Generalizability Of Trial Results Research Articles

Geographical variation in patient characteristics and outcomes in heart failure with mildly reduced and preserved ejection fraction.

Compared to heart failure (HF) with reduced ejection fraction, HF with preserved ejection fraction (HFpEF), and HF with mildly reduced ejection fraction (HFmrEF) are increasing in prevalence, yet little is known about the geographic variation in patient characteristics, treatments and outcomes among these two HF phenotypes. The aim of this study was to investigate geographic differences in HFpEF and HFmrEF. We conducted an individual patient analysis of five clinical trials enrolling patients with HFpEF or HFmrEF from North America (NA), Latin America (LA), Western Europe (WE), Central/Eastern Europe and Russia (CEER), and Asia-Pacific (AP). We compared regions using descriptive statistics and multivariable regression models. Among the 19 959 patients included, 4066 (23.1%) had HFmrEF and 15 353 (76.9%) HFpEF. Regardless of HF phenotype, patients from WE were oldest, and those in CEER youngest. LA had the largest portion of females and NA most black patients. Obesity and diabetes were most prevalent in NA and hypertension and coronary heart disease most common in CEER. Self-reported health status varied strikingly and was the worst in NA and best in AP. Among patients with HFmrEF, rates of the primary composite endpoint (cardiovascular death or HF hospitalization) were: NA 12.56 per 100 patient-years (/100py), AP 11.67/100py, CEER 10.12/100py, LA 8.90/100py, and WE 8.43/100py, driven by differences in the rate of HF hospitalization. The corresponding values in HFpEF were 11.47/100py, 7.80/100py, 5.47/100py, 5.92/100py, and 7.80/100py, respectively. There is substantial geographic variation in patient characteristics, treatment and outcomes among patients with HFpEF and HFmrEF. These findings have implications for interpretation and generalizability of trial results, design and conduct of future trials, and optimization of care for these patients.

Efficacy-effectiveness analysis on survival in a population-based real-world study of BRAF-mutated metastatic colorectal cancer patients treated with encorafenib-cetuximab.

Encorafenib-cetuximab has been approved for pretreated BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients based on efficacy demonstrated in the randomized phase III BEACON trial. The aim of this real-world effectiveness study is to improve knowledge on the generalizability of trial results. This population-based real-world study includes all mCRC patients in the Netherlands treated with encorafenib-cetuximab since approval. Individual patient data and pathology reports were collected. Overall survival (OS) was compared to BEACON and subgroup analyses were conducted for patients who would have been eligible and ineligible for BEACON. 166 patients were included with a median follow-up time of 14.5 months. Median OS was 6.7 months (95% CI:6.0-8.3) and differed from BEACON (9.3 months; 95% CI:8.0-11.3, p-value 0.002). Thirty-six percent of real-world patients would have been ineligible for the BEACON trial. Trial ineligible subgroups with symptomatic brain metastases and WHO performance status ≥2 had the poorest median OS of 5.0 months (95% CI:4.0-NR) and 3.9 months (95% CI:2.4-NR). This real-world cohort of mCRC patients treated with encorafenib-cetuximab showed a clinically relevant efficacy-effectiveness gap for OS. The chance of survival benefit from encorafenib-cetuximab in patients with brain metastases and/or WHO performance status ≥2 is negligible as neither efficacy nor effectiveness has been demonstrated.

Harnessing the Potential of Real-World Evidence in the Treatment of Colorectal Cancer: Where Do We Stand?

Treatment guidelines for colorectal cancer (CRC) are primarily based on the results of randomized clinical trials (RCTs), the gold standard methodology to evaluate safety and efficacy of oncological treatments. However, generalizability of trial results is often limited due to stringent eligibility criteria, underrepresentation of specific populations, and more heterogeneity in clinical practice. This may result in an efficacy-effectiveness gap and uncertainty regarding meaningful benefit versus treatment harm. Meanwhile, conduct of traditional RCTs has become increasingly challenging due to identification of a growing number of (small) molecular subtypes. These challenges-combined with the digitalization of health records-have led to growing interest in use of real-world data (RWD) to complement evidence from RCTs. RWD is used to evaluate epidemiological trends, quality of care, treatment effectiveness, long-term (rare) safety, and quality of life (QoL) measures. In addition, RWD is increasingly considered in decision-making by clinicians, regulators, and payers. In this narrative review, we elaborate on these applications in CRC, and provide illustrative examples. As long as the quality of RWD is safeguarded, ongoing developments, such as common data models, federated learning, and predictive modelling, will further unfold its potential. First, whenever possible, we recommend conducting pragmatic trials, such as registry-based RCTs, to optimize generalizability and answer clinical questions that are not addressed in registrational trials. Second, we argue that marketing approval should be conditional for patients who would have been ineligible for the registrational trial, awaiting planned (non) randomized evaluation of outcomes in the real world. Third, high-quality effectiveness results should be incorporated in treatment guidelines to aid in patient counseling. We believe that a coordinated effort from all stakeholders is essential to improve the quality of RWD, create a learning healthcare system with optimal use of trials and real-world evidence (RWE), and ultimately ensure personalized care for every CRC patient.

Balancing evidence-based care with patient-centered individualized care

Weak evidence, when manifested in clinical guidelines, can translate into biased vascular care. In vascular surgery, we have few randomized controlled trials with appropriate representation of females and persons of color, so generalizability of trial results can be problematic. Physicians are required to balance evidenced-based care (which is only as good as the underlying evidence) with personalized treatment recommendations that are often based on demographics, social circumstances, and/or existing therapeutic relationships. Biases, whether implicit or explicit, have an oversized effect on treatment decisions, and patient outcomes. In this commentary, we propose three principles to strengthen the vascular surgery evidence foundation and patient-centered decision-making going forward: (1) generating evidence designed for individualized care, (2) constructing clinical guidelines that are context specific and complexity aware, and (3) strengthening the training and support for surgeons to deliver patient-centered individualized care.

Overall survival of patients with BRAF-mutant metastatic colorectal cancer treated with encorafenib-cetuximab in a real-world nationwide study in the Netherlands.

3589 Background: Approximately 10-15% of patients with metastatic colorectal cancer (mCRC) have BRAFV600E mutated tumors. Encorafenib plus cetuximab (EC) combination treatment was approved following the results of the randomized phase III BEACON trial and is currently recommended for all pretreated patients with BRAFV600E-mutant mCRC. Selection of patients in randomized controlled trials is based on restrictive eligibility criteria and often not representative of the patient population in daily clinical practice. Complementary real-world effectiveness studies can improve knowledge on the generalizability of trial results, and support decision making in clinical practice. Methods: This population-based study included all mCRC patients in the Netherlands treated with EC since approval in October 2020 until June 2022. Individual patient data and original pathology reports were collected. Primary endpoint was overall survival (OS), defined as time from EC initiation until death by any cause, analyzed by Kaplan-Meier curves. WebPlotDigitizer was used to reconstruct the Kaplan-Meier survival curve of the BEACON trial. Uni- and multivariable analyses were performed. Subgroup analyses were conducted for patients who would have been eligible for the BEACON trial based on key eligibility criteria: BRAFV600E mutation, 1-2 prior regimens, world health organization performance status (WHO PS) of 0-1, normal neutrophil count, absence of brain metastases, no prior RAS/RAF/MEK treatment, and no concurrent malignancies. Results: 155 patients were included with a median follow-up time of 11.1 months. Patient characteristics differed from BEACON in mean age (64 versus 60 years), primary tumor sidedness (69% versus 50% right-sided) and WHO PS (23% versus 51% WHO 0). Median OS of the total real-world cohort was 6.6 months (95% CI: 6.0-8.3) and differed significantly from BEACON (9.3 months; 95% CI: 8.0-11.3; p = 0.003). 35% of real-world patients treated with EC would not have been eligible for the BEACON trial, showing an inferior median OS of 6.0 months (95% CI: 4.6-9.2) compared to 7.0 months (95% CI: 6.4-9.8) in trial eligible real-world patients. WHO PS was independently associated with poor survival in multivariable analysis. Patients with WHO PS≥2 had a median OS of 3.9 months (95% CI: 2.4-NA) with a hazard rate of 2.5 (95% CI: 1.1-5.5; p = 0.003). Conclusions: This largest to date - unselected - population-based cohort of mCRC patients treated with EC showed an efficacy-effectiveness gap for OS. These outcomes should be considered in clinical practice for treatment decision making. Omitting EC for subgroups demonstrating very short OS, such as patients with WHO PS ≥2, needs to be considered. Further research is warranted to adapt treatment guidelines towards a more personalized approach for patients with BRAFV600E-mutated mCRC.

Global representation of heart failure clinical trial leaders and collaborators: a systematic bibliometric review 2000–2020

Abstract Aims Heart Failure (HF) has a disproportionate burden in low- and middle-income countries. The geographic representation of those who lead HF randomized clinical trials (RCTs) may not reflect the geographic burden of disease. We assessed temporal trends and trial characteristics associated with leadership outside Europe and North America, and explored whether there was a geographic association between trial leadership and participant enrolment. Methods and results We searched MEDLINE, EMBASE, and CINAHL for HF RCTs published in journals with an impact factor ≥10 between January 1, 2000, and June 17, 2020. We used the Jonckheere-Terpstra test to assess temporal trends and multivariable logistic regression models to determine associations between predictor and outcome variables. There were 414 eligible RCTs. Only 80 of 828 trial leaders (9.7%; 95% CI: 7.8% to 11.8%), and 453 of 4656 collaborators (9.7%; 95% CI: 8.8% to 10.6%) were from regions outside Europe and North America, with no temporal change in geographic representation. The odds of trial leadership outside Europe and North America were significantly lower with industry versus public funding (OR: 0.33; 95% CI: 0.15 to 0.75; P=0.008). Trial leadership outside Europe and North America was associated with enrolment of patients outside Europe and North America (OR: 10.0; 95% CI 5.6–19.0; P<0.001). Conclusion Trial leadership outside Europe and North America is rare, particularly in industry funded trials, and is associated with participant enrolment in regions with disproportionate disease burden. Building research capacity and networks in under-represented regions could increase generalizability of trial results. Funding Acknowledgement Type of funding sources: None.

Characteristics of Clinical Trial Participants with Duchenne Muscular Dystrophy: Data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet).

Background: Therapeutic trials are critical to improving outcomes for individuals diagnosed with Duchenne muscular dystrophy (DMD). Understanding predictors of clinical trial participation could maximize enrollment. Methods: Data from six sites (Colorado, Iowa, Piedmont region North Carolina, South Carolina, Utah, and western New York) of the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) were analyzed. Clinical trial participation and individual-level clinical and sociodemographic characteristics were obtained from medical records for the 2000–2015 calendar years. County-level characteristics were determined from linkage of the most recent county of residence identified from medical records and publicly available federal datasets. Fisher’s exact and Wilcoxon two-sample tests were used with statistical significance set at one-sided p-value (<0.05) based on the hypothesis that nonparticipants had fewer resources. Results: Clinical trial participation was identified among 17.9% (MD STARnet site: 3.7–27.3%) of 358 individuals with DMD. Corticosteroids, tadalafil, and ataluren (PTC124) were the most common trial medications recorded. Fewer non-Hispanic blacks or Hispanics than non-Hispanic whites participated in clinical trials. Trial participants tended to reside in counties with lower percentages of non-Hispanic blacks. Conclusion: Understanding characteristics associated with clinical trial participation is critical for identifying participation barriers and generalizability of trial results. MD STARnet is uniquely able to track clinical trial participation through surveillance and describe patterns of participation.

Systematic Review of PD-1/PD-L1 Inhibitors in Oncology: From Personalized Medicine to Public Health.

BackgroundTo review and summarize all U.S. Food and Drug Administration (FDA) approvals of programmed death (PD)‐1 and PD‐ligand 1 blocking antibodies (collectively referred to as PD‐[L]1 inhibitors) over a 6‐year period and corresponding companion/complementary diagnostic assays.Materials and MethodsTo determine the indications and pivotal trials eligible for inclusion, approval letters and package inserts available on Drugs@FDA were evaluated for approved PD‐[L]1 inhibitors to identify all new indications granted from the first approval of a PD‐[L]1 inhibitor on September 4, 2014, through September 3, 2020. The corresponding FDA drug and device reviews from the marketing applications for the approved indications were identified through FDA internal records. Two reviewers independently extracted information for the endpoints, efficacy data, basis for approval, type of regulatory approval, and corresponding in vitro diagnostic device test. The results were organized by organ system and tumor type.ResultsOf 70 Biologic Licensing Application or supplement approvals that resulted in new indications, 32 (46%) were granted based on response rate (ORR) and durability of response, 26 (37%) on overall survival, 9 (13%) on progression‐free survival, 2 (3%) on recurrence‐free survival, and 1 (1%) on complete response rate. Most ORR‐based approvals were granted under the accelerated approval provisions and were supported with prolonged duration of response. Overall, 21% of approvals were granted with a companion diagnostic. Efficacy results according to tumor type are discussed.ConclusionPD‐[L]1 inhibitors are an effective anticancer therapy in a subset of patients. This class of drugs has provided new treatment options for patients with unmet need across a wide variety of cancer types. Yet, the modest response rates in several tumor types signal a lack of understanding of the biology of these diseases. Further preclinical and clinical investigation may be required to identify a more appropriate patient population, particularly as drug development continues and additional treatment alternatives become available.Implications for PracticeThe number of PD‐[L]1 inhibitors in drug development and the associated companion and complementary diagnostics have led to regulatory challenges and questions regarding generalizability of trial results. The interchangeability of PD‐L1 immunohistochemical assays between PD‐1/PD‐L1 drugs is unclear. Furthermore, robust responses in some patients with low levels of PD‐L1 expression have limited the use of PD‐L1 as a predictive biomarker across all cancers, particularly in the setting of diseases with few alternative treatment options. This review summarizes the biomarker thresholds and assays approved as complementary and companion diagnostics and provides regulatory perspective on the role of biomarkers in oncology drug development.

Real-world validity of randomized controlled phase III trials in newly diagnosed glioblastoma: to whom do the results of the trials apply?

BackgroundThe survival rates in population-based series of glioblastoma (GBM) differ substantially from those reported in clinical trials. This discrepancy may be attributed to that patients recruited to trials tend to be younger with better performance status. However, the proportion and characteristics of the patients in a population considered either eligible or ineligible for trials is unknown. The generalizability of trial results is therefore also uncertain.MethodsUsing the Cancer Registry of Norway and the Brain Tumor Database at Oslo University Hospital, we tracked all patients within a well-defined geographical area with newly diagnosed GBM during the years 2012–2017. Based on data from these registries and the medical records, the patients were evaluated for trial eligibility according to criteria employed in recent phase III trials for GBM.ResultsWe identified 512 patients. The median survival was 11.7 months. When we selected a potential trial population at the start of concurrent chemoradiotherapy (radiotherapy [RT]/ temozolomide [TMZ]) by the parameters age (18–70 y), passed surgery for a supratentorial GBM, Eastern Cooperative Oncology Group (ECOG) ≤2, normal hematologic, hepatic and renal function, and lack of severe comorbidity, 57% of the patients were excluded. Further filtering the patients who progressed during RT/TMZ and never completed RT/TMZ resulted in exclusion of 59% and 63% of the patients, respectively. The survival of patients potentially eligible for trials was significantly higher than of the patients not fulfilling trial eligibility criteria (P < .0001).ConclusionsPatients considered eligible for phase III clinical trials represent a highly selected minority of patients in a real-world GBM population.

BioPETsurv: Methodology and open source software to evaluate biomarkers for prognostic enrichment of time-to-event clinical trials.

Biomarkers can be used to enrich a clinical trial for patients at higher risk for an outcome, a strategy termed "prognostic enrichment." Methodology is needed to evaluate biomarkers for prognostic enrichment of trials with time-to-event endpoints such as survival. Key considerations when considering prognostic enrichment include: clinical trial sample size; the number of patients one must screen to enroll the trial; and total patient screening costs and total per-patient trial costs. The Biomarker Prognostic Enrichment Tool for Survival Outcomes (BioPETsurv) is a suite of methods for estimating these elements to evaluate a prognostic enrichment biomarker and/or plan a prognostically enriched clinical trial with a time-to-event primary endpoint. BioPETsurv allows investigators to analyze data on a candidate biomarker and potentially censored survival times. Alternatively, BioPETsurv can simulate data to match a particular clinical setting. BioPETsurv's data simulator enables investigators to explore the potential utility of a prognostic enrichment biomarker for their clinical setting. Results demonstrate that both modestly prognostic and strongly prognostic biomarkers can improve trial metrics such as reducing sample size or trial costs. In addition to the quantitative analysis provided by BioPETsurv, investigators should consider the generalizability of trial results and evaluate the ethics of trial eligibility criteria. BioPETsurv is freely available as a package for the R statistical computing platform, and as a webtool at www.prognosticenrichment.com/surv.

Can relapse prevention interventions help adults who have quit smoking while hospitalized to maintain abstinence?

RCT evidence regarding interventions to prevent relapse among adults who have quit smoking while hospitalized is insufficient to allow conclusions. Relapse prevention interventions, such as post‐discharge telephone or in‐person counseling/buddy support and nicotine patch therapy, do not appear to improve abstinence rates on follow‐up after discharge among patients who achieve abstinence in the hospital. In both behavioral and drug intervention trials, both control and intervention groups received a brief in‐hospital intervention before discharge. Due to uncertainty regarding allocation concealment and blinding of participants and outcome assessors, as well as small numbers of trials and participants, the quality of these trials is uncertain. In addition, generalizability of trial results may be limited, as all included trial participants were 50 to 60 years of age, all participants in one trial were women, and two trials comprised solely patients with cardiovascular disease. For effects of relapse prevention in other populations, see CCA 2613 (for pregnant women), 2615 (for adults who quit smoking alone), and 2616 (for adults who quit smoking after receiving assistance).

Assessment of enrollment characteristics for Children’s Oncology Group (COG) upfront therapeutic clinical trials 2004-2015.

6564 Background: Improvements in pediatric cancer survival are attributed to cooperative clinical trials. Under representation of specific demographic groups has been described in adult and pediatric cancer and poses a threat to the generalizability of trial results. A comprehensive evaluation of data provided by the Children’s Oncology Group (COG) of upfront trial enrollment for US patients 0 to 29 years old between 2004 and 2015 was performed to assess for disparities in participation. Methods: Estimates of cancer cases were calculated using the Surveillance, Epidemiology, and End Results registry and the US Census and compared to observed COG cases. Percent enrollment and Standardized Ratios of enrollment were calculated across various demographic, disease, and socioeconomic groups. The COG website was utilized to quantify available upfront trials during the study period and assess age eligibility criteria. Results: 21.3% of estimated US cancer patients age 0 to 19 years enrolled on COG trials. Younger patients were consistently more represented across disease types and race/ethnicities. Patients with hematologic malignancies were more represented compared to solid and central nervous system (CNS) tumors. Conclusions: COG clinical trial enrollment rates are declining, which may be due to challenges in pediatric drug development, difficulty designing feasible trials for highly curable diseases, and issues in ensuring trial availability for the heterogeneous group of solid and CNS tumors. Though racial/ethnic groups and county-level socioeconomic factors were proportionally represented, under representation of the adolescent/young adult (AYA) population and younger patients with solid and CNS tumors remain significant concerns. Targeted enrollment efforts should focus on the identified subgroups and further research should evaluate AYA enrollment across all available trials to provide continued treatment advances for all patients.

Reappraisal of eligibility criteria in cancer clinical trials.

We aimed to summarize the recent reflections and collaborative initiatives pertaining to the definition of more appropriate eligibility criteria in cancer clinical trials. There is an intrinsic tension between two opposite purposes when it comes to defining eligibility criteria: on the one hand, participants must be protected, and on the other, the study population must be defined as accurately as possible. However, stringent eligibility criteria jeopardize the feasibility of trials, and, consequently, the generalizability of trial results. Therefore, interdisciplinary working groups under the auspices of the American Society of Clinical Oncology and Friends of Cancer Research propose to adapt/relax some of the classical eligibility criteria. In-depth reflection of the existing eligibility criteria, and implementation of recent recommendations are needed.

The \u201cRCT augmentation\u201d: a novel simulation method to add patient heterogeneity into phase III trials

BackgroundPhase III randomized controlled trials (RCT) typically exclude certain patient subgroups, thereby potentially jeopardizing estimation of a drug’s effects when prescribed to wider populations and under routine care (“effectiveness”). Conversely, enrolling heterogeneous populations in RCTs can increase endpoint variability and compromise detection of a drug’s effect. We developed the “RCT augmentation” method to quantitatively support RCT design in the identification of exclusion criteria to relax to address both of these considerations. In the present manuscript, we describe the method and a case study in schizophrenia.MethodsWe applied typical RCT exclusion criteria in a real-world dataset (cohort) of schizophrenia patients to define the “RCT population” subgroup, and assessed the impact of re-including each of the following patient subgroups: (1) illness duration 1–3 years; (2) suicide attempt; (3) alcohol abuse; (4) substance abuse; and (5) private practice management. Predictive models were built using data from different “augmented RCT populations” (i.e., subgroups where patients with one or two of such characteristics were re-included) to estimate the absolute effectiveness of the two most prevalent antipsychotics against real-world results from the entire cohort. Concurrently, the impact on RCT results of relaxing exclusion criteria was evaluated by calculating the comparative efficacy of those two antipsychotics in virtual RCTs drawing on different “augmented RCT populations”.ResultsData from the “RCT population”, which was defined with typical exclusion criteria, allowed for a prediction of effectiveness with a bias < 2% and mean squared error (MSE) = 5.8–6.8%. Compared to this typical RCT, RCTs using augmented populations provided improved effectiveness predictions (bias < 2%, MSE = 5.3–6.7%), while returning more variable comparative effects. The impact of augmentation depended on the exclusion criterion relaxed. Furthermore, half of the benefit of relaxing each criterion was gained from re-including the first 10–20% of patients with the corresponding real-world characteristic.ConclusionsSimulating the inclusion of real-world subpopulations into an RCT before running it allows for quantification of the impact of each re-inclusion upon effect detection (statistical power) and generalizability of trial results, thereby explicating this trade-off and enabling a controlled increase in population heterogeneity in the RCT design.

Analysis of potential disparities by race, ethnicity, and age in adult accruals to NCI National Clinical Trials Network (NCTN) breast, lung, prostate, and colorectal trials.

e18072 Background: Previous studies have raised concerns about disparities in patient accrual to NCI cancer trials and how this could impact the generalizability of trial results. This study compared the demographics of patients enrolled in NCTN cancer trials to the incident US population. Methods: We analyzed US adult accruals aged 40 or older to NCTN breast, lung, prostate, and colorectal cancer treatment trials between the launch of the NCTN on 3/1/14 and 12/31/16. Accruals were compared to the proportion of patients with these cancers by race, ethnicity, and age in the US population estimated using census-adjusted SEER incidence data for 2010-2013. Results: There were 14,247 accruals across 56 NCTN group treatment trials in breast (39.7% of accruals), prostate (25.9%), lung (23.9%), and colorectal cancers (10.5%). Hispanic and black patients were underrepresented in prostate, lung, and colorectal trials, but overrepresented in breast trials (see table). American Indian/Alaska Native populations were slightly overrepresented in 3 of 4 disease areas, and Asian populations in 2 of 4. Elderly patients were underrepresented in breast, lung, and colorectal cancers, with the greatest disparities in colorectal cancer patients over age 70 (19% of accruals versus 48% of incident patients). However, prostate cancer patients aged 65 to 84 were overrepresented (46% versus 36%). Conclusions: Disparities in race and ethnicity between patients accrued to NCTN studies and the incident population were smaller than seen in previous studies. However, challenges remain in certain diseases, and particularly in enrollment of elderly patients. Improvement efforts should focus on key disparities. [Table: see text]

Abstract TP132: Selection and Activation of Sites in a Large Multi-Center Randomized Clinical Trial

Introduction: Careful selection and timely activation of clinical sites in multicenter clinical trials is critical for successful enrollment, subject safety, and generalizability of results. Methods: In the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2), a multidisciplinary Site Selection Committee evaluated applicants referred via participation in CREST, CREST principal investigators (PIs) and other investigators, StrokeNet and industry partners. Data for consideration included performance metrics in CREST and other carotid trials and a site selection questionnaire containing information on the investigators as well as quantitative data on carotid procedures performed. Any FDA warning letters were reviewed. Results: The Committee met bi-weekly for 36 months (n=64 meetings). Applications from 176 sites between March 2014 and July 2016 were evaluated: 153 were approved, 7 are under Committee review, 5 were approved but withdrew, 5 were placed on a waiting list, and 6 were rejected. One-hundred-four sites have completed the regulatory and training requirements to randomize: 51 (49%) academic medical centers, 31 (30%) private hospital-based centers, 16 (15%) private office-based practices, and 6 (6%) Veterans Administration medical centers. The mean times from application-to- approval was 5.2 weeks (interquartile range, 1.9, 6.2), and from approval-to-randomization status was 46.7 weeks (interquartile range, 35.4, 51.7). Specialties of the 104 site PIs are vascular surgery for 35 (33.7%), cardiology for 30 (28.8%), neurology for 25 (24%), neurosurgery for 8 (7.7%), interventional radiology for 4 (3.8%), and interventional neuroradiology for 2 (1.9%). Conclusions: Careful site selection is time-consuming for prospective sites and for trial leadership. Times from application-to-site-approval were modest (mean = 5.2 weeks), in contrast to the times for completing regulatory and training requirements (mean = 46.7 weeks). However, subject enrollment by teams from a wide range of medical centers led by a multi-disciplinary cohort of PIs will promote the generalizability of trial results.

Umbilical Cord Blood (UCB) Transplantation in Children with Acute Leukemia: Impact of Conditioning Regimen on Transplant Outcomes

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0501; NCT00412360) randomized children with hematologic malignancy to one or two cord blood unit transplantation between December 2006 and February 2012. While the trial concluded that survival was similar regardless of number of units infused, results were generally better than those previously reported after single UCB transplant. The apparently improved survival in recipients of BMT CTN 0501 compared to prior studies in children transplanted with a single UCB unit prompted a comparison of trial versus non-trial treatment outcomes to determine 1) the generalizability of trial results and 2) whether survival was better for patients treated with the trial regimen. Using data reported to the Center for International Blood and Marrow Transplant Research during the trial period, 396 recipients of one UCB unit transplant met the broad eligibility criteria for BMT CTN 0501 (i.e. aged 1- 21 years, high-risk acute leukemia, performance score ≥70). Trial and non-trial patients were comparable in their HCT-CI score. Trial patients (n=100) received total body irradiation (TBI) 1320 cGy, cyclophosphamide 120 mg/kg, and fludarabine 75 mg/m2 (TCF). Non-trial patients either received the same regimen as in the trial (N=62; non-trial TCF) or an alternative regimen (N=334; non-trial non-TCF regimen). Excluded were 13 patients on BMT CTN 0501 randomized to receive a single UCB unit for malignant diseases other than acute leukemia. Patient and disease characteristics of those treated on BMT CTN 0501 and others were similar except that those who received non-trial TCF regimen were more likely to report performance scores of 80 or 70 (24% versus 11%, p=0.04) and transplanted in relapse (18% vs. 5%, p=0.02) and those that received non-TCF regimens were more likely to 1-10 years of age (76% versus 53%, p<0.0001). Sixty-three percent of non-trial non-TCF regimens included TBI (≥1000 cGy) and the predominant non-TBI regimen was busulfan and cyclophosphamide. All patients received a calcineurin inhibitor for graft-versus-host disease (GVHD) prophylaxis. Donor-recipient HLA-match, median infused total nucleated cells and median follow up times were similar across the groups. Three-year survival rates were similar between patients receiving TCF regimen either on (A) or off trial (B), Figure1A, p=0.83. Similarly, there were no differences in hematopoietic recovery, relapse or non-relapse mortality between trial and non-trial TCF. However, compared to TCF on trial (A), overall survival rates were significantly lower with non-TCF non-TBI (C) and TBI (D) containing regimens after adjusting for age, CMV serostatus, disease and disease status; Figure 1B, 68% versus 55% (p=0.001) and 68% versus 50% (p=0.04), respectively. Results of multivariate analysis are shown in Table 1. Compared to patients treated on trial (TCF regimen; 20% at 3-years) relapse rates were higher with non-TCF non-TBI (42%, p=0.003) but not TBI-containing regimens (25%, p=0.38) after adjusting for age, disease, disease status and CMV seropositivity. Among non-TCF patients, relapse risk was higher for non-TBI compared to TBI-containing regimens (hazard ratio [HR] 1.61, p=0.02) but not mortality risk (HR 0.93, p=0.74). Cytogenetic risk features were not associated with relapse or survival. There were no differences in hematopoietic recovery, acute and chronic GVHD. The results of BMT CTN 0501 appear generalizable to the population of trial eligible patients. The survival differences between the trial specified and other conditioning regimens support use of the TCF regimen to improve survival. It also indicates the importance of conditioning regimen for outcome and may serve as a stimulus to design trials to identify the optimal regimen for children with acute leukemia undergoing UCB transplantation. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Statistical lessons learned for designing cluster randomized pragmatic clinical trials from the NIH Health Care Systems Collaboratory Biostatistics and Design Core.

Pragmatic clinical trials embedded within health care systems provide an important opportunity to evaluate new interventions and treatments. Networks have recently been developed to support practical and efficient studies. Pragmatic trials will lead to improvements in how we deliver health care and promise to more rapidly translate research findings into practice. The National Institutes of Health (NIH) Health Care Systems Collaboratory was formed to conduct pragmatic clinical trials and to cultivate collaboration across research areas and disciplines to develop best practices for future studies. Through a two-stage grant process including a pilot phase (UH2) and a main trial phase (UH3), investigators across the Collaboratory had the opportunity to work together to improve all aspects of these trials before they were launched and to address new issues that arose during implementation. Seven Cores were created to address the various considerations, including Electronic Health Records; Phenotypes, Data Standards, and Data Quality; Biostatistics and Design Core; Patient-Reported Outcomes; Health Care Systems Interactions; Regulatory/Ethics; and Stakeholder Engagement. The goal of this article is to summarize the Biostatistics and Design Core's lessons learned during the initial pilot phase with seven pragmatic clinical trials conducted between 2012 and 2014. Methodological issues arose from the five cluster-randomized trials, also called group-randomized trials, including consideration of crossover and stepped wedge designs. We outlined general themes and challenges and proposed solutions from the pilot phase including topics such as study design, unit of randomization, sample size, and statistical analysis. Our findings are applicable to other pragmatic clinical trials conducted within health care systems. Pragmatic clinical trials using the UH2/UH3 funding mechanism provide an opportunity to ensure that all relevant design issues have been fully considered in order to reliably and efficiently evaluate new interventions and treatments. The integrity and generalizability of trial results can only be ensured if rigorous designs and appropriate analysis choices are an essential part of their research protocols.

Abstract PR06: Empowering Latina breast cancer patients to make informed decisions about clinical trials: A multicommunication approach

Abstract Background: Without adequate minority representation in clinical trials, researchers cannot assess differential effects in outcomes or ensure the safety of therapies across a range of biological and genetic characteristics among groups, nor can they ensure generalizability of trial results. In response, this theory-based educational intervention aims to empower Latinas to make informed decisions about breast cancer clinical trials (BCCTs) by enhancing their knowledge, attitudes, skills and self-efficacy required to support discussion of BCCTs as a treatment option with doctors and family members. Methods: This is a cohort study with random assignment of 112 Latina breast cancer patients eligible to participate in a BCCT at the Cancer Therapy &amp; Research Center at the University of Texas Health Science Center at San Antonio. The intervention includes: participation in a culturally sensitive, individually tailored, computer-based BCCTs video; a bilingual, low-literacy booklet; and assistance from a patient navigator. The control includes usual care clinical trial information materials for eligible patients. Results: Preliminary analysis showed that participants exposed to the intervention had significant higher awareness of clinical trials, particularly understanding their purpose and requirements, benefits and risks and their potential as an appropriate treatment for a serious disease, than participants in the usual care control group. In addition, patients in the intervention group showed significant changes between baseline and post intervention on stages of change compared to the control group. In the intervention group the percentage of women in preparation increased from 26.4% at baseline to 62.3% at post-intervention and the proportion of those in action rose from 35.8% to 67.9% at post-intervention. Conclusion: Computer-based videos if specifically tailored to Latinos may be a cost-effective strategy to effectively address awareness, cultural and attitudinal barriers and decision making skills needed to make informed decisions about clinical trial participation. The study is funded by the Susan G. Komen for the Cure (Award No. SAB08-00005) and the Cancer Therapy &amp; Research Center (Grant No. P30 CA054174). This abstract was also presented as Poster A5. Citation Format: Patricia Chalela, Edgar Muñoz, Kipling J. Gallion, Anand Karnad, Amelie G. Ramirez. Empowering Latina breast cancer patients to make informed decisions about clinical trials: A multicommunication approach. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr PR06.

Eligibility criteria in knee osteoarthritis clinical trials: systematic review

There is an increasing concern over generalizability of trial results. We investigated eligibility criteria of knee osteoarthritis clinical trials. Eligible trials were randomized, placebo-controlled trials that were identified by searches in MEDLINE, SCOPUS, and the Cochrane Central Register of Controlled Trials. We then attempted to extract data on the eligibility criteria by employing predetermined criteria. From 355 randomized knee osteoarthritis trials, we reviewed data categorized by non-osteoarthritis-related and osteoarthritis-related factors. A variety of items were used in the eligibility criteria. Regarding the non-osteoarthritis-related factors, ethical considerations, such as inability to give an informed consent (79.4 %) or medical conditions potential for risks by test treatments (56.0 %) or by participation in a trial (57.2 %), were the common reasons for excluding patients from a trial. Concerning the osteoarthritis-related factors, most of the trials did not specify age and symptom severity. When trials specifying these items were investigated, patients with 40 to 80 years in age and grade 2 in the Kellgren-Lawrence scale were mostly included into a trial. For the pain intensity, patients with ≥20-40 in the 100-mm visual analog scale and ≥6-8 in the WOMAC pain subscale were commonly enrolled into a trial. These findings warrant further investigation on the generalizability of trial results.