and survey of experts. Using levels of certainty developed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group, experts expressed their preferences about the use of RS and NRS in health syntheses. RESULTS: Of 189 respondents, 123 had the expertise required to answer the questionnaire; 116 provided their extent of agreement with approaches to use NRS with RS. Most respondents would include NRS when RS was unfeasible (83.6%) or unethical (71.5%) and a majority to maximize the body of evidence (66.3%), compare results in NRS and RS (53.5%) and to identify subgroups (51.7%). Sizable minorities would include NRS and RS to address the effect of randomization (29.5%) or because the question being addressed was a public-health intervention (36.5%). In summary of findings tables, most respondents would include both bodies of evidence-in two rows in the same table-when RS provided moderate, low, or very-low certainty evidence; even when RS provided high certainty evidence, a sizable minority (25%) would still present results from both bodies of evidence. Very few (3.6%) would, under realistic circumstances, pool RS and NRS results. CONCLUSIONS: Most experts would include both RS and NRS in the same review under a wide variety of circumstances, but almost all would present results of two bodies of evidence separately.