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Objective: Hard-to-heal (chronic) wounds are treated differently at varying healing stages and often require long periods of time to heal completely. Therefore, it is often very difficult to achieve this primary endpoint in clinical trials with wound products which are used temporarily. Thus, it seems reasonable to use valid wound healing parameters determined at an early stage, such as the percentage (wound) area reduction (PAR), as surrogates for predicting complete wound healing. Method: To identify studies on the association between potential surrogate endpoints and complete wound healing, a systematic literature search in MEDLINE, Embase and the Cochrane Library databases was performed. The findings of the studies were summarised qualitatively. Results: A total of 23 publications with a focus on hard-to-heal wounds (n=10 diabetic foot ulcers (DFUs), n=10 venous leg ulcers (VLUs), n=3 other ulcers) and various wound care regimens were identified. All studies showed a high bias potential. The available clinical evidence confirmed that the PAR at week 4 showed a good discriminatory capacity to predict which wounds would eventually heal and which would not. The chance to achieve complete wound healing was significantly higher for wounds achieving a PAR of >40% (VLU) or ≥50% (DFU) at week 4. Conclusion: The PAR thresholds of 40% (VLU) and 50% (DFU) can be used to identify the proportion of the wounds that will heal, and those that will not heal, to compare the efficacy of different wound dressings as early as week 4 in the setting of clinical trials. The available evidence may be limited by a potential risk of bias. [ABSTRACT FROM AUTHOR]

ABSTRACT In a causal inference framework, a new metric has been proposed to quantify surrogacy for a continuous putative surrogate and a binary true endpoint, based on information theory. The proposed metric, termed the individual causal association (ICA), was quantified using a joint causal inference model for the corresponding potential outcomes. Due to the non‐identifiability inherent in this type of models, a sensitivity analysis was introduced to study the behavior of the ICA as a function of the non‐identifiable parameters characterizing the aforementioned model. In this scenario, to reduce uncertainty, several plausible yet untestable assumptions like monotonicity, independence, conditional independence or homogeneous variance–covariance, are often incorporated into the analysis. We assess the robustness of the methodology regarding these simplifying assumptions via simulation. The practical implications of the findings are demonstrated in the analysis of a randomized clinical trial evaluating an inactivated quadrivalent influenza vaccine. [ABSTRACT FROM AUTHOR]

AbstractAdaptive designs have garnered widespread attention in drug discovery studies as they are often more flexible, efficient, informative, and ethical. However, the planning of oncology trials with seamless phase 2/3 design is not as commonplace, especially when the primary endpoint involves time-to-event survival time and is expected to be immature at the interim for the purpose of treatment selection of the most-promising regimen. In this article, we establish a seamless phase 2/3 design with a review of the framework and adaptation to survival analysis, incorporation of treatment selection scheme guided by surrogate short-term endpoint at interim analysis, and integration of copula modeling for endpoints. We also explore parametric copula estimation using historical data, and investigate mis-specification among copulas families as well as against a straightforward family of the stratified model. For illustration, we provide extensive simulation with operating characteristics. The article concludes with a discussion of practical issues in the implementation of such designs. [ABSTRACT FROM AUTHOR]

Purpose: Quantifying the association of chemotherapy relative dose intensity (RDI) with overall survival may enable supportive care interventions that improve chemotherapy RDI to estimate their magnitude of potential clinical benefit. Methods: This cohort study included 533 patients with stage II–III colon cancer who initiated a planned regimen of 12 cycles of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. The primary exposure was chemotherapy RDI. The primary outcome was overall survival. Restricted cubic splines estimated hazard ratios (HR). Results: Chemotherapy regimen RDI was associated with overall survival in an L-shaped pattern (linear P = 0.006; nonlinear P = 0.057); the risk of death was flat above 85% but increased linearly below 85%. For example, a decrease in RDI from 85 to 75% was associated with an increased risk of death [HR: 1.20 (95% CI: 1.08, 1.52)], whereas an increase in RDI from 85 to 95% was not associated with the risk of death [HR: 1.06 (95% CI: 0.82, 1.38)]. Conclusion: If chemotherapy RDI is considered a potential surrogate of overall survival, supportive care interventions that improve chemotherapy RDI might confer a potential clinical benefit in this population. [ABSTRACT FROM AUTHOR]

Background: For the development of pharmaceutical products in kidney field, appropriate surrogate endpoints which can predict long-term prognosis are needed as an alternative to hard endpoints, such as end-stage kidney disease. Though international workshop has proposed estimated glomerular filtration rate (GFR) slope reduction of 0.5–1.0 mL/min/1.73 m /year and 30% decrease in albuminuria/proteinuria as surrogate endpoints in early and advanced chronic kidney disease (CKD), it was not clear whether these are applicable to Japanese patients. Methods: We analyzed J-CKD-DB and CKD-JAC, Japanese databases/cohorts of CKD patients, and J-DREAMS, a Japanese database of patients with diabetes mellitus to investigate the applicability of eGFR slope and albuminuria/proteinuria to the Japanese population. Systematic review on those endpoints was also conducted including the results of clinical trials published after the above proposal. Results: Our analysis showed an association between eGFR slope and the risk of end-stage kidney disease. A 30% decrease in albuminuria/proteinuria over 2 years corresponded to a 20% decrease in the risk of end-stage kidney disease patients with baseline UACR ≥ 30 mg/gCre or UPCR ≥ 0.15 g/gCre in the analysis of CKD-JAC, though this analysis was not performed on the other database/cohort. Those results suggested similar trends to those of the systematic review. Conclusion: The results suggested that eGFR slope and decreased albuminuria/proteinuria may be used as a surrogate endpoint in clinical trials for early CKD (including diabetic kidney disease) in Japanese population, though its validity and cutoff values must be carefully considered based on the latest evidence and other factors. [ABSTRACT FROM AUTHOR]

Background: Late-stage cancer incidence has been proposed as an early surrogate for mortality in randomized controlled trials (RCTs) of cancer screening; however, its validity has not been systematically evaluated across screening RCTs of different cancers. Methods: We conducted a meta-regression analysis of cancer screening RCTs that reported both late-stage cancer incidence and cancer mortality. Based on a systematic literature review, we included 33 RCTs of screening programs targeting seven cancer types, including lung (n = 12), colorectal (n = 8), breast (n = 5), and prostate (n = 4), among others. We regressed the relative reduction of cancer mortality on the relative reduction of late-stage cancer incidence, inversely weighted for each RCT by the variance of estimated mortality reduction. Results: Across cancer types, the relative reduction of late-stage cancer incidence was linearly associated with the relative reduction of cancer mortality. Specifically, we observed this association for lung (R2 = 0.79 and 0.996 in three recent large trials), breast (R2 = 0.94), prostate (R2 = 0.98), and colorectal cancer (R2 = 0.75 for stage III/IV cancers and 0.93 for stage IV cancers). Trials with a 20% or greater reduction in late-stage cancers were more likely to achieve a significant reduction in cancer mortality. Our results also showed that no reduction of late-stage cancer incidence was associated with no or minimal reduction in cancer mortality. Conclusions: Meta-regression of historical screening RCTs showed a strong linear association between reductions in late-stage cancer incidence and cancer mortality. [ABSTRACT FROM AUTHOR]

Abstract Purpose To address this evidence gap and validate short-term OS at less than 5 years as a reliable surrogate endpoint for 5-year OS. Methods We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database, focusing on non-metastatic NPC patients diagnosed between 2010 and 2015. Patients were categorized into radiotherapy and chemoradiotherapy groups. Results This retrospective study examined 2,047 non-metastatic NPC patients. Among them, 217 received radiotherapy, and 1,830 received chemoradiotherapy. Our analysis results indicated that the 4-year OS may serve as a reliable surrogate endpoint for patients with AJCC clinical stage I (80 vs. 78%, P = 0.250), regardless of the treatment received. Specifically, in the radiotherapy group, patients with stage I, T0-T1, and N0 NPC showed similar OS rates at 4 and 5 years (83 vs. 82%, P = 1.000; 78 vs. 76%, P = 0.250; 78 vs. 77%, P = 0.500, respectively). Similarly, patients with stage II-IV, T2-T4, and N1-3 NPC showed no significant difference in OS rates between 3 and 5 years (57 vs. 51%, P = 0.063; 52 vs. 46%, P = 0.250; 54 vs. 46%, P = 0.125, respectively) in the radiotherapy group. In the chemoradiotherapy group, only the 3-year OS rate did not significantly differ from that at 5 years in stage I patients (79vs. 72%, P = 0.063). Conclusions Our study suggests that short-term surrogate endpoints may be valuable for evaluating 5-year OS outcomes in NPC patients in non-endemic areas.

ABSTRACT In clinical trials with time‐to‐event data, the evaluation of treatment efficacy can be a long and complex process, especially when considering long‐term primary endpoints. Using surrogate endpoints to correlate the primary endpoint has become a common practice to accelerate decision‐making. Moreover, the ethical need to minimize sample size and the practical need to optimize available resources have encouraged the scientific community to develop methodologies that leverage historical data. Relying on the general theory of group sequential design and using a Bayesian framework, the methodology described in this paper exploits a documented historical relationship between a clinical “final” endpoint and a surrogate endpoint to build an informative prior for the primary endpoint, using surrogate data from an early interim analysis of the clinical trial. The predictive probability of success of the trial is then used to define a futility‐stopping rule. The methodology demonstrates substantial enhancements in trial operating characteristics when there is a good agreement between current and historical data. Furthermore, incorporating a robust approach that combines the surrogate prior with a vague component mitigates the impact of the minor prior‐data conflicts while maintaining acceptable performance even in the presence of significant prior‐data conflicts. The proposed methodology was applied to design a Phase III clinical trial in metastatic colorectal cancer, with overall survival as the primary endpoint and progression‐free survival as the surrogate endpoint. [ABSTRACT FROM AUTHOR]

AbstractClinical trials are an essential aspect of the drug development process. Clinical endpoints and surrogate endpoints are two terms used in clinical trials to measure the effectiveness of a treatment. While clinical endpoints typically require higher costs and longer durations of observation to show direct clinical benefits, surrogate endpoints have been introduced as a cheaper and faster method that may be used to predict clinical effects. When there is a linear relationship between the surrogate and the clinical endpoint, the surrogate may still need to rule out a threshold that corresponds to no clinical benefit. The determination of such a threshold uses the knowledge of numerous parameters in the bivariate statistical distribution of the clinical response and the surrogate. In our work, we present a concept of “working” threshold to incorporate statistical uncertainties in determination of such a threshold. [ABSTRACT FROM AUTHOR]

In randomized clinical trials that use a long‐term efficacy endpoint, the follow‐up time necessary to observe the endpoint may be substantial. In such trials, an attractive option is to consider an interim analysis based solely on an early outcome that could be used to expedite the evaluation of treatment's efficacy. Garcia Barrado et al. (Pharm Stat. 2022; 21: 209–219) developed a methodology that allows introducing such an early interim analysis for the case when both the early outcome and the long‐term endpoint are normally‐distributed, continuous variables. We extend the methodology to any combination of the early‐outcome and long‐term‐endpoint types. As an example, we consider the case of a binary outcome and a time‐to‐event endpoint. We further evaluate the potential gain in operating characteristics (power, expected trial duration, and expected sample size) of a trial with such an interim analysis in function of the properties of the early outcome as a surrogate for the long‐term endpoint. [ABSTRACT FROM AUTHOR]

Objective: To assess the correlation between recurrence-free survival (RFS) and overall survival (OS) in the hepatobiliary-pancreatic (HBP) surgical setting to validate RFS as a surrogate endpoint. Background: Reliable surrogate endpoints for OS are still limited in the field of HBP surgery. Methods: We analyzed patients who underwent curative resection for HBP disease [986 patients with pancreatic ductal adenocarcinoma (PDAC), 1168 with biliary tract cancer (BTC), 1043 with hepatocellular carcinoma, and 1071 with colorectal liver metastasis] from September 2002 to June 2022. We also conducted meta-analyses of randomized controlled trials of neoadjuvant or adjuvant therapy to validate the surrogacy in PDAC and BTC. Results: Correlation coefficients between RFS and OS were low for hepatocellular carcinoma (p = 0.67) and colorectal liver metastasis (p = 0.53) but strong for PDAC (p = 0.80) and BTC (p = 0.75). In a landmark analysis, the concordance rates between survival or death at 5 years postoperatively and the presence or absence of recurrence at each time point (1, 2, 3, and 4 years) were 50%, 70%, 74%, and 77% for PDAC and 54%, 67%, 73%, and 78% for BTC, respectively, both increasing and reaching a plateau at 3 years. In a meta-analysis, the correlation coefficients for the RFS hazard ratio and OS hazard ratio in PDAC and BTC were p = 0.88 (P < 0.001) and p = 0.87 (P < 0.001), respectively. Conclusions: Three-year RFS can be a reliable surrogate endpoint for OS in clinical trials of neoadjuvant or adjuvant therapy for PDAC and BTC. [ABSTRACT FROM AUTHOR]

A traditional phase 3 clinical efficacy study for a Zika vaccine may be unfeasible because of the current low transmission of Zika virus (ZIKV). An alternative clinical development approach to evaluate Zika vaccine efficacy (VE) is therefore required, delineated in the US FDA's Accelerated Approval Program for licensure, which utilizes an anti-Zika neutralizing antibody (Zika NAb) titer correlated with non-human primate (NHP) protection as a surrogate endpoint. In this accelerated approval approach, the estimation of VE would be inferred from the percentage of phase 3 trial participants achieving the established surrogate endpoint. We provide a statistical framework to predict the probability of protection for human participants vaccinated with a purified inactivated ZIKV vaccine (TAK-426), in the absence of VE measurements, using NHP data under a single-correlate model. Based on a logistic regression (LR) with bias-reduction model, a probability of 90% protection in humans is expected with a ZIKV NAb geometric mean titer (GMT) ≥ 3.38 log10 half-maximal effective concentration (EC50). The predicted probability of protection of TAK-426 against ZIKV infection was determined using the two-parameter LR model that fit the calculated VE in rhesus macaques and the flavivirus-naïve phase 1 trial participants' ZIKV NAb GMTs log10 EC50, measured by a ZIKV reporter virus particle assay, at 1 month post dose 2. The TAK-426 10 µg dose predicted a probability of protection from infection of 98% among flavivirus-naïve phase 1 trial participants. [ABSTRACT FROM AUTHOR]

Abstract Objectives The goal of the research was to assess the quantitative relationship between median progression-free survival (PFS) and median overall survival (OS) specifically among patients with relapsed/refractory multiple myeloma (RRMM) based on published randomized controlled trials (RCTs). Methods Two bibliographic databases (PubMed and Embase, 1970–2017) were systematically searched for RCTs in RRMM that reported OS and PFS, followed by an updated search of studies published between 2010 and 2022 in 3 databases (Embase, MEDLINE, and EBM Reviews, 2010–2022). The association between median PFS and median OS was assessed using the nonparametric Spearman rank and parametric Pearson correlation coefficients. Subsequently, the quantitative relationship between PFS and OS was assessed using weighted least-squares regression adjusted for covariates including age, sex, and publication year. Study arms were weighted by the number of patients in each arm. Results A total of 31 RCTs (56 treatment arms, 10,450 patients with RRMM) were included in the analysis. The average median PFS and median OS were 7.1 months (SD 5.5) and 28.1 months (SD 11.8), respectively. The Spearman and Pearson correlation coefficients between median PFS and median OS were 0.80 (P

Single-arm trials (SATs) and surrogate endpoints were adopted as pivotal evidence for accelerated approval of anticancer drugs for more than 30 years. However, concerns regarding clinical evidence quality in trials, particularly in the SATs of anticancer drugs have increasingly been raised. SAT may not always provide strong evidence due to the lack of control and endpoint of overall survival that is typically present in randomized controlled trials. Clinical trial endpoint adjudication is a crucial factor in surrogate outcome measurement to ensure the data quality of the clinical trial of anticancer drugs. In this review, we systematically discuss the characteristics of adjudications in assessments in surrogate endpoint and safety outcome respectively, which are essential for ensuring reliable and transparent outcomes. Endpoint adjudication effectively reduces potential bias and mitigates variance that may be introduced by investigators when analyzing the medical records for the surrogate endpoints. We analyze the advantages and disadvantages of each type of adjudicator and provide a summary of the roles of adjudicators. By suggestion of improving data reliability and transparency in pivotal trials, this review aims to supply a strategy for better clinical investigation for anticancer drugs, ultimately leading to better patient outcomes. [ABSTRACT FROM AUTHOR]

Objectives: The goal of the research was to assess the quantitative relationship between median progression-free survival (PFS) and median overall survival (OS) specifically among patients with relapsed/refractory multiple myeloma (RRMM) based on published randomized controlled trials (RCTs). Methods: Two bibliographic databases (PubMed and Embase, 1970–2017) were systematically searched for RCTs in RRMM that reported OS and PFS, followed by an updated search of studies published between 2010 and 2022 in 3 databases (Embase, MEDLINE, and EBM Reviews, 2010–2022). The association between median PFS and median OS was assessed using the nonparametric Spearman rank and parametric Pearson correlation coefficients. Subsequently, the quantitative relationship between PFS and OS was assessed using weighted least-squares regression adjusted for covariates including age, sex, and publication year. Study arms were weighted by the number of patients in each arm. Results: A total of 31 RCTs (56 treatment arms, 10,450 patients with RRMM) were included in the analysis. The average median PFS and median OS were 7.1 months (SD 5.5) and 28.1 months (SD 11.8), respectively. The Spearman and Pearson correlation coefficients between median PFS and median OS were 0.80 (P < 0.0001) and 0.79 (P < 0.0001), respectively. In individual treatment arms of RRMM trials, each 1-month increase in median PFS was associated with a 1.72-month (95% CI 1.26–2.17) increase in median OS. Conclusion: Analysis of the relationship between PFS and OS incorporating more recent studies in RRMM further substantiates the use of PFS to predict OS in RRMM. [ABSTRACT FROM AUTHOR]

Adaptive seamless phase 2/3 subgroup enrichment design plays a pivotal role in streamlining efficient drug development within a competitive landscape, while also enhancing patient access to promising treatments. This design approach identifies biomarker subgroups with the highest potential to benefit from investigational regimens. The seamless integration of Phase 2 and Phase 3 ensures a timely confirmation of clinical benefits. One significant challenge in adaptive enrichment decisions is determining the optimal timing and maturity of the primary endpoint. In this paper, we propose an adaptive seamless 2-in-1 biomarker-driven subgroup enrichment design that addresses this challenge by allowing subgroup selection using an early intermediate endpoint that predicts clinical benefits (i.e. a surrogate endpoint). The proposed design initiates with a Phase 2 stage involving all participants and can potentially expand into a Phase 3 study focused on the subgroup demonstrating the most favorable clinical outcomes. We will show that, under certain correlation assumptions, the overall type I error may not be inflated at the end of the study. In scenarios where the assumptions may not hold, we present a general framework to control the multiplicity. The flexibility and efficacy of the proposed design are highlighted through an extensive simulation study and illustrated in a case study in multiple myeloma. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to examine the effectiveness of the best response rate (BRR) as a surrogate for overall survival (OS), using the modified Response Evaluation Criteria in Solid Tumors (mRECIST), in patients with unresectable hepatocellular carcinoma (HCC) undergoing hepatic arterial infusion chemotherapy (HAIC) with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) combined with molecular targeting and immunotherapy. Methods: This study enrolled 111 consecutive patients who had complete imaging data. The median age of patients was 58 years (IQR 50.5-65.0). Among the patients, those with Barcelona Clinic Liver Cancer (BCLC) stage A, BCLC stage B, and BCLC stageCcomprised 6.4%, 19.1%, and 73.6%, respectively. The optimal threshold of BRR can be determined using restricted cubic splines (RCS) and the rank sum statistics of maximumselection. Survival curvesofpatients inthehigh ratingand lowrating groups were plotted. We then used the change-in-estimate (CIE) method to filter out confounders and the inverse probability of treatment weighting (IPTW) to balance confounders between the two groups to assess the robustness of the results. Results: The median frequency of the combination treatment regimens administered in the overall population was 3 times (IQR 2.0-3.0). The optimal BRR truncation value calculated was -0.2. Based on this value, 77 patients were categorized as the low rating group and 34 as the high rating group. The differences in the OS between the high and low rating groups were statistically significant (7 months [95%CI 6.0-14.0] vs. 30 months [95%CI 30.0-]; p< 0.001). Using the absolute 10% cut-off value, the CIE method was used to screen out the following confounding factors affecting prognosis: successful conversion surgery, baseline tumor size, BCLC stage, serum total bilirubin level, number of interventional treatments, alpha-fetoprotein level, presence of inferior vena cava tumor thrombus, and partial thrombin activation time. The survival curve was then plotted again using IPTW for confounding factors, and it was found that the low rating group continued to have better OS than the high rating group. Finally, the relationship between BRR and baseline factors was analyzed, and inferior vena cava tumor thrombus and baseline tumor size correlated significantly with BRR. Conclusions: BRR can be used as a surrogate endpoint for OS in unresectable HCC patients undergoing FOLFOX-HAIC in combination with molecular targeting and immunotherapy. Thus, by calculating the BRR, the prognosis of HCC patients after combination therapy can be predicted. Inferior vena cava tumor thrombus and baseline tumor size were closely associated with the BRR. [ABSTRACT FROM AUTHOR]

• Many statistical approaches have been applied to vaccine efficacy (VE) trials to evaluate CoPs. • Four distinct statistical frameworks for evaluating CoPs in VE trials are summarized. • Criteria for a 'good CoP' according to the four frameworks are suggested. • This article constitutes a reference resource for promoting harmonization of CoP evaluation. A central goal of vaccine research is to characterize and validate immune correlates of protection (CoPs). In addition to helping elucidate immunological mechanisms, a CoP can serve as a valid surrogate endpoint for an infectious disease clinical outcome and thus qualifies as a primary endpoint for vaccine authorization or approval without requiring resource-intensive randomized, controlled phase 3 trials. Yet, it is challenging to persuasively validate a CoP, because a prognostic immune marker can fail as a reliable basis for predicting/inferring the level of vaccine efficacy against a clinical outcome, and because the statistical analysis of phase 3 trials only has limited capacity to disentangle association from cause. Moreover, the multitude of statistical methods garnered for CoP evaluation in phase 3 trials renders the comparison, interpretation, and synthesis of CoP results challenging. Toward promoting broader harmonization and standardization of CoP evaluation, this article summarizes four complementary statistical frameworks for evaluating CoPs in a phase 3 trial, focusing on the frameworks' distinct scientific objectives as measured and communicated by distinct causal vaccine efficacy parameters. Advantages and disadvantages of the frameworks are considered, dependent on phase 3 trial context, and perspectives are offered on how the frameworks can be applied and their results synthesized. [ABSTRACT FROM AUTHOR]

Background: Measurable residual disease (MRD) test positivity during and after treatment in patients with acute myeloid leukemia (AML) has been associated with higher rates of relapse and worse overall survival. Current approaches for MRD testing are not standardized leading to inconsistent results and poor prognostication of disease. Pertinent studies evaluating AML MRD testing at specific times points, with various therapeutics and testing methods are presented. Summary: AML is a set of diseases with different molecular and cytogenetic characteristics and is often polyclonal with evolution over time. This genetic diversity poses a great challenge for a single AML MRD testing approach. The current ELN 2021 MRD guidelines recommend MRD testing by quantitative polymerase chain reaction in those with a validated molecular target or multiparameter flow cytometry (MFC) in all other cases. The benefit of MFC is the ability to use this method across disease subsets, at the relative expense of suboptimal sensitivity and specificity. AML MRD detection may be improved with molecular methods. Genetic characterization at AML diagnosis and relapse is now standard of care for appropriate therapeutic assignment, and future initiatives will provide the evidence to support testing in remission to direct clinical interventions. Key Messages: The treatment options for patients with AML have expanded for specific molecular subsets such as FLT3 and IDH1/2 mutated AML, with development of novel agents for NPM1 mutated or KMT2A rearranged AML ongoing, but also due to effective venetoclax-combinations. Evidence regarding highly sensitive molecular MRD detection methods for specific molecular subgroups, in the context of these new treatment approaches, will likely shape the future of AML care. [ABSTRACT FROM AUTHOR]

Significant progress has been made in kidney transplantation, with 1-year graft survival nearing 95%. However, long-term allograft survival remains suboptimal, with a 10-year overall graft survival rate of only 53.6% for deceased donor transplant recipients. Chronic active antibody-mediated rejection (ABMR) is a leading cause of death-censored graft loss, yet no therapy has demonstrated efficacy in large, randomized trials, despite substantial investment from pharmaceutical companies. Several clinical trials aimed to treat chronic ABMR in the past decade have yielded disappointing results or were prematurely terminated, attributed to factors including incomplete understanding of disease mechanisms, heterogeneous patient populations with comorbidities, slow disease progression, and limited patient numbers. This review aims to discuss opportunities for improving retrospective and prospective studies of ABMR, focusing on addressing heterogeneity, outcome measurement, and strategies to enhance patient enrollment to inform study design, data collection, and reporting.

Abstract Background The increasing number of sequential treatments complicates the evaluation of overall survival (OS) in clinical trials for hepatocellular carcinoma (HCC), therefore, reliable surrogate endpoints (SEs) are required. This study aimed to evaluate the surrogacy of progression-free survival (PFS) and one-year (1-yr) milestone survival for OS in HCC trials. Methods We systematically searched databases for randomized clinical trials that evaluated systemic treatments for advanced HCC. Individual patient data were reconstructed to calculate the 1-yr survival rate. We adopted a two-stage meta-analytic validation model to evaluate the correlation between SEs and OS, and the correlation between treatment effects on SEs and OS. The hazard ratio (HR) was calculated to assess the treatment effects on PFS and OS, and the 1-yr survival ratio was calculated to evaluate the treatment effects on the 1-yr milestone survival. Results Thirty-two HCC trials involving 13,808 patients were included. A weak correlation was detected between the median PFS and median OS (R2 = 0.32), whereas the correlation improved between PFS HR and OS HR (R2 = 0.58). We identified strong correlations between the 1-yr survival rate and median OS and between the 1-yr survival ratio and OS HR (R2 = 0.74 and 0.65, respectively). In subgroup analyses, PFS HR strongly correlated with OS HR in trials relevant to immune checkpoint inhibitors (ICIs). Although the correlation remained weak between PFS and OS even in trials with PFS HR ≤ 0.6, the 1-yr survival rate and 1-yr survival ratio were strong surrogates for median OS and OS HR, respectively (R2 = 0.77 and 0.75). Conclusions One-year milestone survival outperformed PFS as a SE for OS in HCC, indicating the application of 1-yr survival as a secondary endpoint. In particular, PFS HR was a potential SE for OS HR in the ICI trials.

Abstract Background Surrogate endpoints, such as those of interest in chronic kidney disease (CKD), are often evaluated using Bayesian meta-regression. Trials used for the analysis can evaluate a variety of interventions for different sub-classifications of disease, which can introduce two additional goals in the analysis. The first is to infer the quality of the surrogate within specific trial subgroups defined by disease or intervention classes. The second is to generate more targeted subgroup-specific predictions of treatment effects on the clinical endpoint. Methods Using real data from a collection of CKD trials and a simulation study, we contrasted surrogate endpoint evaluations under different hierarchical Bayesian approaches. Each approach we considered induces different assumptions regarding the relatedness (exchangeability) of trials within and between subgroups. These include partial-pooling approaches, which allow subgroup-specific meta-regressions and, yet, facilitate data adaptive information sharing across subgroups to potentially improve inferential precision. Because partial-pooling models come with additional parameters relative to a standard approach assuming one meta-regression for the entire set of studies, we performed analyses to understand the impact of the parameterization and priors with the overall goals of comparing precision in estimates of subgroup-specific meta-regression parameters and predictive performance. Results In the analyses considered, partial-pooling approaches to surrogate endpoint evaluation improved accuracy of estimation of subgroup-specific meta-regression parameters relative to fitting separate models within subgroups. A random rather than fixed effects approach led to reduced bias in estimation of meta-regression parameters and in prediction in subgroups where the surrogate was strong. Finally, we found that subgroup-specific meta-regression posteriors were robust to use of constrained priors under the partial-pooling approach, and that use of constrained priors could facilitate more precise prediction for clinical effects in trials of a subgroup not available for the initial surrogacy evaluation. Conclusion Partial-pooling modeling strategies should be considered for surrogate endpoint evaluation on collections of heterogeneous studies. Fitting these models comes with additional complexity related to choosing priors. Constrained priors should be considered when using partial-pooling models when the goal is to predict the treatment effect on the clinical endpoint.

Background: The increasing number of sequential treatments complicates the evaluation of overall survival (OS) in clinical trials for hepatocellular carcinoma (HCC), therefore, reliable surrogate endpoints (SEs) are required. This study aimed to evaluate the surrogacy of progression-free survival (PFS) and one-year (1-yr) milestone survival for OS in HCC trials. Methods: We systematically searched databases for randomized clinical trials that evaluated systemic treatments for advanced HCC. Individual patient data were reconstructed to calculate the 1-yr survival rate. We adopted a two-stage meta-analytic validation model to evaluate the correlation between SEs and OS, and the correlation between treatment effects on SEs and OS. The hazard ratio (HR) was calculated to assess the treatment effects on PFS and OS, and the 1-yr survival ratio was calculated to evaluate the treatment effects on the 1-yr milestone survival. Results: Thirty-two HCC trials involving 13,808 patients were included. A weak correlation was detected between the median PFS and median OS (R2 = 0.32), whereas the correlation improved between PFS HR and OS HR (R2 = 0.58). We identified strong correlations between the 1-yr survival rate and median OS and between the 1-yr survival ratio and OS HR (R2 = 0.74 and 0.65, respectively). In subgroup analyses, PFS HR strongly correlated with OS HR in trials relevant to immune checkpoint inhibitors (ICIs). Although the correlation remained weak between PFS and OS even in trials with PFS HR ≤ 0.6, the 1-yr survival rate and 1-yr survival ratio were strong surrogates for median OS and OS HR, respectively (R2 = 0.77 and 0.75). Conclusions: One-year milestone survival outperformed PFS as a SE for OS in HCC, indicating the application of 1-yr survival as a secondary endpoint. In particular, PFS HR was a potential SE for OS HR in the ICI trials. [ABSTRACT FROM AUTHOR]

Background: Surrogate endpoints, such as those of interest in chronic kidney disease (CKD), are often evaluated using Bayesian meta-regression. Trials used for the analysis can evaluate a variety of interventions for different sub-classifications of disease, which can introduce two additional goals in the analysis. The first is to infer the quality of the surrogate within specific trial subgroups defined by disease or intervention classes. The second is to generate more targeted subgroup-specific predictions of treatment effects on the clinical endpoint. Methods: Using real data from a collection of CKD trials and a simulation study, we contrasted surrogate endpoint evaluations under different hierarchical Bayesian approaches. Each approach we considered induces different assumptions regarding the relatedness (exchangeability) of trials within and between subgroups. These include partial-pooling approaches, which allow subgroup-specific meta-regressions and, yet, facilitate data adaptive information sharing across subgroups to potentially improve inferential precision. Because partial-pooling models come with additional parameters relative to a standard approach assuming one meta-regression for the entire set of studies, we performed analyses to understand the impact of the parameterization and priors with the overall goals of comparing precision in estimates of subgroup-specific meta-regression parameters and predictive performance. Results: In the analyses considered, partial-pooling approaches to surrogate endpoint evaluation improved accuracy of estimation of subgroup-specific meta-regression parameters relative to fitting separate models within subgroups. A random rather than fixed effects approach led to reduced bias in estimation of meta-regression parameters and in prediction in subgroups where the surrogate was strong. Finally, we found that subgroup-specific meta-regression posteriors were robust to use of constrained priors under the partial-pooling approach, and that use of constrained priors could facilitate more precise prediction for clinical effects in trials of a subgroup not available for the initial surrogacy evaluation. Conclusion: Partial-pooling modeling strategies should be considered for surrogate endpoint evaluation on collections of heterogeneous studies. Fitting these models comes with additional complexity related to choosing priors. Constrained priors should be considered when using partial-pooling models when the goal is to predict the treatment effect on the clinical endpoint. [ABSTRACT FROM AUTHOR]

Background: An analysis of European and American individuals revealed that a reduction in estimated glomerular filtration rate (eGFR) slope by 0.5 to 1.0 mL/min/1.73 m2 per year is a surrogate endpoint for end-stage kidney disease (ESKD) in patients with early chronic kidney disease. However, it remains unclear whether this can be extrapolated to Japanese patients. Methods: Using data from the Japan diabetes comprehensive database project based on an advanced electronic medical record system (J-DREAMS) cohort of 51,483 Japanese patients with diabetes and a baseline eGFR ≥ 30 mL/min/1.73 m2, we examined whether the eGFR slope could be a surrogate indicator for ESKD. The eGFR slope was calculated at 1, 2, and 3 years, and the relationship between each eGFR slope and ESKD risk was estimated using a Cox proportional hazards model to obtain adjusted hazard ratios (aHRs). Results: Slower eGFR decline by 0.75 mL/min/1.73 m2/year reduction in 1-, 2-, and 3-year slopes was associated with lower risk of ESKD (aHR 0.93 (95% confidence interval (CI) 0.92–0.95), 0.84 (95% CI 0.82–0.86), and 0.77 (95% CI 0.73–0.82), respectively); this relationship became more apparent as the slope calculation period increased. Similar results were obtained in subgroup analyses divided by baseline eGFR or baseline urine albumin-creatinine ratio (UACR), with a stronger correlation with ESKD in the baseline eGFR < 60 mL/min/1.73 m2 group and in the baseline UACR < 30 mg/gCre group. Conclusion: We found that changes in the eGFR slope were associated with ESKD risk in this population. [ABSTRACT FROM AUTHOR]

Background: Individual-level surrogates are important for management in patients treated for advanced gastric cancer (AGC). This study aimed to comprehensively investigate the correlation of multiple clinical endpoints in the first-line chemotherapy of AGC. Methods: Individual patient data (IPD) were collected from four Japanese Phase III trials comparing S-1-based first-line chemotherapies (SPIRITS, START, GC0301/TOP-002, and G-SOX trials). Patients without Response Evaluation Criteria in Solid Tumors (RECIST)-based radiological assessments were excluded. Spearman's rank correlation coefficient was tested for correlation among overall survival (OS), progression-free survival (PFS), and postprogression survival (PPS). OS, PFS, and PPS were compared between responders (best response: complete response or partial response) and nonresponders (best response: stable disease or progressive disease). Results: The study included a total of 1492 patients. Eighty percent of the patients (n=1190) received subsequent chemotherapies after the failure of each trial's treatment protocol. PFS moderately correlated with OS (Spearman correlation coefficient=0.66, p<0.005), whereas the correlation between PPS and OS was strong (Spearman correlation coefficient=0.87, p<0.005). Responders had significantly longer OS (median, 17.7 vs. 9.1months, p<0.005), PFS (median, 6.9 vs. 2.8months, p<0.005), and PPS (median, 10.5 vs. 6.0months, p<0.005) than nonresponders. Conclusions: Our results reacknowledged the mild surrogacy of PFS and importance of postprogression treatments in patients with AGC receiving first-line chemotherapy. Consistent longer survival outcomes in better RECIST categories suggested that tumor response might be a useful individual-level surrogate. [ABSTRACT FROM AUTHOR]

We wanted to evaluate if event-free survival (EFS) is a reliable surrogate for overall survival (OS) in patients with resectable non-small cell lung cancer (r-NSCLC) receiving neoadjuvant therapy. We conducted a systematic literature review and meta-analysis to investigate the statistical association between EFS and OS. Electronic databases were searched on 30 July 2021 to identify sources reporting both EFS and OS data in patients with stage I–IIIB r-NSCLC receiving neoadjuvant therapy. Correlation and regression analyses evaluated the association between the effect of treatment on EFS and OS using log-hazard ratios (HRs). Sources in which the entire population had epidermal growth factor receptor mutations were excluded from the analyses. We identified 74 sources, of which 8 reported EFS and OS HRs from randomized controlled trials. Based on these, we found a positive linear correlation and a strong association between EFS and OS log-HRs (weighted Pearson's correlation coefficient r = 0.864; 95% confidence interval 0.809–0.992; P = 0.006; random-effects meta-regression, R2 = 0.777). We found a strong association between treatment effects for EFS and OS, indicating that improvements in EFS are likely to be predictive of improvements in OS. EFS may therefore be a reliable surrogate for OS after neoadjuvant therapy in r-NSCLC. [ABSTRACT FROM AUTHOR]

Purpose: Patients with locally advanced or metastatic differentiated thyroid cancer (DTC) have a variable prognosis, and the development of more effective treatment strategies is an important research topic. Overall survival (OS) is the gold standard for research endpoints in randomized controlled trials (RCTs), but observing an OS benefit requires the inclusion of a large number of patients and a long follow-up period. In this study, we aimed to investigate whether progression-free survival (PFS) could be used as a surrogate endpoint for OS in locally advanced or metastatic DTC clinical trials. Materials and methods: We conducted a search in the PubMed and EMBASE databases to include all RCTs of locally advanced or metastatic DTC and extracted survival data. A weighted linear regression analysis was performed to explore the correlation between PFS benefit and OS benefit by taking the logarithm of the hazard ratios (HRs) of PFS and OS for each trial with a base of 10 and weighted by the number of patients in each RCT. Results: Seven RCTs, including 1410 patients, were included. At the trial level, PFS benefit was weakly correlated with OS benefit (R2 = 0.210, 95% CI: 0.000–0.811) and did not meet the statistical criteria for the surrogate endpoint. Conclusion: This study does not support PFS as a surrogate endpoint for OS in locally advanced or metastatic DTC clinical trials. Trial registration: PROSPERO Identifier: CRD42022334898 [ABSTRACT FROM AUTHOR]

A traditional phase 3 clinical efficacy study for a Zika vaccine may be unfeasible because of the current low transmission of Zika virus (ZIKV). An alternative clinical development approach to evaluate Zika vaccine efficacy (VE) is therefore required, delineated in the US FDA’s Accelerated Approval Program for licensure, which utilizes an anti-Zika neutralizing antibody (Zika NAb) titer correlated with non-human primate (NHP) protection as a surrogate endpoint. In this accelerated approval approach, the estimation of VE would be inferred from the percentage of phase 3 trial participants achieving the established surrogate endpoint. We provide a statistical framework to predict the probability of protection for human participants vaccinated with a purified inactivated ZIKV vaccine (TAK-426), in the absence of VE measurements, using NHP data under a single-correlate model. Based on a logistic regression (LR) with bias-reduction model, a probability of 90% protection in humans is expected with a ZIKV NAb geometric mean titer (GMT) ≥ 3.38 log10 half-maximal effective concentration (EC50). The predicted probability of protection of TAK-426 against ZIKV infection was determined using the two-parameter LR model that fit the calculated VE in rhesus macaques and the flavivirus-naïve phase 1 trial participants’ ZIKV NAb GMTs log10 EC50, measured by a ZIKV reporter virus particle assay, at 1 month post dose 2. The TAK-426 10 µg dose predicted a probability of protection from infection of 98% among flavivirus-naïve phase 1 trial participants.

Rigorous evaluation of surrogate endpoints is performed in a trial‐level analysis in which the strength of the association between treatment effects on the clinical and surrogate endpoints is quantified across a collection of previously conducted trials. To reduce bias in measures of the performance of the surrogate, the statistical model must account for the sampling error in each trial's estimated treatment effects and their potential correlation. Unfortunately, these within‐study correlations can be difficult to obtain, especially for meta‐analysis of published trial results where individual patient data is not available. As such, these terms are frequently partially or completely missing in the analysis. We show that improper handling of these missing terms can meaningfully alter the perceived quality of the surrogate and we introduce novel strategies to handle the missingness. [ABSTRACT FROM AUTHOR]

Background: Pathological response is a critical factor in predicting long-term survival of patients with esophageal cancer after preoperative therapy. However, the validity of using pathological response as a surrogate for overall survival (OS) for esophageal cancer has not yet been established. In this study, a literature-based meta-analysis was conducted to evaluate pathological response as a proxy endpoint for survival in esophageal cancer. Methods: Three databases were systematically searched to identify relevant studies investigating neoadjuvant treatment for esophageal cancer. The correlation between pathological complete response (pCR) and OS were assessed using a weighted multiple regression analysis at the trial level, and the coefficient of determination (R2) was calculated. The research design and histological subtypes were considered in the performance of subgroup analysis. Results: In this meta-analysis, a total of 40 trials, comprising 43 comparisons and 55,344 patients were qualified. The surrogacy between pCR and OS was moderate (R2 = 0.238 in direct comparison, R2 = 0.500 for pCR reciprocals, R2 = 0.541 in log settings). pCR could not serve as an ideal surrogate endpoint in randomized controlled trials (RCTs) (R2 = 0.511 in direct comparison, R2 = 0.460 for pCR reciprocals, R2 = 0.523 in log settings). A strong correlation was observed in studies comparing neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy (R2 = 0.595 in direct comparison, R2 = 0.840 for pCR reciprocals, R2 = 0.800 in log settings). Conclusions: A lack of surrogacy of pathological response for long-term survival at trial level is established in this study. Hence, caution should be exercised when using pCR as the primary endpoint in neoadjuvant studies for esophageal cancer. [ABSTRACT FROM AUTHOR]

Background: In clinical trials targeting early chronic kidney disease (CKD), eGFR slope has been proposed as a surrogate endpoint for predicting end-stage kidney disease (ESKD). However, it is unclear whether the eGFR slope serves as a surrogate endpoint for predicting long-term prognosis in Japanese early CKD populations. Methods: The data source was the J-CKD-Database, which contains real-world data on patients with CKD in Japan. eGFR slope was calculated from the eGFR of each period, 1-year (1-year slope), 2-year (2-year slope), and 3-year (3-year slope), for participants with a baseline eGFR ≥ 30 ml/min/1.73 m2. The outcome was ESKD (defined as dialysis initiation or incidence of CKD stage G5). The relationship between eGFR slope and the sub-distribution hazard ratio (SHR) of ESKD with death as a competing event was investigated using a Fine-Gray proportional hazard regression model. Results: The number of participants and mean observation periods were 7768/877 ± 491 days for 1-year slope, 6778/706 ± 346 days for 2-year slope, and 5219/495 ± 215 days for 3-year slope. As the eGFR slope decreased, a tendency toward a lower risk of ESKD was observed. Compared with the 1-year slope, there was a smaller variation in the slope values for the 2-year or 3-year slope and a greater decrease in the SHR; therefore, a calculation period of 2 or 3 years for the eGFR slope was considered appropriate. Conclusion: Even in Japanese patients with early stage CKD, a slower eGFR slope calculated from eGFR values over 2–3 years was associated with a decreased risk of ESKD. [ABSTRACT FROM AUTHOR]

Summary: Background: Cancer immunotherapy shows unique efficacy kinetics that differs from conventional treatment. These characteristics may lead to the prolongation of trial duration, hence reliable surrogate endpoints are urgently needed. We aimed to systematically evaluate the study-level performance of commonly reported intermediate clinical endpoints for surrogacy in cancer immunotherapy. Methods: We searched the Embase, PubMed, and Cochrane databases, between database inception and October 18, 2022, for phase 3 randomised trials investigating the efficacy of immunotherapy in patients with advanced solid tumours. An updated search was done on July, 15, 2023. No language restrictions were used. Eligible trials had to set overall survival (OS) as the primary or co-primary endpoint and report at least one intermediate clinical endpoint including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and 1-year overall survival. Other key inclusion and exclusion criteria included: (1) adult patients (>18 years old) with advanced solid tumour; (2) no immunotherapy conducted in the control arms; (3) follow-up is long enough to achieve OS; (4) data should be public available. A two-stage meta-analytic approach was conducted to evaluate the magnitude of the association between these intermediate endpoints and OS. A surrogate was identified if the coefficient of determination (R2) was 0.7 or greater. Leave-one-out cross-validation and pre-defined subgroup analysis were conducted to examine the heterogeneity. Potential publication bias was evaluated using the Egger's and Begg's tests. This trial was registered with PROSPERO, number CRD42022381648. Findings: 52,342 patients with 15 types of tumours from 77 phase 3 studies were included. ORR (R2 = 0.11; 95% CI, 0.00–0.24), DCR (R2 = 0.01; 95% CI, 0.00–0.01), and PFS (R2 = 0.40; 95% CI, 0.23–0.56) showed weak associations with OS. However, a strong correlation was observed between 1-year survival and clinical outcome (R2 = 0.74; 95% CI, 0.64–0.83). These associations remained relatively consistent across pre-defined subgroups stratified based on tumour types, masking methods, line of treatments, drug targets, treatment strategies, and follow-up durations. No significant heterogeneities or publication bias were identified. Interpretation: 1-year milestone survival was the only identified surrogacy endpoint for outcomes in cancer immunotherapy. Ongoing investigations and development of new endpoints and incorporation of biomarkers are needed to identify potential surrogate markers that can be more robust than 1-year survival. This work may provide important references in assisting the design and interpretation of future clinical trials, and constitute complementary information in drafting clinical practice guidelines. Funding: None.

In large epidemiologic studies, it is typical for an inexpensive, non-invasive procedure to be used to record disease status during regular follow-up visits, with less frequent assessment by a gold standard test. Inexpensive outcome measures like self-reported disease status are practical to obtain, but can be error-prone. Association analysis reliant on error-prone outcomes may lead to biased results; however, restricting analyses to only data from the less frequently observed error-free outcome could be inefficient. We have developed an augmented likelihood that incorporates data from both error-prone outcomes and a gold standard assessment. We conduct a numerical study to show how we can improve statistical efficiency by using the proposed method over standard approaches for interval-censored survival data that do not leverage auxiliary data. We extend this method for the complex survey design setting so that it can be applied in our motivating data example. Our method is applied to data from the Hispanic Community Health Study/Study of Latinos to assess the association between energy and protein intake and the risk of incident diabetes. In our application, we demonstrate how our method can be used in combination with regression calibration to additionally address the covariate measurement error in self-reported diet. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) admission is used as a study endpoint in clinical trials. However, it remains unclear whether it can be a valid surrogate endpoint for mortality. Objectives: To validate whether HF admission is a valid surrogate for mortality. Methods: In PubMed and EMBASE, randomized controlled trials (RCTs) of interventions to treat patients with heart failure at the enrolment were searched on 13 April 2022. We extracted RCTs in which event numbers of both HF admission and all‐cause mortality were reported as either primary or secondary outcomes. Trial‐level correlations (R‐squared) between HF admission and mortality were assessed. We performed subgroup analyses by study year, follow‐up duration, baseline HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF), and whether the intervention was pharmacological. We followed the Preferred Reporting Items for Systematic Reviews and Meta‐analyses guideline. Results: A total of 117 RCTs met the criteria for inclusion. Overall, the trial‐level R‐squared between HF admission and all‐cause mortality was 0.39 (95% confidence interval (CI), 0.26 to 0.53). However, in the subgroup analyses, the trial‐level R‐squared was increased when the follow‐up duration was ≥24 months (0.70 [95% CI: 0.55, 0.85]), when intervention was pharmacological (0.51 [95% CI: 0.34, 0.68]) and when the baseline HF type was HFrEF (0.57 [95% CI: 0.42, 0.73]). Conclusions: Our findings indicate that HF admission may not always be a valid surrogate for mortality in patients with HF. Rather, the surrogacy of HF admission may be dependent on clinical background and interventions. [ABSTRACT FROM AUTHOR]

Objective: Traditionally, validation of surrogate endpoints has been carried out using randomized controlled trial (RCT) data. However, RCT data may be too limited to validate surrogate endpoints. In this article, we sought to improve the validation of surrogate endpoints with the inclusion of real-world evidence (RWE). Methods: We use data from comparative RWE (cRWE) and single-arm RWE (sRWE) to supplement RCT evidence for the evaluation of progression-free survival (PFS) as a surrogate endpoint to overall survival (OS) in metastatic colorectal cancer (mCRC). Treatment effect estimates from RCTs, cRWE, and matched sRWE, comparing antiangiogenic treatments with chemotherapy, were used to inform surrogacy patterns and predictions of the treatment effect on OS from the treatment effect on PFS. Results: Seven RCTs, 4 cRWE studies, and 2 matched sRWE studies were identified. The addition of RWE to RCTs reduced the uncertainty around the estimates of the parameters for the surrogate relationship. The addition of RWE to RCTs also improved the accuracy and precision of predictions of the treatment effect on OS obtained using data on the observed effect on PFS. Conclusion: The addition of RWE to RCT data improved the precision of the parameters describing the surrogate relationship between treatment effects on PFS and OS and the predicted clinical benefit of antiangiogenic therapies in mCRC. Highlights: Regulatory agencies increasingly rely on surrogate endpoints when making licensing decisions, and for the decisions to be robust, surrogate endpoints need to be validated. In the era of precision medicine, when surrogacy patterns may depend on the drug's mechanism of action and trials of targeted therapies may be small, data from randomized controlled trials may be limited. Real-world evidence (RWE) is increasingly used at different stages of the drug development process. When used to enhance the evidence base for surrogate endpoint evaluation, RWE can improve inferences about the strength of surrogate relationships and the precision of predicted treatment effect on the final clinical outcome based on the observed effect on the surrogate endpoint in a new trial. Careful selection of RWE is needed to reduce risk of bias. [ABSTRACT FROM AUTHOR]

Abstract Objective This study aims to systematically validate the performance of surrogate endpoints in phase II and III clinical trials for NSCLC patients under various trial settings. Methods A literature search retrieved all registered phase II and III trials of NSCLC patients in which OS, with at least one of ORR and PFS, were reported. Associations between surrogate and true endpoints were assessed on two levels. On the arm level, three pairs of correlations, i.e., ORR vs. median OS, ORR vs. median PFS, and median PFS vs. median OS, were analysed using Spearman’s rho. On the trial level, similarly, three pairs of correlations, i.e., ΔORR vs. HR of OS, ΔORR vs. HR of PFS, and HR of PFS vs. HR of OS, were analysed using Spearman’s rho and weighted linear regression model respectively. Finally, sensitivity analyses were performed to explore surrogacy under various trial settings. Results At arm level, three pairs of correlations are all high (Spearman’s rho = 0.700, 0.831, 0.755, respectively). At trial level, there is a low correlation between ΔORR and HR of OS, a high correlation between ΔORR and HR of PFS and a moderate correlation between HR of PFS and HR of OS (Spearman’s rho = 0.462, 0.764, 0.584, respectively). In the sensitivity analysis, we find correlations between surrogate and true endpoints vary by different trial settings. It is noteworthy that the strength of surrogacy of these intermediate endpoints in targeted therapy is greater than that in immunotherapy. Conclusion According to the arm-level and trial level-analysis, we suggest that in phase II and III trials of targeted therapy and immunotherapy for NSCLC patients: 1) ORR lacks validity for the surrogacy of OS, excluding in first-line therapy, and 2) ORR may be an appropriate surrogate endpoint for PFS, and 3) PFS may be considered a modest surrogacy for OS, with better performance in first-line therapy trials. Moreover, to provide more convincing evidence of surrogacy of the surrogate endpoints, patient-level analyses are in desperate need.

Objective: To analyze whether other outcome measures used in health technology assessment (HTA) address the criticisms of quality‐adjusted life years (QALYs). Data Sources and Study Setting: HTA methods guidance from 11 US comparator countries (the G10 and Australia) and six value frameworks from US organizations were reviewed to identify health outcome measures currently used to evaluate the benefits of a drug. Study Design: The study involved a documentary analysis of guidelines to identify outcome measures used by the sampled HTA organizations. Similar outcomes were grouped together into outcome types. Each type was analyzed to determine the extent to which it replicates key advantages and responds to criticisms of QALYs extracted from the literature. Extraction Methods: Outcomes were included if guidance from at least one HTA organization identified the outcome as acceptable for HTA. Outcomes measuring or evaluating the benefit, clinical effect, or impact of a drug or health technology was included; methods of calculating costs were excluded. Principal Findings: Seven types of outcome measures were identified falling into three groups: preference‐based, single‐dimension outcomes, and outcomes using non‐health perspectives. Among the seven QALY alternative outcome measures currently used for HTA by the sampled countries, no one outcome measure addresses all the QALY criticisms while retaining the advantageous features of the QALY. Conclusions: Proposals to adopt health technology assessment (HTA) to support value‐based pricing of prescription drugs in the US have faced pushback over the use of the QALY. There is no single "right" outcome measure, and the criticisms of QALYs apply to other outcome measures used to evaluate health. The measures identified have different features and strengths, which may be appropriate for specific decision making goals, but the QALY remains the best option for decision making that requires comparisons of the overall societal value of health gains. [ABSTRACT FROM AUTHOR]

The new European Union (EU) Regulations for medical devices (MDs) and health technology assessment (HTA) are welcome developments that should increase the quality of clinical evidence for MDs and reduce fragmentation in the EU market access process. To fully exploit anticipated benefits, their respective assessment processes should be closely coordinated, particularly for promising, highly innovative MDs. Accelerated approval is worth exploring for certain categories of high-risk MDs to keep the EU regulatory process competitive compared to accelerated MD approval programs elsewhere (e.g. US). Problems observed in worldwide accelerated drug and MD regulatory approval programs are reviewed, including greater uncertainty in premarket clinical evidence generation and lack of oversight for post approval evidence requirements. Implications for MD approval, HTA and coverage are explored. Through analysis of two decades of drug and MD accelerated approval programs worldwide, recommendations for an Accelerated Access Pathway for select innovative, high-risk MDs are proposed to fit the EU context, leverage the two new regulations, increase opportunities for Expert Panels to provide timely advice regarding manufacturers' evidence generation plans along the MD lifecycle (pre, postmarket), and safely speed patient access while promoting increased collaboration among Member States on coverage decisions. [ABSTRACT FROM AUTHOR]

Measurable residual disease (MRD) is defined as the presence of residual cancer cells after treatment in patients with clinically undetectable disease, who would otherwise be considered in complete remission. It is a highly sensitive parameter which indicates the disease burden and predicts survival in this setting of patients. In recent years, MRD has gained a role in many hematological malignancies as a surrogate endpoint for clinical trials: undetectable MRD has been correlated to longer progression free survival (PFS) and overall survival (OS). New drugs and combinations have been developed with the aim to achieve MRD negativity, which would indicate favorable prognosis. Different methods to measure MRD have also been devised, which include flow cytometry, polymerase chain reaction (PCR) and next generation sequencing (NGS), with different sensitivity and accuracy in evaluating deep remission after treatment. In this review, we will analyze the current recommendations for the detection of MRD, with particular focus on its role in Chronic Lymphocytic Leukemia (CLL), as well as the different detection methods. Moreover, we will discuss the results of clinical trials and the role of MRD in new therapeutic schemes with inhibitors and monoclonal antibodies. MRD is not currently used in the clinical practice to evaluate response to treatment, due to technical and economical limitations, but it's gaining more and more interest in trials settings, especially since the introduction of venetoclax. The use of MRD in trials will likely be followed by a broader practical application in the future. The aim of this work is to provide a reader-friendly summary of the state of art in the field, as MRD will soon become an accessible tool to evaluate our patients, predict their survival and guide physician's therapeutic choices and preferences. [ABSTRACT FROM AUTHOR]

BackgroundImproved prediction of Parkinson's disease (PD) progression is needed to support clinical decision-making and to accelerate research trials.ObjectivesTo examine whether baseline measures and their 1-year change predict longer-term progression in early PD.MethodsParkinson's Progression Markers Initiative study data were used. Participants had disease duration ≤2 years, abnormal dopamine transporter (DAT) imaging, and were untreated with PD medications. Baseline and 1-year change in clinical, cerebrospinal fluid (CSF), and imaging measures were evaluated as candidate predictors of longer-term (up to 5 years) change in Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score and DAT specific binding ratios (SBR) using linear mixed-effects models.ResultsAmong 413 PD participants, median follow-up was 5 years. Change in MDS-UPDRS from year-2 to last follow-up was associated with disease duration (β= 0.351; 95% CI = 0.146, 0.555), male gender (β= 3.090; 95% CI = 0.310, 5.869), and baseline (β= -0.199; 95% CI = -0.315, -0.082) and 1-year change (β= 0.540; 95% CI = 0.423, 0.658) in MDS-UPDRS; predictors in the model accounted for 17.6% of the variance in outcome. Predictors of percent change in mean SBR from year-2 to last follow-up included baseline rapid eye movement sleep behavior disorder score (β= -0.6229; 95% CI = -1.2910, 0.0452), baseline (β= 7.232; 95% CI = 2.268, 12.195) and 1-year change (β= 45.918; 95% CI = 35.994,55.843) in mean striatum SBR, and 1-year change in autonomic symptom score (β= -0.325;95% CI = -0.695, 0.045); predictors in the model accounted for 44.1% of the variance.ConclusionsBaseline clinical, CSF, and imaging measures in early PD predicted change in MDS-UPDRS and dopamine-transporter binding, but the predictive value of the models was low. Adding the short-term change of possible predictors improved the predictive value, especially for modeling change in dopamine-transporter binding.

Abstract Aims No biomarker has achieved widespread acceptance as a surrogate endpoint for early‐phase heart failure (HF) trials. We assessed whether changes over time in a panel of plasma biomarkers were associated with subsequent morbidity/mortality in HF with reduced ejection fraction (HFrEF). Methods and results In 1040 patients with HFrEF from the BIOSTAT‐CHF cohort, we investigated the associations between changes in the plasma concentrations of 30 biomarkers, before (baseline) and after (9 months) attempted optimization of guideline‐recommended therapy, on top of the BIOSTAT risk score and the subsequent risk of HF hospitalization/all‐cause mortality using Cox regression models. C‐statistics were calculated to assess discriminatory power of biomarker changes/month‐nine assessment. Changes in N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and WAP four‐disulphide core domain protein HE4 (WAP‐4C) were the only independent predictors of the outcome after adjusting for their baseline plasma concentration, 28 other biomarkers (both baseline and changes), and BIOSTAT risk score at baseline. When adjusting for month‐nine rather than baseline biomarkers concentrations, only changes in NT‐proBNP were independently associated with the outcome. The C‐statistic of the model including the BIOSTAT risk score and NT‐proBNP increased by 4% when changes were considered on top of baseline concentrations and by 1% when changes in NT‐proBNP were considered on top of its month‐nine concentrations and the BIOSTAT risk score. Conclusions Among 30 relevant biomarkers, a change over time was significantly and independently associated with HF hospitalization/all‐cause death only for NT‐proBNP. Changes over time were modestly more prognostic than baseline or end‐values alone. Changes in biomarkers should be further explored as potential surrogate endpoints in early phase HF trials.

The introduction of new and more effective therapeutic options for Multiple Myeloma (MM) has significantly deepened and prolonged patients’ remission. As currently used treatment protocols induce high rates of complete responses, Measurable Residual Disease (MRD) assessment has become essential to enhance the evaluation of treatment efficacy. Detection of MRD has improved with the development of highly sensitive and standardized techniques such as Next Generation Flow or Next Generation Sequencing, complemented by functional imaging techniques. These advances offer a valuable opportunity to further optimize criteria of response to treatment. Currently, extensive data demonstrate that MRD status is a valuable prognostic factor of survival. Since MRD represents a real measurement of disease burden, its incorporation in clinical trials to guide treatment decisions will certainly translate into clinical benefits. Sustained MRD negativity can be used to consider optimal candidates for treatment discontinuation, whereas MRD positive high-risk patients may have access to novel immunotherapeutic strategies such as bispecific drugs or CAR T cell therapy. In this review, we describe the available techniques to detect MRD, address the current data regarding MRD as a surrogate endpoint within clinical trials, examine how MRD can be introduced into the clinical management of MM patients, and discuss the future of MRD monitoring.

IntroductionChronic kidney disease (CDK) progression studies increasingly use surrogate endpoints based on the estimated glomerular filtration rate. The clinical characteristics of these endpoints bring new challenges in comparing groups of patients, as traditional Cox models may lead to biased estimates mainly because they do not assume a hazard function.ObjectiveThis study proposes the use of parametric survival analysis models with the three most commonly used endpoints in nephrology based on a case study. Estimated glomerular filtration rate (eGFR) decay > 5 mL/year, eGFR decline > 30%, and change in CKD stage were evaluated.MethodThe case study is a 5-year retrospective cohort study that enrolled 778 patients in the predialysis stage. Exponential, Weibull, Gompertz, lognormal, and logistic models were compared, and proportional hazard and accelerated failure time (AFT) models were evaluated.ResultsThe endpoints had quite different hazard functions, demonstrating the importance of choosing appropriate models for each. AFT models were more suitable for the clinical interpretation of the effects of covariates on these endpoints.ConclusionSurrogate endpoints have different hazard distributions over time, which is already recognized by nephrologists. More flexible analysis techniques that capture these relevant clinical characteristics in decision-making should be encouraged and disseminated in nephrology research.

Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy. We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization. Median OS was 21.6 months (95% CI 18.6–24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7–12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49–0.76; p < 0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51–0.72; p < 0.001 and HR 0.50; 95% CI 0.39–0.65; p < 0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49–0.76; p < 0.001), 4-month (HR 0.63; 95% CI 0.51–0.80; p < 0.001), and 6-month (HR 0.68; 95% CI 0.54–0.86; p < 0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44–0.68; p < 0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38–0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC. Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease. NCT01761266. This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival. [Display omitted] • A post hoc analysis of REFLECT: Is objective response associated with OS in uHCC? • In lenvatinib- or sorafenib-treated patients, OS was assessed by response status using landmark analyses per the Simon-Makuch method. • Responders had longer median OS (21.6 months) vs nonresponders (11.9 months). • Responders had significantly prolonged OS by response status at 2, 4, and 6 months. • Objective response was an independent predictor of OS in individuals with uHCC. [ABSTRACT FROM AUTHOR]

Abstract Background Interstitial lung disease (ILD) is a common organ manifestation in systemic sclerosis (SSc) and is the leading cause of death in patients with SSc. A decline in forced vital capacity (FVC) is an indicator of ILD progression and is associated with mortality in patients with SSc-associated ILD (SSc-ILD). However, the relationship between FVC decline and hospitalisation events in patients with SSc-ILD is largely unknown. The objective of this post hoc analysis was to investigate the relationship between FVC decline and clinically important hospitalisation endpoints. Methods We used data from SENSCIS®, a phase III trial investigating the efficacy and safety of nintedanib in patients with SSc-ILD. Joint models for longitudinal and time-to-event data were used to assess the association between rate of decline in FVC% predicted and hospitalisation-related endpoints (including time to first all-cause hospitalisation or death; time to first SSc-related hospitalisation or death; and time to first admission to an emergency room [ER] or admission to hospital followed by admission to intensive care unit [ICU] or death) during the treatment period, over 52 weeks in patients with SSc-ILD. Results There was a statistically significant association between FVC decline and the risk of all-cause (n = 78) and SSc-related (n = 42) hospitalisations or death (both P < 0.0001). A decrease of 3% in FVC corresponded to a 1.43-fold increase in risk of all-cause hospitalisation or death (95% confidence interval [CI] 1.24, 1.65) and a 1.48-fold increase in risk of SSc-related hospitalisation or death (95% CI 1.23, 1.77). No statistically significant association was observed between FVC decline and admission to ER or to hospital followed by admission to ICU or death (n = 75; P = 0.15). The estimated slope difference for nintedanib versus placebo in the longitudinal sub-model was consistent with the primary analysis in SENSCIS®. Conclusions The association of lung function decline with an increased risk of hospitalisation suggests that slowing FVC decline in patients with SSc-ILD may prevent hospitalisations. Our findings also provide evidence that FVC decline may serve as a surrogate endpoint for clinically relevant hospitalisation-associated endpoints. Trial registration ClinicalTrials.gov NCT02597933 . Registered on 8 October 2015.

Measurable residual disease (MRD) is defined as the presence of residual cancer cells after treatment in patients with clinically undetectable disease, who would otherwise be considered in complete remission. It is a highly sensitive parameter which indicates the disease burden and predicts survival in this setting of patients. In recent years, MRD has gained a role in many hematological malignancies as a surrogate endpoint for clinical trials: undetectable MRD has been correlated to longer progression free survival (PFS) and overall survival (OS). New drugs and combinations have been developed with the aim to achieve MRD negativity, which would indicate favorable prognosis. Different methods to measure MRD have also been devised, which include flow cytometry, polymerase chain reaction (PCR) and next generation sequencing (NGS), with different sensitivity and accuracy in evaluating deep remission after treatment. In this review, we will analyze the current recommendations for the detection of MRD, with particular focus on its role in Chronic Lymphocytic Leukemia (CLL), as well as the different detection methods. Moreover, we will discuss the results of clinical trials and the role of MRD in new therapeutic schemes with inhibitors and monoclonal antibodies. MRD is not currently used in the clinical practice to evaluate response to treatment, due to technical and economical limitations, but it’s gaining more and more interest in trials settings, especially since the introduction of venetoclax. The use of MRD in trials will likely be followed by a broader practical application in the future. The aim of this work is to provide a reader-friendly summary of the state of art in the field, as MRD will soon become an accessible tool to evaluate our patients, predict their survival and guide physician’s therapeutic choices and preferences.