Recommendations for a Clinically Relevant Effect Size for Phase III AIT Studies

Null hypothesis significance testing is one of the most widely used forms of statistical testing in environmental toxicology. In this short communication, the authors show that the reporting of statistical information when using null hypothesis significance testing is frequently inadequate in environmental toxicology research. The authors demonstrate this by analyzing the statistical information reported for papers employing t tests or analyses of variance in the Environmental Toxicology section of Environmental Toxicology and Chemistry in 2010, which comprised 68% of papers published by this journal in that year. Of these papers, 60% fail to report exact p values, 85% fail to provide degrees of freedom, and 90% fail to report critical effect sizes. Statistical power was reported in only <2% of the published papers. The insufficient provision of statistical information makes interpretation of study results by reviewers and readers difficult. Consistently reporting exact p values with degrees of freedom, considering and explicitly stating biologically relevant critical effect sizes, and reporting statistical power associated with nonsignificant results would be easy to implement and would promote scientific progress in environmental toxicology through increased statistical transparency.

BACKGROUND: Activated ALK by mutation or amplification is a validated therapeutic target in neuroblastoma, and identifying therapeutic strategies to overcome primary resistance to direct ALK kinase inhibition will be critical to improve clinical responses. We hypothesized that simultaneous targeting of ALK and additional oncogenic networks would improve efficacy. METHODS: We performed a synergy screen combining molecularly targeted compounds (n=14) and standard-of-care chemotherapy agents (n=8) in extensively characterized human neuroblastoma cell lines (n=14). We investigated the combination of LDK378 and LEE011 on in vitro proliferation, cell cycle, viability, caspase activation, and the Cyclin D/CDK4/CDK6/RB and pALK signaling networks in neuroblastoma-derived cell lines with representative ALK status. Transport inhibitor studies were performed in Caco2 cells. We performed in vivo trials in neuroblastoma CB17 xenograft models comparing LDK378 alone, LEE011 alone, and the combination of LDK378 and LEE011, with plasma and tumor pharmacokinetics to evaluate for drug-drug interactions. RESULTS: Pairwise combination screening for in vitro cell viability identified synergistic interactions of LDK378, an ALK inhibitor, with LEE011, a CDK4 and CDK6 inhibitor. In mutant and wild-type ALK cell lines there was moderate to strong synergy with combination indices of 0.2 - 0.8 at clinically relevant high effect sizes with the fraction of cells affected ≥ 0.8. Compared to either drug alone, combination LEE011 and LDK378 increased dose dependent abrogation of pALK and pRb, inhibition of proliferation, apoptosis and decreased cell viability. LDK378 did not show significant cellular accumulation after P-gp, BCRP, and MRP2 inhibition or after LEE011 1uM and 10uM. LEE011 showed only modest accumulation with MRP2 inhibition, but not after BCRP or P-gp inhibition. In NB1691 (ALK wild-type) and SHSY5Y (ALK-F1174L, resistant mutation) neuroblastoma xenografts, combination therapy significantly prolonged survival compared to either drug alone (P&amp;lt;0.0001). In SHSY5Y xenografts, combination therapy achieved complete regressions using murine doses that achieved plasma drug exposures comparable to the adult recommended doses for LEE011 and LDK378. Combination therapy increased tumor LEE011 and LDK378 maximum concentration (Cmax) and area under curve (AUC) 2-3 fold over monotherapy, but plasma concentrations were unaltered. CONCLUSION: Dual ALK and CDK4/6 inhibition in neuroblastoma models demonstrates potent on-target in vitro synergy and in vivo activity with augmented abrogation of respective molecular targets, resulting in inhibition of proliferation and cell death. While mechanisms for altered intratumoral drug distribution require further investigation, these data support the development of a combination ALK and CDK4/6 inhibitor clinical trial with eligibility not restricted to cases with somatic ALK mutations. Citation Format: Andrew C. Wood, Kateryna Krytska, Hannah Ryles, Renata Sano, Nanxin Li, Frederick King, Timothy Smith, Tove Tuntland, Sunkyu Kim, Giordano Caponigro, You Qun He, Harris Jennifer, Yael Mosse. Combination CDK4/6 and ALK inhibition demonstrates on-target synergy against neuroblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1000. doi:10.1158/1538-7445.AM2014-1000

BackgroundSuicide is a major public health concern. However, little is known about whether dementia is associated with suicide outcomes, and if so what the risk factors for suicide are in this group. This study aimed to conduct meta‐analyses to examine pooled associations between dementia and suicide outcomes (ideation, attempts, death by suicide) as well as pooled associations between risk factors (sex, dementia subtype) and suicidality in people living with dementia (PLWD).MethodSystematic searches were conducted in Medline, Embase, Psycinfo, Cinahl Plus, and Web of Science for keywords related to dementia and suicide. Quantitative studies with a sample of PLWD and suicidality as an outcome and that were available in English were included. Experimental studies, case reports and studies with a focus on euthanasia/assisted suicide, or self‐harm without suicidal intentionality were excluded. Relevant effect sizes were extracted and inverse variance weighted meta‐analyses were run using a random‐effects model.Result55 studies were included. Meta analyses showed that compared to people without dementia, having dementia was significantly associated with death by suicide (OR = 2.48, 95% CI:1.82;3.38), and suicidal ideation (OR = 2.29, 95% CI:1.75‐2.99), but not suicide attempts. Men with dementia were more at risk of attempting (OR = 1.28, 95% CI:1.25;1.31) and death by suicide (OR = 2.84, 95% CI:1.51;5.37) than women with dementia, but there was no difference in suicidal ideation. Compared with Alzheimer’s disease, people with vascular dementia (VaD), frontotemporal dementia (FTD), and other dementia (OD) types were significantly more likely to attempt suicide. People with Lewy body dementia (LBD) were significantly more likely to report suicidal ideation.ConclusionPLWD are at higher risk of suicidal ideation and death by suicide than those without dementia, but not suicide attempts. This could suggest that PLWD are not more likely to attempt suicide but are more likely to be successful when an attempt is made. Key risk factors for suicide attempts amongst PLWD are being male, sub‐type of dementia diagnosis (VaD, FTD and OD), while having a diagnosis of LBD is a risk factor for suicidal ideation. These results are important for understanding and managing risk in PLWD.

Ongoing controversy exists on postoperative weightbearing status after open reduction and internal fixation of an ankle fracture. This prospective randomized controlled trial aimed to compare patient-based and physician-based outcomes after early weightbearing at 2 vs 6 weeks postoperatively. Fifty patients with unstable rotational-type ankle fractures were treated operatively with subsequent immobilization in a below-the-knee cast for 2 weeks and were then randomly allocated to 2 groups. The first group had early weightbearing at 2 weeks postoperation and the second group at 6 weeks postoperation. Follow-up included subjective and objective evaluations performed at 2, 6, 12, and 26 weeks postoperatively. The primary outcome was the patient-based general health status as measured with the EuroQol-5D (EQ-5D) scoring system. Secondary outcome was the Olerud and Molander ankle score. Power analysis revealed a study group of 50 patients was needed to show a clinically relevant effect size of 10 points in both EQ-5D visual analog scale (VAS) score and Olerud and Molander score. Patients in the early weightbearing group had higher mean EQ-5D VAS scores at a 6-week follow-up (P = .014) of 77 ± 14 compared to 66 ± 15 for late mobilization. No difference was found at other follow-up points or between groups for physician-based outcome measures. At 26 weeks postoperatively, mean Olerud and Molander ankle scores were similar at 84 ± 16 and 81 ± 17 for mobilization at 2 and 6 weeks postoperation, respectively. Early weightbearing after operative fixation of rotational-type ankle fractures had a clinically relevant and statistically significant benefit in patient-based general health status, as quantified with EQ-5D VAS scores, at 6 weeks postoperation. These results contribute to our understanding of early weightbearing and may encourage consideration of weightbearing at 2 weeks postoperatively in standard protocols. Therapeutic Level I, prospective randomized controlled trial.

The literature on typically developing siblings of individuals with autism spectrum disorder (ASD-Sibs) provides inconsistent results, with some studies reporting ASD-Sibs are more likely to have negative outcomes than comparison groups, and others reporting no significant differences. Therefore, the purpose of this study was to meta-analytically aggregate study effect sizes to more accurately calculate the degree to which ASD-Sibs function similarly or differently compared to siblings of people who do not have ASD. Studies were eligible for inclusion if they had a sample of ASD-Sibs older than 5; reported on emotional, psychological, behavioral, or social functioning; and provided information necessary for calculating relevant effect sizes. Results from 69 independent samples indicated that ASD-Sibs have significantly more negative outcomes than comparison groups overall (g = - 0.26); specific areas of functioning in which ASD-Sibs fared worse include internalizing behavior problems, psychological functioning, beliefs, social functioning, and the sibling relationship, but no significant differences in adjustment, attention/hyperactivity, externalizing behavior problems, coping, or family functioning. Noteworthy sub-areas of functioning in which ASD-Sibs also fared worse included beliefs about disability (g = - 0.56), anxiety symptoms (g = - 0.25), and depression symptoms (g = - 0.36). In terms of comparison group, ASD-Sibs had significantly lower functioning than siblings of individuals with other intellectual and developmental disabilities (g = - 0.31), including Down syndrome (g = - 0.40) and siblings of individuals without any disabilities (g = - 0.31). Clinicians and service providers should work to ensure that ASD-Sibs are included in family interventions and support strategies, and researchers should further explore individual differences that may relate to enhanced or impaired functioning in ASD-Sibs.

THE heart is not only a pumping organ but also an endocrine organ. B-type natriuretic peptide (BNP) is secreted primarily by cardiac ventricular myocytes in response to increased ventricular wall stress induced by volume expansion, pressure overload, or ischemia.1 BNP protein formation begins with intracellular translation into a large preprohormone that is processed to pro-brain natriuretic peptide (proBNP) and then is cleaved and released into the circulation as active BNP and biologically inactive N-terminal proBNP (NT-proBNP) fragment.1 Commercial assays are available to measure circulating BNP and NT-proBNP. Although BNP has known compensatory natriuretic, diuretic, and vasodilatory properties, studies of both ambulatory and surgical patients have found that elevations of circulating BNP or NT-proBNP significantly associate with increased adverse cardiac events.1–3 Worldwide, approximately 200 million noncardiac surgeries are performed every year, with 30-day postoperative mortality estimated at approximately 2%.4,5 A number of studies therefore have evaluated whether elevations in preoperative BNP or NT-proBNP predict cardiac morbidity and mortality after noncardiac surgeries. In this issue of Anesthesiology, Potgieter et al.6 provide an elegant comparison of two different approaches to meta-analysis of 14 studies of noncardiac surgical patients (n = 2,196) that assess the association between elevated preoperative NT-proBNP and the composite outcome of 30-day postoperative mortality or nonfatal myocardial infarction (MI). The authors report that meta-analysis that aggregates study findings using the different optimal cut-points and corresponding odd ratios (ORs) established for each individual study cohort (i.e., aggregate data approach) results in a substantially inflated reported OR for association between NT-proBNP and 30-day postoperative outcome when compared with meta-analysis that combines individual-level data across all studies to define one optimal NT-proBNP cut-point to be used across all study cohorts (i.e., individual patient-level data approach). These findings provide an important warning regarding likely overestimation of effect size reported in aggregate data meta-analyses of biomarker studies. However, although the results of the individual patient-level data meta-analysis by Potgieter et al. demonstrate a marked shrinkage in resulting OR from the OR identified using aggregate data meta-analysis, their findings still highlight a clinically relevant effect size (OR for association between NT-proBNP >367.15 pg/ml and 30-day outcome = 3.61; 95% CI, 2.73 to 4.78). Thus, the question remains regarding what next studies and steps can be undertaken to determine whether perioperative NT-proBNP or BNP assessments can be used in clinical practice to predict and mitigate postoperative morbidity and mortality.A key impediment to moving evaluation of perioperative BNP or NT-proBNP into routine clinical practice for risk stratification and management of surgical patients is the lack of clarity from presently available literature regarding what cut-points of these biomarkers should be used to determine the risk. Several factors contribute to this lack of clarity. First, although both elevated BNP and NT-proBNP associate with adverse cardiovascular outcomes in ambulatory and surgical cohorts,1–3 NT-proBNP has a longer half-life than BNP and typically has two- to three-fold higher circulating concentrations than BNP. For clinical use, any cut-points identified in the literature should be considered specific to the BNP or NT-proBNP assay that was used. Second, BNP and NT-proBNP are increasingly elevated along the spectrum from subclinical heart disease to fulminant clinical cardiac decompensation. Patients presenting for one type of surgery are not necessarily like patients presenting for another type of surgery with regard to overall presenting burden of cardiovascular pathology. Magnitude and range of preoperative BNP or NT-proBNP concentrations will differ according to the presenting cardiac disease burden of different surgical groups. For example, aortic stenosis patients generally will have higher BNP or NT-proBNP concentrations than primary coronary artery bypass graft (CABG) patients, and vascular surgical patients (likely high incidence of coronary artery disease) generally will have higher BNP or NT-proBNP concentrations than healthy day-surgery patients.So to identify clinically relevant BNP or NT-proBNP cut-points for potential use in risk assessment and management of surgical patients, these cut-points need to be established for specific types of surgeries. One way to accomplish this is to identify assay-specific cut-points associated with adverse postoperative outcomes by doing large prospective observational studies of specific surgical groups (e.g., higher-risk noncardiac surgery vs. primary CABG surgery vs. aortic valve replacement, and more). Ideally, each cut-point is then validated in additional large surgical cohorts. Large multicenter collaborative studies such as the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) study (ClinicalTrials.gov, NCT00512109) will make this approach possible for certain subgroups of noncardiac surgeries. However, feasibility, time, and cost are significant deterrents to the large, surgery-specific discovery and validation cohort study approach for identification of biomarker cut-points.The results of the individual patient-level data meta- analysis of NT-proBNP by Potgieter et al. suggest that this meta-analysis approach could provide an alternate approach for identifying the usable perioperative biomarker cut-points. The individual patient-level data meta-analysis by Potgieter et al. demonstrated a clinically relevant OR for association between preoperative NT-proBNP and 30-day mortality or MI, but their findings are also potentially useful because this OR was derived from studies that include a grouping of higher-risk noncardiac surgeries: thoracic, vascular, urology, orthopedic, and general surgery with known coronary artery disease or multiple cardiac risk factors. Based on the findings by Potgieter et al., future studies might be warranted to assess whether preoperative optimization and enhanced postoperative surveillance of noncardiac surgical patients with preoperative NT-proBNP greater than 367 pg/ml are associated with improved postoperative outcome. Although not addressed in the meta-analysis of individual patient-level data performed by Potgieter et al., future individual patient-level data meta-analyses could also enhance comparability of studies by leveraging inclusion and exclusion criteria and allowing subgroup analyses and adjustments for covariates.7Potgieter et al. assessed NT-proBNP but did not assess studies of BNP and its association with 30-day mortality or MI. Although I can anticipate similar shrinkage in OR when compared with previously published aggregate data meta-analyses of BNP in noncardiac surgery, it would also be interesting to see what individual patient-level combined data reveal for assay-specific BNP cut-points for risk prediction in noncardiac surgical patients.An additional concept that is not addressed in the article by Potgieter et al. is that preoperative BNP and NT-proBNP assessments are often reported to have higher specificity but lower sensitivity for predicting adverse postoperative outcomes.2 What is worth considering for the design of future biomarker studies is that the sensitivity of a biomarker test is likely to be higher if it is assessed for association with an outcome that closely relates to the biology of the biomarker. For example, in a study done by my colleagues and me, the C-index was lower for association between preoperative BNP and all-cause mortality up to 5 yr after primary CABG surgery.8 However, in a later study, we assessed the association between preoperative BNP and heart failure hospitalization or heart failure death during the 5 yr after CABG surgery, and in that study, the C-index was higher and equaled 0.75.3 The biology of BNP makes it unlikely to be highly sensitive for future death from noncardiac causes, but our findings in CABG patients were that assessing a more cardiac-specific outcome improved sensitivity. Ideally, the area under the receiver operating characteristic curve (C-index; an indicator of the balance between sensitivity and specificity of a test, with 1.0 indicating a perfect test and 0.75 indicating a good test) would approach 0.75 for the majority of the studies.9 For more extensive explanation of statistics and biomarker thresholds, Ray et al.9 published a clear and expansive review of statistical evaluation of biomarkers in Anesthesiology. The outcome assessed by Potgieter et al. was 30-day postoperative all-cause mortality or nonfatal MI. Many of these outcome events were cardiac, which reinforces the concept that the NT-proBNP cut-point identified in the individual-level meta-analysis by Potgieter et al. might be useful for designing future clinical trials of noncardiac surgical patients.In summary, to move BNP and NT-proBNP assessment into perioperative clinical practice, useful cut-points or risk thresholds must be identified. These cut-points need to demonstrate reasonable sensitivity as well as specificity for adverse postoperative cardiac outcomes. Only then can randomized controlled trials be performed to determine whether better preoperative optimization and closer postoperative surveillance of patients with high BNP result in reduced adverse postoperative cardiac outcomes.2,3,10,11 Individual patient-level data meta-analysis of studies of cardiac-specific adverse outcomes after surgery may help to identify cut-points in cardiac biomarkers such as BNP, NT-proBNP, and troponins to identify patients at risk who might benefit from further perioperative optimization and intensive care.The author is not supported by, nor maintains any financial interest in, any commercial activity that may be associated with the topic of this article.

<h3>Summary</h3> <h3>Background</h3> The impact of COVID-19 on mental health is unclear. Evidence from longitudinal studies with pre pandemic data are needed to address (1) how mental health has changed from pre-pandemic levels to during the COVID-19 pandemic and (2), whether there are groups at greater risk of poorer mental health during the pandemic? <h3>Methods</h3> We used data from COVID-19 surveys (completed through April/May 2020), nested within two large longitudinal population cohorts with harmonised measures of mental health: two generations of the Avon Longitudinal Study of Parents and Children (ALPSAC): the index generation ALSPAC-G1 (n= 2850, mean age 28) and the parent’s generation ALSPAC-G0 (n= 3720, mean age = 59) and Generation Scotland: Scottish Family Health Study (GS, (n= 4233, mean age = 59), both with validated pre-pandemic measures of mental health and baseline factors. To answer question 1, we used ALSPAC-G1, which has identical mental health measures before and during the pandemic. Question 2 was addressed using both studies, using pre-pandemic and COVID-19 specific factors to explore associations with depression and anxiety in COVID-19. <h3>Findings</h3> In ALSPAC-G1 there was evidence that anxiety and lower wellbeing, but not depression, had increased in COVID-19 from pre-pandemic assessments. The percentage of individuals with probable anxiety disorder was almost double during COVID-19: 24% (95% CI 23%, 26%) compared to pre-pandemic levels (13%, 95% CI 12%, 14%), with clinically relevant effect sizes. In both ALSPAC and GS, depression and anxiety were greater in younger populations, women, those with pre-existing mental and physical health conditions, those living alone and in socio-economic adversity. We did not detect evidence for elevated risk in key workers or health care workers. <h3>Interpretation</h3> These results suggest increases in anxiety and lower wellbeing that may be related to the COVID-19 pandemic and/or its management, particularly in young people. This research highlights that specific groups may be disproportionally at risk of elevated levels of depression and anxiety during COVID-19 and supports recent calls for increasing funds for mental health services. <h3>Funding</h3> The UK Medical Research Council (MRC), the Wellcome Trust and University of Bristol.

When designing a clinical trial, a number of design features including the sample size have to be decided upon. The sample size calculation usually requires some discussion of relevant effect sizes and information about nuisance parameters such as standard deviations or overall event rates, with nuisance parameters being estimated from previous studies. Using a novel endpoint or moving into a new indication, no or only very limited information might be available and the sample size calculation is therefore subject to considerable uncertainty. Internal pilot study designs that allow sample size reestimation midcourse of the ongoing study have been proposed to make trials more robust to misspecifications of nuisance parameters in the planning phase. In this article we present the design of a recently completed randomized active controlled trial in dermatology as a case study. Furthermore, we demonstrate how type I error rate control can be achieved when testing for noninferiority and explore operating characteristics such as power and sample size distributions through simulations motivated by the case study. Finally, relevant regulatory guidelines on sample size reestimation are referred to.

Increases in overweight and obesity have been observed globally in both developed and developing countries. The authors assessed the relation between lifestyle factors and body mass index (BMI) (weight (kg)/height (m)2) in a population-based longitudinal study, using BMI and its subsequent change as responses in a multilevel model. The authors included 11,115 men and women aged 20-61 years at baseline who were living in the municipality of Tromsø, Norway, and who participated in three or four consecutive health surveys between 1979-1980 and 2001. Baseline age, physical activity at work, coffee consumption, and desired BMI (i.e., the BMI that the subjects reported they would like to have) were positively associated with baseline BMI, whereas height, alcohol consumption, leisure-time physical activity, and level of education were inversely associated. Most relations were found to be stronger in women than in men. Clinically relevant effect sizes were observed for most of the significant associations, especially in women. For instance, on an ordinal scale, a one-category increase in educational level would decrease the mean baseline BMI among women by 0.30 kg/m2. Significant associations between several lifestyle factors and subsequent BMI change revealed that observed baseline associations were strengthened over time, especially in women.

Do IVF treatment and laboratory factors affect singleton birthweight (BW)? BWs of IVF-conceived singleton babies are increasing with time, but we cannot identify the specific treatment factors responsible. IVF-conceived singleton babies from fresh transfers have slightly lower BW than those conceived naturally, whilst those from frozen embryo transfer (FET) cycles are heavier and comparable to naturally conceived offspring. Our recent studies have shown that BW varies significantly between different IVF centres, and in a single centre, is also increasing with time, without a corresponding change in BWs of naturally conceived infants. Although it is likely that factors in the IVF treatment cycle, such as hormonal stimulation or embryo laboratory culture conditions, are associated with BW differences, our previous study designs were not able to confirm this. Data relating to BW outcomes, IVF treatment and laboratory parameters were collated from pre-existing electronic records in five participating centres for all singleton babies conceived between August 2007 and December 2014. Seven thousand, five hundred and eighty-eight births, 6207 from fresh and 1381 from FET. Infants with severe congenital abnormalities were excluded. The primary outcome of gestation-adjusted BW and secondary outcomes of unadjusted BW and gestation were analysed using multivariable regression models with robust standard errors to allow for the correlation between infants with the same mother. The models tested treatment factors allowing for confounding by centre, time and patient characteristics. A similar matched analysis of a subgroup of 379 sibling pairs was also performed. No significant associations of birth outcomes with IVF embryo culture parameters were seen independent of clinic or time, including embryo culture medium, incubator type or oxygen level, although small differences cannot be ruled out. We did not detect any significant differences associated with hormonal stimulation in fresh cycles or hormonal synchronization in FET cycles. Gestation-adjusted BW increased by 13.4 (95% CI 0.6-26.1) g per year over the period of the study, and babies born following FET were 92 (95% CI 57-128) g heavier on average than those from the fresh transfer. Although no specific relationships have been identified independent of clinic and time, the confidence intervals remain large and do not exclude clinically relevant effect sizes. As this is an observational study, residual confounding may still be present. This study demonstrates the potential for large scale analysis of routine data to address critical questions concerning the long-term implications of IVF treatment, in accordance with the Developmental Origins of Health and Disease hypothesis. However, much larger studies, at a national scale with sufficiently detailed data, are required to identify the treatment parameters associated with differences in BW or other relevant outcomes. This work was supported by the EU FP7 project grant, EpiHealthNet (FP7-PEOPLE-2012-ITN-317146). No competing interests were identified. N/A.

Design and conduct of a provider survey to determine a clinically persuasive effect size in planning VA Cooperative Study #590 (Li+).

<b>Background:</b> Up to now there have been no RCTs exploring the effectiveness of pulmonary rehabilitation (PR) vs. usual care for patients with uncontrolled asthma with regard to asthma control (AC). <b>Method:</b> EPRA is a single-center randomized controlled waiting-list trial. Asthma patients with uncontrolled asthma were included. The patients of the intervention group (IG) underwent a 3-week inpatient PR. Data were assessed at randomization (T0), after 4 weeks (T1; IG: begin of PR, CG: usual care), 7 weeks (T2; IG: end of PR, CG: usual care), and 20 weeks (T3; IG: 3 months after PR, CG: begin of PR). Primary outcome is AC assessed using asthma control test (ACT). Secondary outcome is quality of life (QoL) assessed using asthma quality of life questionnaire (AQLQ). 412 patients were included (IG n = 202, CG n = 210), mean age, 51.2 ± 8.8 y, 58.3% male. <b>Results:</b> At T0 there was no intergroup difference concerning ACT and AQLQ, while at T2 and T3 there were significant intergroup differences with regard to AC and QoL (p &lt; .001). At T3 more than 70% of the patients of the IG reached AC, compared with about 20% of the CG. Also, more than 70% of the IG reached an improvement of ≥ 1 point of the AQLQ (moderate effect), compared with about 20% of the CG. <b>Discussion:</b> PR improves AC and QoL with clinically relevant effect sizes. EPRA is to our best knowledge the first RCT demonstrating the effectiveness of PR in patients with uncontrolled asthma.

11018 Background: The conventional interpretation of superiority oncology trials relies on statistical significance defined by P values, which are frequently misinterpreted and oversimplified. On the other hand, Bayesian analysis, which incorporates prior knowledge, directly estimates the probability of a hypothesis, with greater flexibility to examine clinically relevant effect sizes. Here, we studied the effects of Bayesian models on phase III trial interpretation. We further hypothesized that Bayesian approaches, using differential priors for efficacy and futility, would improve trial efficiency. Methods: Phase III superiority-design, two-arm oncology trials were screened from ClinicalTrials.gov for this meta-epidemiological study. Individual patient-level data were manually reconstructed from the Kaplan-Meir curves of the primary endpoint. First, Bayesian Cox regressions of reconstructed data applied skeptical N (0, 0.355), enthusiastic N (-0.41, 0.4), and neutral priors N (0, 10 6 ), where N (mean, standard deviation) denotes a normal distribution, to estimate posterior probabilities of the primary endpoint effects with Markov chain Monte Carlo sampling. Minimum clinically important differences (MCID) in the experimental arm were defined by HR &lt; 0.8 per ASCO criteria (Ellis et al, J Clin Oncol 2014). Second, a single event or enrollment-driven interim analysis with Bayesian stopping rules was simulated 100 times for each trial using in silico models of randomly varying accrual kinetics with published patient outcomes. Interim efficacy and futility were defined per simulation by probabilities ≥ 85% for achieving effect sizes larger than the MCID/3 using a skeptical or enthusiastic prior, respectively. Early trial closure was recommended if ≥ 75% of simulations met efficacy or futility criteria. Results: After screening,194,129 patient outcomes from 230 trials were reconstructed. Overall survival was the primary endpoint in 90 trials (39%). All trials interpreted as positive had &gt; 90% probabilities of marginal benefits (HR &lt; 1). However, 38% of trials interpreted as positive had ≤ 90% probabilities of achieving the MCID (HR &lt; 0.8), even under an enthusiastic prior. Conversely, 24% of trials interpreted as negative had &gt; 90% probability of achieving marginal benefits, even under a skeptical prior. In the interim analysis simulations, early closure was recommended for 82 trials (36%). Bayesian interim analysis was associated with &gt;99% probability of reducing enrollment sizes. The trial and its simulated interim analysis remained concordant (Bayesian Cohen’s κ, 0.95). Conclusions: Bayesian models add unique interpretative value for clinically relevant effects, and may improve trial efficiency without compromising trial interpretation. Bayesian models should be increasingly incorporated in phase III trials.

BackgroundMany common disorders across the lifespan feature impaired working memory (WM). Reported benefits of a WM training program include improving inattention in daily life, but this has not been evaluated in a meta-analysis. This study aimed to evaluate whether one WM training method has benefits for inattention in daily life by conducting a systematic review and meta-analysis.MethodsWe searched Medline and PsycINFO, relevant journals and contacted authors for studies with an intervention and control group reporting post-training estimates of inattention in daily life. To reduce the influence of different WM training methods on the findings, the review was restricted to trials evaluating the Cogmed method. A meta-analysis calculated the pooled standardised difference in means (SMD) between intervention and control groups.ResultsA total of 622 studies were identified and 12 studies with 13 group comparisons met inclusion criteria. The meta-analysis showed a significant training effect on inattention in daily life, SMD=-0.47, 95% CI -0.65, -0.29, p<.00001. Subgroup analyses showed this significant effect was observed in groups of children and adults as well as users with and without ADHD, and in studies using control groups that were active and non-adaptive, wait-list and passive as well as studies using specific or general measures. Seven of the studies reported follow-up assessment and a meta-analysis showed persisting training benefits for inattention in daily life, SMD=-0.33, 95% CI -0.57 -0.09, p=.006. Additional meta-analyses confirmed improvements after training on visuospatial WM, SMD=0.66, 95% CI 0.43, 0.89, p<.00001, and verbal WM tasks, SMD=0.40, 95% CI 0.18, 0.62, p=.0004.ConclusionsBenefits of a WM training program generalise to improvements in everyday functioning. Initial evidence shows that the Cogmed method has significant benefits for inattention in daily life with a clinically relevant effect size.

In this dissertation, the difficulties and challenges related to the approval of anticancer medicinal products are discussed. In Chapter 1, a general introduction is provided, which focusses on the shift towards precision medicine, the European Union legal framework, authorised anticancer medicinal products and the relevance of evidence generation. In Chapter 2, an overview on European Commission (EC) designated orphan medicinal products (OMPs) for the treatment of pancreatic cancer is provided. We conclude that the success rate of OMPs for pancreatic cancer that reach the market is low. Increasing this rate is something to aspire. Developers are advised to make optimal use of orphan incentives. In addition, developers are strongly encouraged to provide yearly updates on advancements in development. Chapter 3 is dedicated to the question if investigational medicinal products that were granted Breakthrough Therapy designation (BTD) by the Food and Drug Administration (FDA) are truly breakthroughs. Based on our findings, we conclude that the success rate of the BTD program is lower than anticipated, given the few clinical trials that were assigned a high ESMO-MCBS score. Nonetheless, we believe that programs for fast drug approval do have a place in current regulatory practices. Chapter 4 provides detail on how clinical benefit of anticancer medicinal products tested in single-arm trials (SATs) was determined. Our research indicates that there is some room for improvement. This includes prespecifying and motivating a clinically relevant effect size and aligning the sample size to that effect. External controls may facilitate in the contextualisation process, but the limitations associated with such indirect comparisons must be addressed. We consider it of value to further discuss among stakeholders when approval on the basis of lower levels of evidence is justified. In Chapter 5, the possibilities to extend the therapeutic indication(s) of an already authorised medicinal product on the basis of results from investigator-initiated trials (IIT) are explored. We conclude that it is possible to support an extension of indication of an authorised medicinal product on the basis of results from IITs, but regulatory requirements still need to be met. Therefore, a collaborative approach and early dialogue between stakeholders is of importance for future decision-making. In Chapter 6, decision-making aspects of the first tissue-agnostic approvals are compared between the European Medicines Agency (EMA), FDA and Pharmaceuticals and Medical Devices Agency (PMDA). Post-marketing measures related to the tissue-agnostic indication were of specific interest. Our results show that there are different approaches to further confirm the tissue-agnostic indication in the post-marketing setting, albeit these are not without inherent limitations. For future applications, a global strategy toward data generation post-marketing may be of interest. The final chapter (Chapter 7) provides a general discussion and perspectives for follow-up research. It is concluded that further research is needed to ensure that beneficial medicinal products are timely authorised, especially when they address an unmet medical need. Reflecting on prior decision-making and exploring regulatory possibilities, from a multi-stakeholder perspective, will be necessary to continue safeguarding public health.