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In patients with acute myocardial infarction (AMI), traditional clinical endpoints used to assess drug efficacy and prognosis include infarct size (IS), incidence of heart failure, and mortality rates. Although these metrics are commonly employed to evaluate outcomes in AMI patients, their utility is limited in small-scale studies. The introduction of the myocardial salvage index (MSI) reduces variability in assessments across multiple dimensions, thereby enhancing the sensitivity of outcome measures and reducing the required sample size. Moreover, MSI is increasingly utilized to evaluate drug efficacy, prognosis, and risk stratification in AMI patients. Although a variety of methodologies for measuring the MSI are currently available, the incorporation of these methods as clinical endpoints remains limited. In the clinical application of cardioprotective strategies, it is recommended that MSI be evaluated using late gadolinium enhancement measured along the endocardial surface length combined with IS in cardiac magnetic resonance. In dynamic single-photon emission computed tomography, an assessment of MSI using methods based on abnormalities in myocardial wall thickening combined with perfusion anomalies is advocated. This review comprehensively outlines the principles, advantages, and limitations of different MSI assessment methods and discusses the prospects and challenges of MSI in cardiac protective therapies. Additionally, we summarize recommended strategies for employing MSI as a clinical surrogate endpoint in various clinical scenarios, providing direction for future clinical practice and research. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 4.

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The use of digital health technologies to measure outcomes in clinical trials opens new opportunities as well as methodological challenges. Digital outcome measures may provide more sensitive and higher-frequency measurements but pose vital statistical challenges around how such outcomes should be defined and validated and how trials incorporating digital outcome measures should be designed and analysed. This article presents eight methodological questions, exploring issues such as the length of measurement period, choice of summary statistic and definition and handling of missing data as well as the potential for new estimands and new analyses to leverage the time series data from digital devices. The impact of key issues highlighted by the eight questions on a primary analysis of a trial are illustrated through a simulation study based on the 2019 Bellerophon INOPulse trial which had time spent in MVPA as a digital outcome measure. These eight questions present broad areas where methodological guidance is needed to enable wider uptake of digital outcome measures in trials.

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BACKGROUND: Considering multiple endpoints in clinical trials provide a more comprehensive understanding of treatment effects and may lead to increased power or reduced sample size, which may be beneficial in rare diseases. Besides the small sample sizes, allocation bias is an issue that affects the validity of these trials. We investigate the impact of allocation bias on testing decisions in clinical trials with multiple endpoints and offer a tool for selecting an appropriate randomization procedure (RP). METHODS: We derive a model for quantifying the effect of allocation bias depending on the RP in the case of two-arm parallel group trials with continuous multiple endpoints. We focus on two approaches to analyze multiple endpoints, either the Sidák procedure to show efficacy in at least one endpoint and the all-or-none procedure to show efficacy in all endpoints. RESULTS: To evaluate the impact of allocation bias on the test decision we propose a biasing policy for multiple endpoints. The impact of allocation on the test decision is measured by the family-wise error rate of the Sidák procedure and the type I error rate of the all-or-none procedure. Using the biasing policy we derive formulas to calculate these error rates. In simulations we show that, for the Sidák procedure as well as for the all-or-none procedure, allocation bias leads to inflation of the mean family-wise error and mean type I error, respectively. The strength of this inflation is affected by the choice of the RP. CONCLUSION: Allocation bias should be considered during the design phase of a trial to increase validity. The developed methodology is useful for selecting an appropriate RP for a clinical trial with multiple endpoints to minimize allocation bias effects.

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BACKGROUND: Diabetic peripheral neuropathy (DPN) is a prevalent and debilitating complication of diabetes, often leading to severe neuropathic pain. Although other diabetes-related complications have witnessed a surge of emerging treatments in recent years, DPN has seen minimal progression. This stagnation stems from various factors, including insensitive diagnostic methods and inadequate treatment options for neuropathic pain. METHODS: In this comprehensive review, we highlight promising novel diagnostic techniques for assessing DPN, elucidating their development, strengths, and limitations, and assessing their potential as future reliable clinical biomarkers and endpoints. In addition, we delve into the most promising emerging pharmacological and mechanistic treatments for managing neuropathic pain, an area currently characterized by inadequate pain relief and a notable burden of side effects. RESULTS: Skin biopsies, corneal confocal microscopy, transcutaneous electrical stimulation, blood-derived biomarkers, and multi-omics emerge as some of the most promising new techniques, while low-dose naltrexone, selective sodium-channel blockers, calcitonin gene-related peptide antibodies, and angiotensin type 2 receptor antagonists emerge as some of the most promising new drug candidates. CONCLUSION: Our review concludes that although several promising diagnostic modalities and emerging treatments exist, an ongoing need persists for the further development of sensitive diagnostic tools and mechanism-based, personalized treatment approaches.

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Early indicators of healing provide valuable information on the potential benefit of treatment. In patients with hard-to-heal (chronic) diabetic foot ulcers (DFUs), timely intervention is critical. Ulcers that fail to show measurable progress within four weeks of treatment are considered recalcitrant. These ulcers increase the risk of soft tissue infection, osteomyelitis and lower extremity amputation. A prognostic indicator or surrogate marker allows for rapid evaluation of treatment efficacy and safety. An inverse correlation between a percentage area reduction (PAR) of ≤50% at week 4 and complete healing by week 12 has been previously established; however, the data were derived from a standard of care (SoC) arm of clinical trials that are over a decade old. In this post hoc analysis, data from a large multicentre prospective randomised controlled trial were reviewed to assess PAR at week 4 as a prognostic indicator in patients treated with SoC. Overall, 65.4% (17/26) of patients with PAR >50% at week 4 achieved complete closure at week 12. The receiver operating characteristic (ROC) curve for area reduction by week 4 showed strong discrimination for predicting non-healing (area under the ROC curve: 0.92; p<0.001; positive predictive value: 70.6%; negative predictive value: 87.2%). These findings are consistent with previous studies and support the use of four-week PAR as a prognostic indicator.

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Evidence grows that standard toxicity testing might underestimate the environmental risk of neurotoxic insecticides. Behavioural endpoints such as locomotion and mobility have been suggested as sensitive and ecologically relevant additions to the standard tested endpoints. Possible interactive effects of chemicals and additional stressors are typically overlooked in standardised testing. Therefore, we aimed to investigate how concurrent exposure to environmental stressors (increased temperature and predation cues) and a nicotinic acetylcholine receptor (nAChR)-modulating insecticide ('sulfoxaflor') impact Chironomus riparius across a range of conventional and non-conventional endpoints. We used a multifactorial experimental design encompassing three stressors, sulfoxaflor (2.0-110 µg/L), predation risk (presence/absence of predatory cues), and elevated temperature (20 °C and 23 °C), yielding a total of 24 distinct treatment conditions. Additional stressors did not change the sensitivity of C. riparius to sulfoxaflor. To assess potential additive effects, we applied an Independent Action (IA) model to predict the impact on eight endpoints, including conventional endpoints (growth, survival, total emergence, and emergence time) and less conventional endpoints (the size of the adults, swimming abilities and exploration behaviour). For the conventional endpoints, observed effects were either lower than expected or well-predicted by the IA model. In contrast, we found greater than predicted effects of predation cues and temperature in combination with sulfoxaflor on adult size, larval exploration, and swimming behaviour. However, in contrast to the non-conventional endpoints, no conventional endpoints detected interactive effects of the neurotoxic insecticide and the environmental stressors. Acknowledging these interactions, increasing ecological context of ecotoxicological test systems may, therefore, advance environmental risk analysis and interpretation as the safe environmental concentrations of neurotoxic insecticides depend on the context of both the test organism and its environment.

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Objective: Wolfram syndrome, an ultra-rare condition, currently lacks effective treatment options. The rarity of this disease presents significant challenges in conducting clinical trials, particularly in achieving sufficient statistical power (e.g., 80%). The objective of this study is to propose a novel clinical trial design based on real-world data to reduce the sample size required for conducting clinical trials for Wolfram syndrome. Methods: We propose a novel clinical trial design with three key features aimed at reducing sample size and improve efficiency: (i) Pooling historical/external controls from a longitudinal observational study conducted by the Washington University Wolfram Research Clinic. (ii) Utilizing run-in data to estimate model parameters. (iii) Simultaneously tracking treatment effects in two endpoints using a multivariate proportional linear mixed effects model. Results: Comprehensive simulations were conducted based on real-world data obtained through the Wolfram syndrome longitudinal observational study. Our simulations demonstrate that this proposed design can substantially reduce sample size requirements. Specifically, with a bivariate endpoint and the inclusion of run-in data, a sample size of approximately 30 per group can achieve over 80% power, assuming the placebo progression rate remains consistent during both the run-in and randomized periods. In cases where the placebo progression rate varies, the sample size increases to approximately 50 per group. Conclusions: For rare diseases like Wolfram syndrome, leveraging existing resources such as historical/external controls and run-in data, along with evaluating comprehensive treatment effects using bivariate/multivariate endpoints, can significantly expedite the development of new drugs.

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Maize is highly susceptible to drought, which affects growth and yield. This study investigated how bacterial volatile organic compounds (BVOCs) affect maize drought tolerance. Drought reduced shoot size but increased root length, an adaptation for accessing deeper soil moisture. BVOCs from strain D12 significantly increased root length and shoot growth under drought conditions. Drought also altered root biochemistry, decreasing enzyme activity, and increased osmolyte levels. BVOCs from strains F11 and FS4-14 further increased osmolyte levels but did not protect membranes from oxidative damage, while BVOCs from strains D12 and D7 strains reduced osmolyte levels and cell damage. In shoots, drought increased the levels of osmolytes and oxidative stress markers. BVOCs from FS4-14 had minimal effects on shoot biochemistry. BVOCs from D12 and F11 partially restored metabolic activity but did not reduce cell damage. BVOCs from D7 reduced metabolic activity and cell damage. These results suggest that BVOCs can modulate the biochemical response of maize to drought, with some strains evidencing the potential to enhance drought tolerance.

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INTRODUCTION: Catheter ablation of atrial fibrillation (AF) is frequently studied in randomized trials, observational and registry studies. The aim of this expert opinion is to provide guidance for clinicians and industry regarding the development of future clinical studies on catheter ablation of AF, implement lessons learned from previous studies, and promote a higher degree of consistency across studies. BACKGROUND: Studies on catheter ablation of AF may benefit from well-described definitions of endpoints and consistent methodology and documentation of outcomes related to efficacy, safety and cost-effectiveness. The availably of new, innovative technologies warrants further consideration about their application and impact on study design and the choice of endpoints. Moreover, recent insights gained from AF ablation studies suggest a reconsideration of some methodological aspects. METHODS: A panel of clinical experts on catheter ablation of AF and designing and conducting clinical studies developed an expert opinion on the design and endpoints for studies on catheter ablation of AF. Discussions within the expert panel with the aim to reach consensus on predefined topics were based on outcomes reported in the literature and experiences from recent clinical trials. RESULTS: A comprehensive set of recommendations is presented. Key elements include the documentation of clinical AF, medication during the study, repeated ablations and their effect on endpoint assessments, postablation blanking and the choice of rhythm-related and other endpoints. CONCLUSION: This expert opinion provides guidance and promotes consistency regarding design of AF catheter ablation studies and identified aspects requiring further research to optimize study design and methodology. CONDENSED ABSTRACT: Recent insights from studies on catheter ablation of atrial fibrillation (AF) and the availability of new innovative technologies warrant reconsideration of methodological aspects related to study design and the choice and assessment of endpoints. This expert opinion, developed by clinical experts on catheter ablation of AF provides a comprehensive set of recommendations related to these methodological aspects. The aim of this expert opinion is to provide guidance for clinicians and industry regarding the development of clinical studies, implement lessons learned from previous studies, and promote a higher degree of consistency across studies.

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Geographic atrophy (GA), the non-neovascular advanced form of age-related macular degeneration, remains an important disease area in which treatment needs are currently unmet. Recent clinical trials using drugs that target the complement pathway have shown modest yet consistent reductions in GA expansion but without commensurate changes in measures of visual function. In this review, we summarize information from the wide range of studies describing the characteristics of GA morphology and enumerate the factors influencing the growth rates of lesions and the directionality of expansion. In addition, we review the relationship between GA growth and the various measures of vision that reflect changes in function. We consider the reasons for the discordance between the anatomical and functional endpoints in current use and discuss methods to align these key outcomes.

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Background & Aims: The goal of treatment in autoimmune hepatitis (AIH) is induction of remission to prevent the development of liver fibrosis, cirrhosis, and its related complications. Various definitions of treatment response and remission have been used. The International Autoimmune Hepatitis Group (IAIHG) recently defined consensus criteria for treatment response. We aimed to validate the IAIHG response criteria in our cohort and establish correlations with survival endpoints. Methods: We performed a retrospective, multicentric cohort study in one tertiary and seven secondary care centres in Belgium. Eligible patients were at least 18 years of age at data collection and were diagnosed with AIH by a simplified IAIHG score of ≥6. Complete biochemical response (CBR) was defined according to the IAIHG consensus criteria as normalisation of transaminases and serum IgG within the first 6 months of treatment. The primary endpoint was liver-related survival - defined as freedom from liver-related death or liver transplantation. Secondary endpoints were overall mortality and transplant-free survival. Outcomes were compared between patients attaining CBR and those with insufficient response. Results: Biochemical response status could be determined in 200 patients with AIH: CBR was achieved in 128 (64.0%) individuals. Patients not achieving CBR more frequently presented with cirrhosis on initial histology (22.2% vs. 10.9%, p = 0.036). Liver-related mortality or liver transplantation as a primary outcome occurred in 26 patients (13.0%). Patients achieving CBR exhibited superior liver-related (hazard ratio 0.118; 95% CI 0.052-0.267; p <0.0001) and overall (hazard ratio 0.253; 95% CI 0.111-0.572; p = 0.0003) survival. Conclusions: We externally validated the IAIHG consensus criteria for CBR and confirmed their correlation with survival endpoints in a multicentric, real-world cohort. Patients with AIH achieving CBR as an intermediate endpoint have significantly superior liver-related and overall survival. Impacts and Implications: Corticosteroids remain the cornerstone of treatment to induce remission of disease activity in autoimmune hepatitis (AIH), and the majority of patients require long-term corticosteroid treatment to achieve sustained remission. Definitions of response to treatment have varied over the years, and consistently used intermediate endpoints are needed to facilitate advancements in non-corticosteroid treatment for autoimmune hepatitis. The International Autoimmune Hepatitis Group (IAIHG) defined consensus criteria on endpoints in the treatment of AIH, for which further external validation is needed. Here, we demonstrate the usefulness of the IAIHG consensus criteria and corroborate their correlation to primary endpoints, such as liver-related survival and native liver survival in a multicentric, real-world setting. The design of future studies can rely on the IAIHG consensus criteria as intermediate endpoints.

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AIM: To describe the use of composite endpoints (CEs) in cardiovascular outcome trials (CVOTs) of type 2 diabetes and to evaluate the significance of the individual outcomes included within these CEs from the perspectives of both patients and clinicians. Secondary objectives were to estimate the gradient of treatment effects and events across outcomes. MATERIALS AND METHODS: Eligible studies were randomized controlled trials assessing CV outcomes for patients with diabetes from 2008 and onwards. Trials were identified by searching the reports from the CVOT Summit of the Diabetes & CV Disease EASD (European Association for the Study of Diabetes) Study Group. The individual outcomes comprising the CE were compared for differences in importance for patients and clinicians, proportion of events, and effect size. RESULTS: We included 22 trials randomizing a mean of 8098 patients to an active intervention or a comparator group for an average of 33 months (standard deviation 16). All primary outcomes were CEs, and from a patient perspective there was no gradient of importance across outcomes in 22 of 22 (100%) CEs, while the gradient was small in 22 of 22 (100%) from a clinician perspective. The gradient of effect was moderate to large in 9 of 18 (50%) reporting studies, while assessment of events was available in 15 of 22 studies (68%), finding that three of 15 (20%) had a gradient of effect of more than 5% points between included outcomes. In 10 of 22 (45%) trial reports, the results were not clearly presented as based on a CE. CONCLUSIONS: To avoid misinterpretation, clinicians and regulatory authorities should be careful when interpreting the results of trials, of which the main outcomes are CEs.

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BACKGROUND AND AIMS: Corticosteroids are widely used in managing inflammatory bowel disease [IBD]. While adverse events [AEs] of corticosteroids are well recognised, current understanding of corticosteroid-related AE burden in IBD remains incomplete. METHODS: AE reports for prednisone/prednisolone and budesonide were extracted from the Food and Drug Administration Adverse Event Reporting System [FAERS] and VigiBase databases. Total and frequently reported AEs were tabulated, and AEs of special interest were compared with reports for all drugs using proportional reporting ratio criteria. Database reports were compared with AEs reported in a patient survey capturing corticosteroid exposure and AE recall. RESULTS: In FAERS and VigiBase, 344,140 and 42,836 AEs were reported, respectively, in patients with IBD; among these, 10,157 [3.0%] and 11,391 [26.6%], respectively, were related to prednisone/prednisolone or budesonide. AEs associated with corticosteroid use in IBD increased over time. Adrenal insufficiency, Cushingoid complications, osteonecrosis, osteoporosis, diabetes and pancreatitis were disproportionately reported for corticosteroids. Among 9229 patients who responded to the survey, 6434 [69.7%] reported corticosteroid exposure. AEs were more frequently recalled by patients exposed to prednisone [61.9%] vs budesonide [27.4%; p = 0.0001]. The most commonly recalled AEs differed from those reported in the pharmacovigilance databases and included weight gain, sleep problems, mood disturbance and skin changes. Younger patients and those with mental health disorders were more likely to recall suicidal thoughts/attempts. CONCLUSIONS: AEs associated with IBD-related corticosteroid use were frequent. Patients reported AEs affecting quality of life, while clinicians disproportionately reported AEs based on objective diagnostic criteria.

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Oncologists and cancer patients generally agree that the primary goals of advanced cancer treatment are to lengthen and/or improve patient survival. Yet over the last two decades, clinical trials of new cancer treatments have moved away from measuring outcomes that matter to patients. Increasingly, new drugs for advanced cancer treatment reach the market by demonstrating improvements in surrogate endpoints such as progression-free survival (PFS), which is not a measure of how a patient feels, functions, or survives. Research has shown that when patients are fully informed about the meaning of PFS, about half would not choose additional treatment for any magnitude of gain in PFS in the absence of an overall survival improvement. It's time to get back to designing trials that answer clinically meaningful questions and measure the outcomes that truly matter to patients. Engaging educated patient advocates in meaningful ways in clinical trial design and reporting would be a step in this direction.

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OBJECTIVES: The main purpose of using a surrogate endpoint is to estimate the treatment effect on the true endpoint sooner than with a true endpoint. Based on a metaregression of historical randomized trials with surrogate and true endpoints, we discuss statistics for applying and evaluating surrogate endpoints. METHODS: We computed statistics from 2 types of linear metaregressions for trial-level data: simple random effects and novel random effects with correlations among estimated treatment effects in trials with more than 2 arms. A key statistic is the estimated intercept of the metaregression line. An intercept that is small or not statistically significant increases confidence when extrapolating to a new treatment because of consistency with a single causal pathway and invariance to labeling of treatments as controls. For a regulator applying the metaregression to a new treatment, a useful statistic is the 95% prediction interval. For a clinical trialist planning a trial of a new treatment, useful statistics are the surrogate threshold effect proportion, the sample size multiplier adjusted for dropouts, and the novel true endpoint advantage. RESULTS: We illustrate these statistics with surrogate endpoint metaregressions involving antihypertension treatment, breast cancer screening, and colorectal cancer treatment. CONCLUSION: Regulators and trialists should consider using these statistics when applying and evaluating surrogate endpoints.

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BACKGROUND: Adaptive behaviour refers to the practical skills necessary for independence and is considered a high-priority intervention target for children with neurogenetic conditions associated with intellectual disability, like Down syndrome (DS). Daily living skills (DLS) are a critical aspect of adaptive behaviour, but they have received little intervention attention, possibly because they involve a wide variety of skills across many settings. The present study aimed to advance DLS intervention science by examining the concurrent and longitudinal association between DLS performances and a cognitive skillset hypothesised to support DLS skill acquisition, executive function (EF). METHODS: Participants were 71 children with DS between the ages of 2.5 and 8.7 years (M = 5.23 years; standard deviation = 1.65) who completed a battery of adapted EF tasks and a primary caregiver who completed the Vineland Adaptive Behavior Scales 3rd Edition Parent/Caregiver Comprehensive Report Form. A subset of caregivers also provided 6- and 12-month follow-up adaptive behaviour information. RESULTS: Results demonstrated a positive association between EF task performance and DLS standard scores and v-scores both concurrently and longitudinally. CONCLUSIONS: The findings have implications for potential future intervention approaches that aim to strengthen DLS performances by advancing EF skills in this population.

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Disease progression in clinical trials is commonly defined by radiologic measures. However, clinical progression may be more meaningful to patients, may occur even when radiologic criteria for progression are not met, and often requires a change in therapy in clinical practice. The objective of this study was to determine the utilization of clinical progression criteria within progression-based trial endpoints among phase III trials testing systemic therapies for metastatic solid tumors. The primary manuscripts and protocols of phase III trials were reviewed for whether clinical events, such as refractory pain, tumor bleeding, or neurologic compromise, could constitute a progression event. Univariable logistic regression computed odds ratios (OR) and 95% CI for associations between trial-level covariates and clinical progression. A total of 216 trials enrolling 148,190 patients were included, with publication dates from 2006 through 2020. A major change in clinical status was included in the progression criteria of 13% of trials (n = 27), most commonly as a secondary endpoint (n = 22). Only 59% of trials (n = 16) reported distinct clinical progression outcomes that constituted the composite surrogate endpoint. Compared with other disease sites, genitourinary trials were more likely to include clinical progression definitions (16/33 [48%] vs. 11/183 [6%]; OR, 14.72; 95% CI, 5.99 to 37.84; p < .0001). While major tumor-related clinical events were seldom considered as disease progression events, increased attention to clinical progression may improve the meaningfulness and clinical applicability of surrogate endpoints for patients with metastatic solid tumors.

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INTRODUCTION: The STRIDE consensus intends to complement the clinical endpoint with an endoscopic endpoint of mucosal healing and others as treatment targets in ulcerative colitis. If these targets are not reached, STRIDE requires dose or timing adjustments or switching the medication. This narrative review provides a critique of this concept. AREAS COVERED: We analyze and discuss the limitations of current endpoints as targets, their currently limited achievability, and the lacking evidence from controlled trials relating to 'treat to target.' The relevant publications in PubMed were identified in a literature review with the key word 'ulcerative colitis.' EXPERT OPINION: In ulcerative colitis, the standard clinical target is measured traditionally by the MAYO-score, but in variable combinations of patient and physician reported outcomes as well as also different definitions of the endoscopic part. Only a score of 0 is more stringent than clinical remission but is only achieved by a minority of patients in first and even less in second line therapy. The concept is not based on clear evidence that patients indeed benefit from appropriate escalation of treatment. Until the STRIDE approach is proven to be superior to standard treatment focusing on clinical well-being, the field should remain reluctant.

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Chen et al. (2022) recently proposed a set of estimating equations that incorporate data from secondary endpoints to improve precision in parameter estimates related to a primary endpoint. We were motivated to translate their methodology to the context of randomized controlled trials to gain precision in treatment effect estimation using data from secondary endpoints. Our results suggest that this estimator cannot gain efficiency in this context because of random treatment assignment, especially when there is a treatment effect on secondary endpoints, and that further methodological work in this area is needed.

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PURPOSE: Novel interventions for the prevention or treatment of acute kidney injury (AKI) are currently lacking. To facilitate the evaluation and adoption of new treatments, the use of the most appropriate design and endpoints for clinical trials in AKI is critical and yet there is little consensus regarding these issues. We aimed to develop recommendations on endpoints and trial design for studies of AKI prevention and treatment interventions based on existing data and expert consensus. METHODS: At the 31st Acute Disease Quality Initiative (ADQI) meeting, international experts in critical care, nephrology, involving adults and pediatrics, biostatistics and people with lived experience (PWLE) were assembled. We focused on four main areas: (1) patient enrichment strategies, (2) prevention and attenuation studies, (3) treatment studies, and (4) innovative trial designs of studies other than traditional (parallel arm or cluster) randomized controlled trials. Using a modified Delphi process, recommendations and consensus statements were developed based on existing data, with > 90% agreement among panel members required for final adoption. RESULTS: The panel developed 12 consensus statements for clinical trial endpoints, application of enrichment strategies where appropriate, and inclusion of PWLE to inform trial designs. Innovative trial designs were also considered. CONCLUSION: The current lack of specific therapy for prevention or treatment of AKI demands refinement of future clinical trial design. Here we report the consensus findings of the 31st ADQI group meeting which has attempted to address these issues including the use of predictive and prognostic enrichment strategies to enable appropriate patient selection.

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