Outcomes In Randomized Clinical Trials Research Articles

Modern approaches to interpretation of clinical trial results to evaluate the effectiveness of heart failure therapy. Analysis of the results of randomized trials PARADIGM-HF, DAPA-HF, EMPEROR-Reduced and VICTORIA

The article discusses the results of modern studies evaluating the effectiveness of drug therapy for heart failure with reduced ejection fraction (HFrEF). Modern approaches to a comprehensive evaluation of data obtained in various randomized clinical trials (RCTs) are presented. The role of methods for presenting the RCT results is considered, as well as the difference between hazard ratio and relative risk is clarified. Expert opinions are discussed about the limitations of simplified approaches to comparing the results of large RCTs, which are based only on comparisons of hazard ratio without taking consideration of patient characteristics, study duration, and the absolute number of adverse outcomes that developed. Information is provided on the role of accounting for multiple comparisons in assessing clinical outcomes in RCTs. The article compares the VICTORIA results on the study of vericiguat in patients with a recent episode of HFrEF decompensation with RCTs on the evaluation of the effects of drugs that are part of standard therapy.

Planning and Monitoring Equitable Clinical Trial Enrollment Using Goal Programming.

Randomized clinical trial (RCT) studies are the gold standard for scientific evidence on treatment benefits to patients. RCT outcomes may not be generalizable to clinical practice if the trial population is not representative of the patients for which the treatment is intended. Specifically, enrollment plans may not adequately include groups of patients with protected attributes, such as gender, race, or ethnicity. Inequities in RCTs are a major concern for funding agencies such as the National Institutes of Health (NIH) and for policy makers. We address this challenge by proposing a goal-programming approach, explicitly integrating measurable enrollment goals, to design equitable enrollment plans for RCTs. We evaluate our model in both single and multisite settings using the enrollment criteria and study population from the Systolic Blood Pressure Intervention Trial (SPRINT) study. Our model can successfully generate equitable enrollment plans that satisfy multiple goals such as sample representativeness and minimum total financial cost. Our model can detect deviations from a target plan during the enrollment process and update the plan to reduce deviations in the remaining process. Finally, through appropriate site selection in the planning stage, the model can demonstrate the possibility of enrolling a nationally representative study population if geographic constraints exist in multisite recruitment (e.g., clinical centers in a particular region). Our model can be used to prospectively produce and retrospectively evaluate how equitable enrollment plans are based on subjects' protected attributes, and it allows researchers to provide justifications on validity of scientific analysis and evaluation of subgroup disparities.

Predictors, Moderators, and Mediators Associated With Treatment Outcome in Randomized Clinical Trials Among Adolescents With Depression

The application of precision medicine principles for the treatment of depressive disorders in adolescents requires an examination of the variables associated with depression outcomes in randomized clinical trials (RCTs). To describe predictors, moderators, and mediators associated with outcomes in RCTs for the treatment of depressive disorders in adolescents. A scoping review of RCTs for the treatment of depression in adolescents was conducted. Databases searched included MEDLINE, Embase, APA PsycInfo, and CINAHL. Included publications tested predictors, moderators, and/or mediators associated with depression symptom outcomes (eg, symptom reduction, response, remission) in RCTs pertaining to the treatment of adolescents, ages 13 to 17 years. Predictors were defined as variables that were associated with depression outcomes, independent of treatment group. Moderators were defined as baseline variables that were associated with differential outcomes between treatment groups. Mediators were defined by a formal mediation analysis. In duplicate, variables were extracted and coded with respect to analysis type (univariable or multivariable), statistical significance, direction of effect size, reporting of a priori hypotheses, and adjustment for multiple comparisons. Aggregated results were summarized by variable domain and RCT sample. Eighty-one articles reporting on variables associated with outcomes across 33 RCTs were identified, including studies of biological (10 RCTs), psychosocial (18 RCTs), and combined (4 RCTs) treatments as well as a service delivery model (1 RCT). Fifty-three variable domains were tested as baseline predictors of depression outcome, 41 as moderators, 19 as postbaseline predictors, and 5 as mediators. Variable domains that were reported as significant in at least 3 RCTs included age, sex/gender, baseline depression severity, early response to treatment, sleep changes, parent-child conflict, overall psychopathology, suicidal ideation, hopelessness, functional impairment, attendance at therapy sessions, and history of trauma. Two publications reported a priori hypotheses and adjustment for multiple comparisons, both finding that baseline depression severity and family conflict were associated with poorer outcomes. This review identified commonly researched variables requiring more scrutiny as well as underresearched variables to inform future study designs. Further efforts to discover predictors, moderators, and mediators associated with treatment response have great potential to optimize care for adolescents with depression.

Do behavioral pharmacology findings predict clinical trial outcomes? A proof-of-concept in medication development for alcohol use disorder.

Behavioral pharmacology paradigms have been used for early efficacy testing of novel compounds for alcohol use disorder (AUD). However, the degree to which early efficacy in the human laboratory predicts clinical efficacy remains unclear. To address this gap in the literature we employed a novel meta-analytic approach. We searched the literature for medications tested for AUD using both behavioral pharmacology (i.e., alcohol administration) and randomized clinical trials (RCTs). For behavioral pharmacology, we computed medication effects on alcohol-induced stimulation, sedation, and craving during the alcohol administration (k = 51 studies, 24 medications). For RCTs, we computed medication effects on any drinking and heavy drinking (k = 118 studies, 17 medications). We used medication as the unit of analysis and applied the Williamson-York bivariate weighted least squares estimation to preserve the errors in both the independent and dependent variables. Results, with correction for publication bias, revealed a significant and positive relationship between medication effects on alcohol-induced stimulation (β = 1.18 p < 0.05), sedation (β = 2.38, p < 0.05), and craving (β = 3.28, p < 0.001) in the laboratory, and drinking outcomes in RCTs, such that medications that reduced stimulation, sedation, and craving during the alcohol administration were associated with better clinical outcomes. A leave-one-out Monte Carlo analysis examined the predictive utility of these laboratory endpoints for each medication. The observed clinical effect size was within one standard deviation of the mean predicted effect size for all but three pharmacotherapies. This proof-of-concept study demonstrates that behavioral pharmacology endpoints of alcohol-induced stimulation, sedation, and craving track medication effects from the human laboratory to clinical trial outcomes. These results apply to alcohol administration phenotypes and may be especially useful to medications for which the mechanisms of action involve alterations in subjective responses to alcohol (e.g., antagonist medication). These methods and results can be applied to a host of clinical questions and can streamline the process of screening novel compounds for AUD. For instance, this approach can be used to quantify the predictive utility of cue-reactivity screening models and even preclinical models of medication development.

Primary outcome reporting in adolescent depression clinical trials needs standardization

BackgroundEvidence-based health care is informed by results of randomized clinical trials (RCTs) and their syntheses in meta-analyses. When the trial outcomes measured are not clearly described in trial publications, knowledge synthesis, translation, and decision-making may be impeded. While heterogeneity in outcomes measured in adolescent major depressive disorder (MDD) RCTs has been described, the comprehensiveness of outcome reporting is unknown. This study aimed to assess the reporting of primary outcomes in RCTs evaluating treatments for adolescent MDD.MethodsRCTs evaluating treatment interventions in adolescents with a diagnosis of MDD published between 2008 and 2017 specifying a single primary outcome were eligible for outcome reporting assessment. Outcome reporting assessment was done independently in duplicate using a comprehensive checklist of 58 reporting items. Primary outcome information provided in each RCT publication was scored as “fully reported”, “partially reported”, or “not reported” for each checklist item, as applicable.ResultsEighteen of 42 identified articles were found to have a discernable single primary outcome and were included for outcome reporting assessment. Most trials (72%) did not fully report on over half of the 58 checklist items. Items describing masking of outcome assessors, timing and frequency of outcome assessment, and outcome analyses were fully reported in over 70% of trials. Items less frequently reported included outcome measurement instrument properties (ranging from 6 to 17%), justification of timing and frequency of outcome assessment (6%), and justification of criteria used for clinically significant differences (17%). The overall comprehensiveness of reporting appeared stable over time.ConclusionsHeterogeneous reporting exists in published adolescent MDD RCTs, with frequent omissions of key details about their primary outcomes. These omissions may impair interpretability, replicability, and synthesis of RCTs that inform clinical guidelines and decision-making in this field. Consensus on the minimal criteria for outcome reporting in adolescent MDD RCTs is needed.

Metastatic melanoma patient outcomes since introduction of immune checkpoint inhibitors in England between 2014 and 2018.

e19310 Background: Population-based research provides real world information about prescribing trends, as well as benefits and harms associated with new interventions first evaluated in randomized clinical trials (RCTs). The national health service in England collects data on systemic anti-cancer therapy (SACT) prescribed to patients. We retrospectively examined outcomes including overall survival (OS) and treatment toxicity for patients (pts) prescribed checkpoint inhibitors (CPIs) approved for 1st line use in metastatic melanoma. Methods: National Cancer Registration and Analysis Service (NCRAS) datasets were used to identify metastatic melanoma pts prescribed 1st line CPIs and calculate survival outcomes. The Hospital Episode Statistics database was used to identify emergency department attendances and emergency hospital admissions. Results: Between April 2014 and March 2018, 5,465 melanoma pts were prescribed SACT. Of these, 2,322 pts received 1st line CPIs for metastatic disease at 56 different hospitals in England: 1,174 were prescribed pembrolizumab (pembro), 724 ipilimumab (ipi), 52 nivolumab (nivo), 372 ipinivo. Prescribing reflected national access, starting with ipi in July 2014, replaced by pembro in Nov 2015 and ipinivo prescriptions started in July 2016. By 2018, 1 in 3 pts were receiving ipinivo as treatment of choice. There was high concordance for 3yr OS with RCT outcomes for ipi (32%) and ipinivo (58%), but pembro outcomes were poorer (40%). Pts prescribed pembro were significantly older (51% vs. 12% &gt;70 years) and frailer (38% vs. 61% ECOG PS 0) than pts prescribed ipinivo (p&lt;0.0001). 30-day rates of emergency hospital attendances/admissions from the earliest SACT and last SACT treatment dates were significantly higher for ipinivo (16%/37% and 19%/55%) compared with pembro (8%/17% and 14%/29%). Colitis was the most common IrAE associated with hospitalization: 25% with ipinivo and 4% with pembro. 30-day mortality from last SACT was 3.8% with ipinivo and 9.1% with pembro (p&lt;0.0001). Conclusions: Linked real world datasets demonstrated OS outcomes remarkably similar to RCTs associated with ipi and ipinivo, while poorer outcomes associated with pembro may reflect patient selection bias. Ipinivo generated the highest rates of emergency hospital visits and admissions, but 30-day mortality was not compromised, potentially reflecting efficient and effective management of complications. Hospital-level outcomes and 30-day mortality causes are now being assessed to explore variations in care.

Metastatic melanoma patient outcomes since introduction of immune checkpoint inhibitors in England between 2014 and 2018.

55 Background: Population-based research provides real world information about prescribing trends, as well as benefits and harms associated with new interventions first evaluated in randomized clinical trials (RCTs). The national health service in England has comprehensive databases which we used to track prescribing of checkpoint inhibitors (CPIs) approved for 1st line use in metastatic melanoma and determine patient outcomes associated with survival and treatment toxicity. Methods: National Cancer Registration and Analysis Services (NCRAS) datasets were used to identify metastatic melanoma patients (pts) prescribed 1st line CPIs and calculate survival outcomes. The HES (Hospital Episode Statistics) database was used to identify emergency attendances and emergency hospital admissions. Results: 5465 melanoma pts were registered between April ‘14 and March ‘18. 2322 pts received 1st line CPIs: 1174 pembrolizumab (pem), 724 ipilimumab (ipi), 52 nivolumab (nivo), 372 ipinivo. Prescribing reflected national access, with ipi starting in July ‘14 and dropping rapidly on approval of pem in Nov ’15. Ipinivo prescriptions increased annually since July ’16. There was good 3yr OS concordance with RCT outcomes for ipinivo (56%), nivo (51%), pembro (40%) and ipi (32%). Pts treated with ipinivo were significantly younger (88% vs 49% &lt;70 years, P&lt;0.001) and fitter (60% vs 38% ECOG PS 0, P&lt;0.0001) than pts treated with antiPD1. 30-day mortality from last SACT was 3.8% for ipinivo, 9.1% for antiPD1 and 9.4% for ipi. 30-day rates of emergency hospital admissions/A&amp;E emergency attendances from the earliest SACT and last SACT treatment dates were significantly higher for ipinivo (37%/16% and 55%/19%) compared with antiPD1 (17%/8% and 29%/14%) and ipi (24%/9% and 40%/15%), P&lt;0.01. 25% of ipinivo-, 4% of antiPD1- and 15% of ipi-treated pts had a hospital admission for colitis. Conclusions: This largest real world dataset demonstrated rapid uptake of CPIs and survival outcomes similar to RCTs. Use of emergency services varied by regimen, with colitis dominating hospitalization after ipi+/-nivo. Pt selection appeared to differ for different regimens, the consequences of which warrant further research.

Understanding of interaction (subgroup) analysis in clinical trials.

When the treatment effect on the outcome of interest is influenced by a baseline/demographic factor, investigators say that an interaction is present. In randomized clinical trials (RCTs), this type of analysis is typically referred to as subgroup analysis. Although interaction (or subgroup) analyses are usually stated as a secondary study objective, it is not uncommon that these results lead to changes in treatment protocols or even modify public health policies. Nonetheless, recent reviews have indicated that their proper assessment, interpretation and reporting remain challenging. Therefore, this article provides an overview of these challenges, to help investigators find the best strategy for application of interaction analyses on binary outcomes in RCTs. Specifically, we discuss the key points of formal interaction testing, including the estimation of both additive and multiplicative interaction effects. We also provide recommendations that, if adhered to, could increase the clarity and the completeness of reports of RCTs. Altogether, this article provides a brief non-statistical guide for clinical investigators on how to perform, interpret and report interaction (subgroup) analyses in RCTs.

Using real-world cohorts to assess the generalizability and relevance of randomized clinical trials (RCTs).

6540 Background: RCTs are the gold standard for understanding the efficacy of new treatments, however, patients (pts) in RCTs often differ from those treated in the real-world. Further, selecting a standard of care (SOC) arm is challenging as treatment options may evolve during the course of a RCT. Our objective was to assess the generalizability and relevance of RCTs supporting recent FDA approvals of anticancer therapies. Methods: RCTs were identified that supported FDA approvals of anticancer therapies (1/1/2016 - 4/30/2018). Relevant pts were selected from the Flatiron Health longitudinal, EHR-derived database, where available. Two metrics were calculated: 1) a trial’s pt generalizability score (% of real-world pts receiving treatment consistent with the control arm therapy for the relevant indication who actually met the trial's eligibility criteria) and 2) a trial’s SOC relevance score (% of real-world pts with the relevant indication and meeting the trial's eligibility criteria who actually received treatment consistent with the control arm therapy). All analyses excluded real-world pts treated after the relevant trial’s enrollment ended. Results: 14 RCTs across 5 cancer types (metastatic breast, advanced non-small cell lung cancer, metastatic renal cell carcinoma, multiple myeloma, and advanced urothelial) were included. There was wide variation in the SOC relevance and pt generalizability scores. The median pt generalizability score was 63% (range 35% - 88%), indicating that most real-world pts would have met the RCT eligibility criteria. The median SOC relevance score was 37% (range 15% - 74%), indicating that most RCT control arms did not reflect the way trial-eligible real-world pts in the US were actually treated. Conclusions: There is great variability across recent RCTs in terms of pt generalizability and relevance of SOC arms. Real-world data can be used to inform selection of control arms, predict impact of inclusion/exclusion criteria, and also assess the generalizability of the results of completed trials. Incorporating real-world data in planning and interpretation of prospective clinical trials could improve accrual and enhance relevance of RCT outcomes.

Short-term neuropsychiatric tolerability of bictegravir combined with emtricitabine/tenofovir alafenamide in clinical practice.

Neuropsychiatric AEs (NPAEs) leading to dolutegravir (DTG) discontinuation were seen more frequently in real-world use than in randomized clinical trials (RCTs). The recently approved fixed-dose combination bictegravir plus emtricitabine and tenofovir alafenamide (BIC/F/TAF) has shown comparable NPAE rates but some favourable patient-reported outcomes in RCTs compared with DTG. We were interested in its neuropsychiatric tolerability in clinical practice. All patients starting BIC/F/TAF from June 2018 in a single centre (two subcentres) were followed retrospectively. Discontinuation rates due to any AEs and NPAEs were compared with those of patients initiating DTG-based regimens. As of May 2019, a total of 943 patients (852 males, 76 females, 15 transgender and gender diverse) initiated BIC/F/TAF outside RCTs. After a median follow-up of 6.2 months, 50 (5.3%) and 31 (3.3%) patients had discontinued BIC/F/TAF due to any AEs or to NPAEs, respectively. In multivariate analysis, a pre-existing depression and subcentre remained predictive for NPAEs, but not age, gender, ethnicity or prior DTG-related AEs. Compared with 1,043 patients treated with DTG-based regimens, the estimated NPAE-related discontinuation rate with BIC/F/TAF was comparable during the first 6 months (P=0.36). Cross-intolerance was low, and only 5/55 patients with prior DTG intolerability had to discontinue BIC/F/TAF due to NPAEs. Short-term tolerability of BIC/F/TAF was comparable to DTG-containing regimens. As seen with DTG, discontinuation rates were higher than in RCTs. A pre-existing depression but also physician's awareness may have an impact on tolerability and continuation of BIC/F/TAF. In contrast, prior intolerability of DTG was of limited predictive value.

An Individualized, Interactive Intervention Promotes Terminally Ill Cancer Patients' Prognostic Awareness and Reduces Cardiopulmonary Resuscitation Received in the Last Month of Life: Secondary Analysis of a Randomized Clinical Trial

Context/ObjectiveHalf of advanced cancer patients do not have accurate prognostic awareness (PA). However, few randomized clinical trials (RCTs) have focused on facilitating patients' PA to reduce their life-sustaining treatments at end of life (EOL). To address these issues, we conducted a double-blinded RCT on terminally ill cancer patients. MethodsExperimental-arm participants received an individualized, interactive intervention tailored to their readiness for advanced care planning and prognostic information. Control-arm participants received a symptom-management educational treatment. Effectiveness of our intervention in facilitating accurate PA and reducing life-sustaining treatments received, two secondary RCT outcomes, was evaluated by intention-to-treat analysis using multivariate logistic regression. ResultsParticipants (N = 460) were randomly assigned 1:1 to experimental and control arms, each with 215 participants in the final sample. Referring to 151–180 days before death, experimental-arm participants had significantly higher odds of accurate PA than control-arm participants 61–90, 91–120, and 121–150 days before death (adjusted odds ratio [95% CI]: 2.04 [1.16–3.61], 1.94 [1.09–3.45], and 1.93 [1.16–3.21], respectively), but not one to 60 days before death. Experimental-arm participants with accurate PA were significantly less likely than control-arm participants without accurate PA to receive cardiopulmonary resuscitation (CPR) (0.16 [0.03–0.73]), but not less likely to receive intensive care unit care and mechanical ventilation in their last month. ConclusionOur intervention facilitated cancer patients' accurate PA early in their dying trajectory, reducing the risk of receiving CPR in the last month. Health care professionals should cultivate cancer patients' accurate PA early in the terminal-illness trajectory to allow them sufficient time to make informed EOL-care decisions to reduce CPR at EOL.

PSS8 - IDENTIFYING THE CONFOUNDERS THAT EXPLAIN THE DIFFERENCE IN READOUTS BETWEEN NON-INTERVENTIONAL STUDIES (NIS) AND RANDOMIZED CONTROLLED TRIALS (RCTS): THE CASE OF TREATMENTS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION (NAMD)

The effectiveness of intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents is usually lower in real-world settings compared to randomized clinical trials (RCTs). Identifying matching cohorts might bridge the gap in clinical outcomes, but there is uncertainty about which factors to include in the matching process. This study aimed to identify potential confounders that explain the difference in readouts between non-interventional studies (NIS) and RCTs in nAMD patients using an algorithm based on ranibizumab real-world data (RWD), in reference to the CATT study1 results. A step-wise, predictive analytics approach was applied to develop a decision model where the terminal nodes represented the most influential factors on visual acuity (VA) at the end of year 1. The decision tree used electronic medical records (EMR) data from the USA. The algorithm was validated using EMR data from UK and Australia. The algorithm identified the following criteria as impactful on readouts: 1) Age>50 years, 2) Baseline VA<73 ETDRS letters, 3) presence of sub-retinal fluid and 4) administration of 3 loading doses by day-90 from drug initiation. When applying criterion 1, patients showed an increase in VA of 0.07. Application of criterion 2 increased VA by 1.08. Similarly, when criteria 3&4 were applied in addition to 1&2, VA increased by 3.22 and 5.25, respectively. VA results after applying the complete algorithm were comparable to those of the CATT trial which demonstrated a 6 letter gain. In nAMD, core attributes that matched NIS with RCT outcomes were age, baseline VA, sub-retinal fluid and loading-dose as label recommended. Our investigation demonstrates that RWD can generate clinical efficacy (VA) comparable to RCTs. These results highlight the impact of under-treatment and loading-dose on VA and build confidence in real-world evidence and its ability to support meaningful dialogue with ophthalmologists and retina specialists. 1Ophthalmology. 2016;123(8):1751-1761.

A Systematic Review of Outcome Measures Employed in Aneurysmal Subarachnoid Hemorrhage (aSAH) Clinical Research.

Consensus on appropriate outcome measures to use in aneurysmal subarachnoid hemorrhage (aSAH) research has not been established, although the transition toward a core outcome set (COS) would provide significant benefits. To inform COS development, we conducted a systematic review to identify outcome measures included in reports of randomized clinical trials (RCTs) of interventions in patients with aSAH. Ovid Medline, EMBASE, CINAHL, and CENTRAL were searched. RCTs investigating aSAH published between January 1996 and May 2015 were included. The primary and secondary outcomes of RCTs were recorded and classified according to the OMERACT Consortium's framework. We identified 1093 potential studies of which 129 met inclusion criteria representing 24 238 patients. There were 285 unique outcome measures. The Glasgow Outcome Scale (GOS) was the most frequently used primary outcome (13/129, 10.1%). Mortality was reported in 84 trials (65.1%) with 3months the most common time point (34/129, 26.4%). The GOS (65/129, 50.4%) and the Modified Rankin Scale (51/129, 39.5%) were the most commonly reported functional measures; however, these were reported at different time points and often dichotomized using different ranges. Patient-reported quality of life measures were used in 11 trials (8.5%). Transcranial Doppler was the most frequently used imaging modality (40/129, 31.0%). Definitions and reporting of vasospasm, delayed cerebral ischemia and imaging modality results were highly variable. The marked heterogeneity of outcomes in reports of RCTs supports the development of a core outcome set for aSAH trials. Our study has identified a wide range of outcomes for potential inclusion in a future aSAH COS.

Device Safety Implications of the Clinical Data Leading to US Food and Drug Administration Approval of Soft-Tissue Fillers: A Systematic Review.

The US Food and Drug Administration (FDA) recently issued a safety warning regarding soft-tissue fillers (STFs) based on the risk of blindness and facial necrosis. To examine the quality of evidence leading to FDA approval of STFs. All original approvals for STFs were mined using the publicly available FDA database. The Cochrane Collaboration's risk of bias assessment tool was applied to all randomized clinical trials (RCTs). A total of 14 STF approvals were identified. Of those, 10 pivotal studies (71%) were RCTs and 9 (60%) were masked. The median number of patients per trial was 144 (range, 30-439). Eleven of 12 studies (92%) met their primary end point. Ten of 14 trials (71%) involved injections solely of the nasolabial folds or cheeks; only 4 trials involved treatment of other facial regions. All 10 RCTs had an unclear risk of selection bias. Only 2 RCTs reported exclusions and attrition. Safety warnings relate more to the off-label use of STFs, which has not been sufficiently studied prospectively. Although STFs remain a safe device, with approval based mostly on RCT outcomes, implementation of unique device identifiers and greater use of physician-led registries would ensure physician, consumer, and regulatory confidence in STF safety.

Use of Bayesian Decision Analysis to Minimize Harm in Patient-Centered Randomized Clinical Trials in Oncology

Randomized clinical trials (RCTs) currently apply the same statistical threshold of alpha = 2.5% for controlling for false-positive results or type 1 error, regardless of the burden of disease or patient preferences. Is there an objective and systematic framework for designing RCTs that incorporates these considerations on a case-by-case basis? To apply Bayesian decision analysis (BDA) to cancer therapeutics to choose an alpha and sample size that minimize the potential harm to current and future patients under both null and alternative hypotheses. We used the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database and data from the 10 clinical trials of the Alliance for Clinical Trials in Oncology. The NCI SEER database was used because it is the most comprehensive cancer database in the United States. The Alliance trial data was used owing to the quality and breadth of data, and because of the expertise in these trials of one of us (D.J.S.). The NCI SEER and Alliance data have already been thoroughly vetted. Computations were replicated independently by 2 coauthors and reviewed by all coauthors. Our prior hypothesis was that an alpha of 2.5% would not minimize the overall expected harm to current and future patients for the most deadly cancers, and that a less conservative alpha may be necessary. Our primary study outcomes involve measuring the potential harm to patients under both null and alternative hypotheses using NCI and Alliance data, and then computing BDA-optimal type 1 error rates and sample sizes for oncology RCTs. We computed BDA-optimal parameters for the 23 most common cancer sites using NCI data, and for the 10 Alliance clinical trials. For RCTs involving therapies for cancers with short survival times, no existing treatments, and low prevalence, the BDA-optimal type 1 error rates were much higher than the traditional 2.5%. For cancers with longer survival times, existing treatments, and high prevalence, the corresponding BDA-optimal error rates were much lower, in some cases even lower than 2.5%. Bayesian decision analysis is a systematic, objective, transparent, and repeatable process for deciding the outcomes of RCTs that explicitly incorporates burden of disease and patient preferences.

Handling clinical comorbidity in randomized clinical trials in psychiatry

The purpose of this paper is to a) outline the importance of including patients with clinical comorbidities in Randomized Clinical Trials (RCTs) of psychiatric treatments; and b) to propose a specific approach for best handling, analyzing and interpreting the data on clinical comorbidities in terms of their impact on treatment outcomes. To do this we first define and describe clinical comorbidity and differentiate it from other forms of comorbidity. We then describe the methodological and analytical problems associated with excluding patients with clinically comorbid conditions from RCTs, including the impact on the outcomes of RCTs in psychiatry and the impact on evidence-based clinical decision-making. We then address the challenges inherent to including patients with clinical comorbidities in RCTs. Finally, we propose a methodological and analytic approach to deal with these issues in RCTs which aims to significantly improve the information yielded from RCTs in psychiatry, and thus improve clinical decision-making.

Targeted Temperature Management and Acute Brain Injury: An Update from Recent Clinical Trials

The neuroprotective effects of therapeutic hypothermia—increasingly known as targeted temperature management (TTM)—have been recognized for decades, but translation into positive randomized clinical trial outcomes has proved difficult. Although there is level I evidence supporting TTM in adult cardiac arrest and neonatal hypoxic–ischemic encephalopathy, uncertainty remains about optimal temperature targets, exemplified by recent adult cardiac arrest data suggesting that cooling to 36 °C is equally as effective as cooling to 33 °C. For other forms of acute brain injury, the evidence supporting TTM is less clear and, in particular, recent traumatic brain injury trial data were disappointing. Further studies are required to address the logistics of implementing TTM in brain injury, including optimal temperature, timing of onset and duration, and complication management. In addition, further high-quality studies are needed to fully assess the role of TTM in stroke and other forms of acute brain injury.

PCV98 - Statin Cost-Effectiveness in Patients with Previous Coronary Heart Disease: A Systematic Review of the Cost-Effectiveness Analysis Derived from Single Randomised Clinical Trials

Large randomized clinical trials (RCT) evidenced the benefits of statins in reducing major cardiovascular events in patients with established coronary heart disease (CHD). These multinational trials are likely to provide internally valid evidence. Cost-effectiveness analysis based on single trials costs and effects are common and represent the potential net benefit of an intervention in a well-controlled environment. The aim of this study is to systematically review the cost-effectiveness studies based on statins single trials in patients with previous CHD. We searched to identify all literature relating to the cost-effectiveness of statins in the secondary prevention in patients with established CHD. Only studies with the effectiveness data extracted from a single RCT and clinical outcomes such as quality assessment, mortality or cardiovascular events rate were included. The cost per QALY was classified according to the WHO, following three categories of cost-effectiveness, Highly cost-effective, Cost-effective and Not cost-effective, adjusted with GDP per capita based on purchasing power parity (constant 2005 international USD). Twenty-one studies were included in the final analysis, covering a period range from 1996 to 2009. 7 large RCTs represented the origin of efficacy data. Most of studies assumed a full compliance, the Markov models were used in 11 out 21 studies. Time horizon ranged from 5 years to time life, with 10 years being the predominant choice. 9 studies performed a cost-utility analysis and showed the average cost per QALY, 8 of them classified as highly cost-effective and 1 cost-effective. Cost per QALY was sensitive for drug price, time horizon and event rates, 6 of this models models worked with composite endpoints. Statins are highly cost-effective in patients with CHD when effect size came from single well designed RCTs. Models heterogeneity and composite endpoints can decrease the robustness of the results.

Typology of the Primary Outcome Construction in Dermatology: A Systematic Review of Published Randomized Controlled Trials

The primary outcome is a major component of a randomized clinical trial (RCT) and several types of outcome can be chosen in a given disease. We systematically reviewed RCTs on nonneoplastic dermatological diseases published in 2009 and referenced in Medline, and described how the main outcome was defined and constructed. We assessed whether those characteristics were associated with a clearly defined primary outcome and whether they were associated with a significant statistical test for the primary outcome. Outcome construction variables were the three "VIP" questions (V denoting Variable: binary vs. quantitative variable; I denoting Item: data collection based on multiple vs. single item(s); and P denoting time Points: outcome assessment based on a "final time point" vs. "final and initial time points"). Among 122 RCTs, 32% did not have a clearly defined primary outcome. In multivariable analyses, a clearly defined primary outcome was associated with a binary variable (odds ratio (OR)=6.7; 2.5-17.7) and the composite variable "both blinding/placebo-controlled arm" (OR=4.5; 1.8-11.2); a significant statistical test was associated with a "final time point"-based outcome construction (OR=2.6; 1.2-5.5). Our study points to areas of improvement related to the definition and construction of the primary outcome in RCTs in dermatology.

Survival after lumpectomy and mastectomy for early stage invasive breast cancer

AbstractBACKGROUND:Randomized clinical trials (RCT) have demonstrated equivalent survival for breast‐conserving therapy with radiation (BCT) and mastectomy for early‐stage breast cancer. A large, population‐based series of women who underwent BCT or mastectomy was studied to observe whether outcomes of RCT were achieved in the general population, and whether survival differed by surgery type when stratified by age and hormone receptor (HR) status.METHODS:Information was obtained regarding all women diagnosed in the state of California with stage I or II breast cancer between 1990 and 2004, who were treated with either BCT or mastectomy and followed for vital status through December 2009. Cox proportional hazards modeling was used to compare overall survival (OS) and disease‐specific survival (DSS) between BCT and mastectomy groups. Analyses were stratified by age group (&lt; 50 years and ≥ 50 years) and tumor HR status.RESULTS:A total of 112,154 women fulfilled eligibility criteria. Women undergoing BCT had improved OS and DSS compared with women with mastectomy (adjusted hazard ratio for OS entire cohort = 0.81, 95% confidence interval [CI] = 0.80‐0.83). The DSS benefit with BCT compared with mastectomy was greater among women age ≥ 50 with HR‐positive disease (hazard ratio = 0.86, 95% CI = 0.82‐0.91) than among women age &lt; 50 with HR‐negative disease (hazard ratio = 0.88, 95% CI = 0.79‐0.98); however, this trend was seen among all subgroups analyzed.CONCLUSIONS:Among patients with early stage breast cancer, BCT was associated with improved DSS. These data provide confidence that BCT remains an effective alternative to mastectomy for early stage disease regardless of age or HR status. Cancer 2013. © 2012 American Cancer Society.