Meta-Analysis of 49 Roche Oncology Trials Comparing Blinded Independent Central Review (BICR) and Local Evaluation to Assess the Value of BICR.

BACKGROUND: Blinded independent central review (BICR) of radiographic images is frequently conducted in oncology trials to address the potential bias of local evaluation (LE) of endpoints such as progression-free survival (PFS) and objective response rate (ORR). Given that BICR is a complex and costly process, we evaluated the agreement between LE- and BICR-based treatment effect results and the impact of BICR on regulatory decision-making. MATERIALS AND METHODS: Meta-analyses were performed using hazard ratios (HRs) for PFS and odds ratios (ORs) for ORR from all randomized Roche-supported oncology clinical trials during 2006-2020 that had both LE and BICR results (49 studies with a total of over 32 000 patients). RESULTS: Overall, the evaluation bias of LE overestimating the treatment effect compared with BICR based on PFS was numerically small and not clinically meaningful, especially for double-blind studies (HR ratio between BICR and LE: 1.044). A larger bias is more likely to occur in studies with open-label design, smaller sample sizes, or an unequal randomization ratio. The majority (87%) of the PFS comparisons led to the same statistical inference by BICR and LE. For ORR, a high degree of agreement between BICR and LE results was also observed (OR ratio of 1.065), although the agreement was slightly lower than for PFS. CONCLUSION: BICR did not notably impact the study interpretation nor drive the sponsor's regulatory submission decisions. Hence, if bias can be diminished by appropriate means, LE is deemed as reliable as BICR for certain study settings.

Examining Resident Power Building in a Place-Based Initiative.

Rates of diseases and disabilities that are otherwise preventable are higher in low-income communities and communities of color. These disparities are attributed, in large part, to a power imbalance between residents and decision makers, and restoring resident power is necessary to improve health outcomes. A key strategy in many health promotion programs, resident power building is a process by which residents gain necessary skills to improve social conditions through their involvement in community change work. This study is part of a larger evaluation of Building Healthy Communities, a ground-breaking 10-year, $1 billion place-based initiative funded by The California Endowment designed to reverse the historical impact of racial and economic discrimination by advancing statewide policy, changing the narrative around health, and transforming underserved communities to achieve health equity. This article presents the resident power framework and identifies five domains that contributed to resident power building: continuity, culture, context, concrete action, and capacity. Continuity and culture mattered most to residents' ability to organize and to their ability to exercise their voice, respectively. While this study examined resident power building within the context of a large-scale place-based initiative, the domains that the authors identified are salient across health promotion programs that use power building as a key strategy to achieve program outcomes. The domains serve as opportunities to modify power-building strategies and allow program staff to allocate resources to specific activities to achieve program outcomes.

A comparison between the assessments of progression-free survival by local investigators versus blinded independent central reviews in phase III oncology trials.

PURPOSE: In this study, we compared the assessments of progression-free survival (PFS) carried out by the local investigator or by a blinded independent central review in the framework of phase III registration randomized controlled trials (RCT) in oncology. METHODS: We carried out a search in the clinicatrials.gov database, looking at the RCTs reporting the results of both independently assessed and investigator-assessed PFS. The hazard ratios (HRs) of investigator-assessed PFS and independently assessed PFS were recorded, and a discrepancy index was obtained by calculating the ratio of their respective HRs. Moreover, we investigated possible factors of discrepancy by analyzing the trials in different groups (by year, by tumor type, by drug type, by study design). RESULTS: We analyzed 28 RCTs meeting the search criteria. The estimated mean discrepancy index was 0.98 (confidence interval 0.927-1.032 (n = 32)). Subgroup analysis showed that the confidence intervals in all cases included the value 1, except in the subgroup of studies started in the period 2003-2006. CONCLUSION: In phase III oncology trials, we found no significant differences between the hazard ratios estimated by local investigators and those estimated by blinded independent central reviews. A relatively higher variability, in terms of large CI, was found in trials with biological agents.

Response assessment in lymphoma: Concordance between independent central review and local evaluation in a clinical trial setting.

BACKGROUND: Independent central review of clinical imaging remains the standard for oncology clinical trials with registration potential. A limited independent central review strategy has been proposed for solid tumor trials based on concordance between central and local evaluation of response. Concordance between independent central review and local evaluation of response in hematological malignancies is not known. METHODS: We retrospectively evaluated concordance between prospectively performed central and local assessments of response using the Revised Response Criteria for Malignant Lymphoma across two international, open-label, single-arm, registration studies of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma (N = 102) or systemic anaplastic large-cell lymphoma (N = 58). RESULTS: Overall objective response rates were similar between assessors for both the trial in Hodgkin lymphoma (75% independent central review, 72% local evaluation) and the trial in anaplastic large-cell lymphoma (86% independent central review, 83% local evaluation). Patient-specific objective response concordance was also substantial (Hodgkin lymphoma: kappa = 0.68; anaplastic large-cell lymphoma: kappa = 0.74). Median progression-free survival was similar between assessors for patients with anaplastic large-cell lymphoma (14.3 months by independent central review (95% confidence interval: 6.9, -); 14.5 months by local evaluation (95% confidence interval: 9.4, -)), but longer by local evaluation in patients with Hodgkin lymphoma (5.8 months by independent central review (95% confidence interval: 5.0, 9.0); 9.0 months by local evaluation (95% confidence interval: 7.1, 12.0)). Median duration of response was longer by local evaluation in both malignancies, which was primarily attributable to earlier computed tomography and positron emission tomography-based scoring of progression by independent central review. CONCLUSION: A limited independent review audit strategy for clinical trials of some lymphomas appears feasible and practical based on substantial concordance in assessments of overall objective response by central and local evaluation in two international, prospective, registration trials in lymphoma. Some variability between assessors in the time-to-event endpoints was observed, which appeared attributable to earlier assignments of progression by independent central review compared with local evaluation.

Progression-free survival assessment by local investigators versus blinded independent central review in randomized clinical trials in metastatic breast cancer: A systematic review and meta-analysis.

INTRODUCTION: In randomized clinical trials (RCTs), blinded independent central review (BICR) is used to minimize heterogeneity and bias associated with radiological response evaluation by local investigators. However, BICR adds costs and complexity to the trial management. We assessed the discrepancy index between progression-free survival (PFS) assessment by local investigators and by BICR in RCTs conducted in patients with metastatic breast cancer (MBC). METHODS: A systematic search of PubMed, Embase, Cochrane databases and conference proceedings (ASCO, SABCS, ESMO) was performed up to January 4, 2023 (PROSPERO: CRD42021229865). All RCTs published from 2000 to 2022, including MBC patients treated in first- or second-line, and reporting PFS assessed by local investigators and BICR were included. A discrepancy index between BICR-assessed and investigator-assessed HR was calculated for each trial and an overall combined DI was obtained using a fixed-effects model. The agreement between hazard ratios (HR) of PFS assessed by local investigators and BICR was measured using intraclass correlation coefficient (ICC). RESULTS: We analyzed 24 studies including 13,168 patients. Among them, 19 (79%) were in first-line, 18 (75%) were phase III trials and 23 (96%) had PFS as primary endpoint. The overall combined discrepancy index was 0.97 (95%CI 0.85-1.10; ICC 0.831, p < 0.001) suggesting no statistically significant difference in PFS assessment between local investigators and BICR. This result was consistent across all analyzed subgroups. CONCLUSIONS: The good concordance between local investigator and BICR assessments supports the reliability of local investigator-assessed PFS as primary endpoint for RCTs in MBC and questions the practical utility of implementing BICR in all RCTs.

Local Investigators Significantly Overestimate Overall Response Rates Compared to Blinded Independent Central Reviews in Phase 2 Oncology Trials.

The overall response rate (ORR) is a largely adopted outcome measure in early-phase oncology trials. ORR is highly relevant in cancer drug development at the time of deciding whether to move to confirmatory phase 3 trials; moreover, ORR is gaining increasing relevance in fast-track registration procedures. No systematic analysis has been conducted so far to investigate whether a discrepancy exists between ORR assessed by local investigators and those assessed by blinded reviewers in phase 2 oncology trials. In this study, we carried out a search in the clinicaltrials.gov and EudraCT databases, looking at the trials reporting the results of both investigator-assessed and independently-assessed ORR. A discrepancy index was obtained by calculating the ratio of each investigator-assessed ORR on the corresponding independently assessed ORR, so that a discrepancy index >1 indicates that the investigator was "more optimistic," whereas a discrepancy index <1 indicates the opposite. We also analyzed different subgroups (by tumor type, by drug type, by year). Twenty trials met the search criteria; in some cases, >1 comparison was conducted in the trial, so that the total number of comparisons analyzed was 33. The estimated mean discrepancy index was 1.175 (95% confidence interval, 1.083-1.264; n = 33). In conclusion, local investigators significantly overestimate ORR compared to paired blinded reviewers in phase 2 oncology trials. This may represent a risk in drug development, when deciding whether to move to confirmatory, more expensive phase 3 trials. Blinded independent central review should be used in ORR assessment if a more conservative estimate of treatment efficacy is required, as in the case of fast-track drug developments leading to accelerated approvals of cancer therapies.

A local evaluation of the individual state-space to scale up Bayesian spatial capture-recapture.

Spatial capture-recapture models (SCR) are used to estimate animal density and to investigate a range of problems in spatial ecology that cannot be addressed with traditional nonspatial methods. Bayesian approaches in particular offer tremendous flexibility for SCR modeling. Increasingly, SCR data are being collected over very large spatial extents making analysis computational intensive, sometimes prohibitively so. To mitigate the computational burden of large-scale SCR models, we developed an improved formulation of the Bayesian SCR model that uses local evaluation of the individual state-space (LESS). Based on prior knowledge about a species' home range size, we created square evaluation windows that restrict the spatial domain in which an individual's detection probability (detector window) and activity center location (AC window) are estimated. We used simulations and empirical data analyses to assess the performance and bias of SCR with LESS. LESS produced unbiased estimates of SCR parameters when the AC window width was ≥5σ (σ: the scale parameter of the half-normal detection function), and when the detector window extended beyond the edge of the AC window by 2σ. Importantly, LESS considerably decreased the computation time needed for fitting SCR models. In our simulations, LESS increased the computation speed of SCR models up to 57-fold. We demonstrate the power of this new approach by mapping the density of an elusive large carnivore-the wolverine (Gulo gulo)-with an unprecedented resolution and across the species' entire range in Norway (> 200,000 km2). Our approach helps overcome a major computational obstacle to population and landscape-level SCR analyses. The LESS implementation in a Bayesian framework makes the customization and fitting of SCR accessible for practitioners working at scales that are relevant for conservation and management.

A Synthetic Comparator Approach to Local Evaluation of School-Based Substance Use Prevention Programming.

We propose a method for creating groups against which outcomes of local pretest-posttest evaluations of evidence-based programs can be judged. This involves assessing pretest markers for new and previously conducted evaluations to identify groups that have high pretest similarity. A database of 802 prior local evaluations provided six summary measures for analysis. The proximity of all groups using these variables is calculated as standardized proximities having values between 0 and 1. Five methods for creating standardized proximities are demonstrated. The approach allows proximity limits to be adjusted to find sufficient numbers of synthetic comparators. Several index cases are examined to assess the numbers of groups available to serve as comparators. Results show that most local evaluations would have sufficient numbers of comparators available for estimating program effects. This method holds promise as a tool for local evaluations to estimate relative effectiveness.