bluuebunny/crossref_metadata_2025_split huggingface dataset:
Double reading performance and the impact of adjudication on progression-free survival estimations: Findings from a lung clinical trial.
Authors: Beaumont Hubert , Iannessi Antoine 
Published: June 2024

e23010 Background: The FDA recommends Blinded Independent Central Review (BICR) with double read for clinical trials with imaging. However, inter-reader variability is a concern in these trials. While studies have investigated the variability of RECIST, the primary response criteria, little attention has been given to the optimal association of readers. The evaluation of therapeutic response in phase III trials relies on the Date of first Progressive Disease (DoPD), with the Discrepancy Rate (DR) as the preferred index for measuring inter-reader variability in DoPD evaluation. Another important index measures readers' bias, assessing their tendency to over or under-estimate diagnoses. In cases of discrepancies, a third reader is brought in for adjudication. However, the impact of adjudication on trials' Progression-Free Survival (PFS) is not well-documented. Our study examines the variability in a lung clinical trial using RECIST, analyzing double reading performance, reader association prediction, and the impact of adjudication on PFS estimations. Methods: We retrospectively analyzed five phase III lung clinical trials using the RECIST 1.1 criteria in BICR with double reads. The trials involved 7 readers organized into 11 teams, each reader having participated in multiple trials and performed over 50 reads, resulting in 1017 patients' reviews. Our analysis included: Calculation of DR and bias for each team, and testing the correlation between DR and bias. Computation of the signed bias for each individual reader. Evaluation of a probabilistic model to predict the DR for each team and the bias for each reader. Comparison of PFS between single and double reads after adjudication and endorsement of one of the readings. Results: A multiple comparisons test did not reveal any difference between teams’ DR (Marascuilo test; q > 0.05). The average DR across all teams was 39.9% [95%CI; 37.8; 41.9]. However, we did find significant differences in bias when comparing 9/55 pairs of teams (Marascuilo test; q < 0.05). The range of absolute bias values was 20% to 100%. We did not find a correlation between bias and DR (p = 0.64). Additionally, when comparing the average bias value per reader, no differences were observed (Marascuilo test; q < 0.05). We failed to predict teams DR and readers' bias. The endorsement rate of readers ranged [18%; 82%]. After adjudication, we found that 27% of the PFS were lower than the minimum value obtained from the single readers, in one case 20.6% shorter. Conclusions: Significant readers' bias has a notable impact on double readings, independent of the DR values. The performance of one reader cannot be generalized based on others. Additionally, adjudication significantly affects the PFS of clinical trials. These findings emphasize the importance of considering readers' bias and the potential consequences of adjudication in clinical trial assessments.
Utility of automated data transfer for cancer clinical trials.
Authors: Altomare Ivy , Shelley Addison , Lu Yichen , Salcuni Paul M. , Graves Nicole , Maiti Abhishek , Govindan Ramaswamy 
Published: June 2024

e23011 Background: The burden of data collection on site staff for cancer clinical trials is steadily increasing, and inefficiencies in data entry into electronic data capture (EDC) systems lead to poor data quality and delays in reporting. Software that facilitates automated transfer of mapped structured data from the electronic health record (EHR) to the study EDC system can help to address these challenges. We examined the impact of multi-site usage of an embedded point and click EHR-to-EDC tool on study data capture across multiple cancer clinical trials. Methods: We conducted a retrospective analysis of usage of an EHR-to-EDC tool among research teams at 3 Academic Medical Centers (AMCs) for 4 industry-sponsored Phase 1 cancer clinical trials from the start of use of the tool at each AMC to a cutoff date of 12/31/23. We assessed the types and volume of structured data accessible via FHIR APIs and amenable for transfer (“mapped”) across protocols, the volume of data transferred per protocol, and the time for data transfer, defined as time from case report form (CRF) launch to submission in EDC and time spent in the software application overall. Descriptive statistics were generated for all study metrics. Results: During the 10 month observation period, the EHR-to-EDC tool was used by 8 users to transfer data for 25 patients enrolled across the 4 protocols. Table 1 shows the percentage of total CRF forms mapped and breakdown of proportion of mapped fields per protocol. Overall, 8,597 individual data points (87% labs, 10% vitals and 3% concomitant medications) were pushed for 718 unique CRF submissions. The average number of individual data points and unique CRF submissions per patient were as follows: 400 and 36 (Study A), 420 and 36 (Study B), 251 and 16 (Study C), 270 and 21 (Study D). The average total time spent in the tool per CRF submission was 2.16 minutes (range 1.17-7.00 minutes, inclusive of potential inactive time, application launch and data search). The average time to complete a CRF was 46 seconds (range 15-65 seconds). Conclusions: Use of EHR-to-EDC software facilitated efficient automated transfer of a high volume of study data due to EDC-required repeat use of mapped CRF forms. The impact appeared consistent across protocols, with dozens of unique CRF submissions and hundreds of individual data points pushed per patient for each study. Time for CRF completion was low and uniform across users. This study supports the growing adoption of EHR-to-EDC technology among sites and sponsors, and highlights the evolving potential to further improve and facilitate clinical trial data entry, as tool capabilities are developed beyond structured fields to enable unstructured data capture and transfer. [Table: see text]
A prospective double-blind clinical study: Effect of probiotics and thalidomide on radiation enteritis in patients with pelvic cancer undergoing concurrent chemoradiotherapy.
Authors: Jiang Chunling , Xu Xiaoyan , Wang Xin , Yi An , Li Bin , Li Jingao , Zhang Huaiwen 
Published: June 2024

e23013 Background: Radiation induced diarrhea (RID) is one of the commonest and most distressing side effects during and after radiotherapy predominantly in patients whose irradiation region is pelvis. Thalidomide reduces severity as well as the frequency indicated in RID but mechanism of action is not elucidated. Probiotics are beneficial microorganisms that may regulate flora of intestines to increase immunity and have a protective effect on RID. This pilot study was designed to ascertain effects of thalidomide and probiotics on RID in patients being subjected to pelvic irradiation. Methods: A double-blind, single-center, randomized pilot study was conducted. Patients were classified into two groups as thalidomide plus probiotics (Lactobacillus rhamnosus + Probio-M9, ) group (TP group) or plus placebo group (P group).Incidence of grade 3/4 diarrhea, was a primary endpoint of the study. Other secondary endpoints analyzed were rates and severity of diarrhea, antibiotics use, body weight, albumin, and lymphocyte changes. 31 patients undergoing pelvic radiotherapy with or without concurrent chemotherapy were randomly selected from government tertiary general hospital. Results: The incidence of grade 3/4 diarrhea was 9.5% (95% CI: 0 to 24.5%) in TP, which was significantly different from historical data of 30% to 60%. The incidence of grade 3/4 diarrhea in group P was 19.8% (95% CI: 0~41.3%). The frequency and severity of diarrhea in group TP were little less than in group P. There is no significant difference between them. Basically, the time for antibiotic use in groups P and TP was the same, with a slightly longer time from first antibiotic exposure in group TP as compared to group P. The moment of first antibiotics have been prescribed in our study patients, this was better than that of a clinical routine treatment experience and other research data according to the literature. The changes in body weight, albumin level, and lymphocyte at different stages before and after radiotherapy in group TP were not statistically significant, and the level of body weight and albumin in group P was slightly reduced compared with before radiotherapy but increased compared with group TP after radiotherapy. Furthermore, there were no severe adverse effects regarding thalidomide as well as probiotics reported among patients who participated in this study. Conclusions: The combined treatment with thalidomide and probiotics is beneficial to ameliorate RID in patients receiving pelvic radiotherapy, yet this study can't represent whole conclusion due to small size of patients. We will also need larger, multicenter double-blind placebo-controlled trials to confirm exact efficacy and safety of this combined treatment. Clinical trial information: NCT05059613 .
Cancer screening and first-time visits to oncology services during and after COVID-19 pandemic in Uruguay.
Authors: Delgado Lucia Beatriz , Camejo Natalia , Castillo Cecilia , Vacca Nicolas , Camargo Bruno , Krygier Gabriel David 
Published: June 2024

e23016 Background: On March 13, 2020, Uruguay confirmed the first cases of COVID-19 and the same day the government declared a Public Health Emergency that was extended until April 4, 2022. The measures implemented to mitigate the transmission included, among others, postponing screening studies and in-person consultations. Added to these measures was the fear of going to health centers and the consequences of the economic crisis, with the increasing difficulties in traveling and facing the co-payments necessary to access health services. This study aims to evaluate the impact of the COVID-19 pandemic on cancer screening and first time- visits to oncology services during the public health emergency and following its lifting. Methods: We compare the number of PAP test, mammograms and fecal immunochemical test (FIT) reported by the same comprehensive health providers during 3 periods: pre-pandemic (2018-2019), public health emergency period (March 13, 2020- April 4, 2022) and post-public health emergency (April 5 2022-June 30,2023). Cancer screening data was obtained from the screening registry of the Honorary Commission to Fight Cancer (CHLCC) and first oncology visits from the Oncology Electronic Health Record (HCEO). Health providers that report PAP, mammograms, and FIT cover around 90%, 30%, and 40% of health system users, respectively, and those that use HCEO, 40%. Results: After two years of COVID-19 public health emergency, the number of reported PAP smears test, mammography and fecal occult blood test, decreased by 26%, 46% and 33% respectively (Table 1). The reduction was greater during the first months of the pandemic and during the peak of the first wave (April-June 2021: PAP -50%, mammography -58%, occult blood test: -70%). Likewise, the number of first-time visits to oncology services decreased by 37%, reaching a 56% decline during the first wave. As shown in Table 1, these declines continued after the health emergency was lifted. Conclusions: Our results show an important decline of cancer screening and first-time visits to oncology services during the pandemic in Uruguay. After emergency was lifted, reported PAP test showed a partial recovery but mammography, occult fecal blood test and first-time visits to oncology services remain well below pre-pandemic levels. [Table: see text]
Pilot study to evaluate automated laboratory data transfer into Medidata Rave for NCI-supported pediatric cooperative group trials in the Pediatric Early Phase Clinical Trials Network (PEP-CTN) and Pediatric Brain Tumor Consortium (PBTC).
Authors: Miller Tamara P. , Aplenc Richard , Minard Charles G. , Wang Yu , Lensing Shelly , Velamuru Prasanna , Foster Jennie Haunani , Silverman Milena , Sung Cheryl , Wong Karina , Beeles Thalia Angelica , Weigel Brenda , Onar-Thomas Arzu , Fox Elizabeth 
Published: June 2024

e23017 Background: Electronic data capture (EDC) has the potential to improve data accuracy and efficiency. As an initial step toward improvement in the accuracy and completeness of data acquisition for clinical trials, PEP-CTN and PBTC conducted a pilot project to assess the feasibility of automated transfer of laboratory data from participating institutions’ electronic health records to the NCI Medidata Rave EDC that is housed within each consortium’s Uniform Resource Locator (URL). The pilot aimed to assess feasibility of automated laboratory data extraction and transfer and to evaluate discrepancies between laboratory data obtained retrospectively through automated extraction and data manually ascertained during the original conduct of the study. Methods: Data from patients treated on 7 completed PEP-CTN or PBTC trials at 7 sites were included. Each consortium created a Rave EDC study to receive data. Sites used the ExtractEHR R package or local methods to map and extract laboratory data for designated patients. Post-extraction data were uploaded via a file transfer protocol (FTP) periodically polled by the Rave Batch Uploader (BU) that uploaded data into Rave EDC. After successful upload, extracted data (EHR) were compared to laboratory data that had been manually reported when patients were enrolled on the trials (MANUAL) and discrepancies were identified. Discrepancy types were categorized and 2 sites reviewed discrepancies at their sites to identify reasons. Results: Preparation and support for automated extraction and upload required significant central operations and local site effort. All sites successfully extracted specified laboratory data and had at least one complete upload via BU to Rave EDC. There were more laboratory data in the EHR datasets than MANUAL datasets across most sites. These results were due to multiple EHR results on a given day or from additional days in the study window than specified in MANUAL. Sites verified that laboratory data in MANUAL and not EHR were stored in un-extractable formats (e.g. PDFs) or outside laboratories. Most discrepant results in both EHR and MANUAL were mismatched values or units. Conclusions: This pilot demonstrated the feasibility of implementing automated laboratory data extraction and transfer in the cooperative group setting. Automated data transfer requires significant central operational support as well as detailed protocols, data specifications, and case report forms and engagement of site technical teams to be successful, but also permits collection of more comprehensive data with reduced manual data entry. Clinical trial information: NCT05020951 .
Fostering diversity and inclusion in the preempt CRC study through strategic site selection and innovative recruitment tools.
Authors: Shaukat Aasma , Kutnik Karolina , Petersen Kristen R. , Xu Chuanbo , Lee Lilian C. , Baldo Lance , Levin Theodore R. 
Published: June 2024

e23025 Background: Diversity in clinical studies is crucial in aligning the study population with the intended patient demographic. Freenome is developing a blood based test (MyTectCRC) intended to offer a convenient and accessible option for colorectal cancer (CRC) screening. Its clinical validation is supported by the PREEMPT CRC study, a prospective, multi-center observational study. PREEMPT CRC was able to achieve a diverse population representing various ethnic, racial, and geographical backgrounds that reflect the United States population. This analysis evaluates the significance of strategic site selection and use of forward-thinking study tools in achieving a diverse and inclusive study population. Methods: Starting in 2020, PREEMPT CRC enrolled participants aged 45-85 at average CRC risk. Eligible and consenting participants underwent a blood draw and a screening colonoscopy, with the blood sample analyzed by MyTectCRC. To ensure diversity, strategic site selection was employed beyond large academic institutions and hospitals to smaller sites and community hospitals. The study also incorporated a decentralized clinical trial (DCT) model to reach broader geographical areas and used electronic consenting and mobile phlebotomy (MP) services to facilitate enrollment. Results: PREEMPT CRC enrolled 48,995 participants and achieved ethnic/racial diversity comparable to 2020 U.S. Census for Blacks (11.2%, vs 13.6%), Asians (6.8%, vs 6.3%) and Hispanic or Hispanic/Latinx (11.2%, vs 19.1%), Native Hawaiian or Other Pacific Islander (0.3% vs 0.4%). The primary site types were community hospitals and regional clinics, accounting for 45.5% of all sites, followed by health systems (12.0%), research institutes (18.5%), and academic centers/teaching hospitals (16.0%). The community clinics and academic centers enrolled the highest proportion of Black participants within their sites (21.4% and 12.1%, respectively). Research institutions had the highest proportion of Asian (24.8%) and Hispanic/Latinx (18.3%) populations. There was no significant difference observed in male versus female distribution between site types. Within traditional sites, 32% used MP service. DCT enrolled 12,137 participants (24.7% of total) from every state in the U.S., including high representation from rural areas (24.5%). Conclusions: PREEMPT CRC integrated multiple methodologies and tools to enhance diversity and inclusivity. This multimodal approach ensured diversified representation through the participation of sites with harder-to-reach populations, which was reflected in ethnic and racial data, as well as the geographical diversity. PREEMPT CRC study underscores the importance of incorporating early diversity planning into study strategy and using multiple methods to broaden the representation of the patient population. Clinical trial information: NCT04369053 .
Modeling any potential change in size, cost or patient benefit, resulting from incorporation of ctDNA, or other “optimizing diagnostic,” as part of a novel “SMARTer” oncology registration trial design.
Authors: Taub Floyd , Wright Suzin Mayerson , Gao Dexiang 
Published: June 2024

e23027 Background: One limitation in speeding more effective new cancer therapies to patients, and saving lives, is the time and expense of clinical trials. A second limitation is cancer is often a chronic disease, sequentially treated with multiple therapies; unlike in most registration trials, patient progress through a series of therapies. Building on previously published Sequential Multiple Assignment Randomized Trial (SMART) design, herein we model a new design to enhance registration (“SMARTer”). An “optimizing diagnostic” (often a ctDNA test) is used to determine, soon after initial use, if the new therapy is working. Those failing it are switched to the Standard of Care (SOC) for analysis they remain in the “new therapy first” arm, which is compared to the SOC arm. The aim is for all patients who benefit from the new therapy to remain on it, and, in contrast, if they are doomed to fail it, switch to SOC promptly to receive benefit from SOC early in the therapy path. Methods: To determine the value of the “new therapy first” arm we compared it to SOC by modeling assumptions of the accuracy of the optimizing test and the level of benefit of SOC after new therapy. The benefits of a new therapy first and switching, vs. SOC, was compared to a standard new therapy vs SOC “head-to-head”, without switching. Six scenarios, varying the effectiveness of the therapies, each with 16 combinations of sensitivity and specificity, were modeled. Results: Surprisingly, a good optimizing test reduces the number of patients by as much as 84% (from 710 to 114 in total) when new therapy alone had a 40% response rate and SOC a 30% rate (see table). When new therapy alone was no better than SOC, a study of 104 patients was sufficient to document that using the new therapy first added to patient benefit and could save lives, assuming independent mechanisms. Conclusions: SMARTer design thus significantly increases chances of approval, better mimics patients’ real world therapy path, and would reduce both time and cost significantly. An Optimizing Diagnostic, predicting appropriateness of a second dose/round of therapy based on the benefit of the first dose/round, thus facilitates clinical trials in a manner analogous to a Companian Diagnostic predicting the appropriateness of starting the first dose of a new therapy. [Table: see text]
Cancer care during a time of crisis: Israel’s experience during wartime.
Authors: Yakir Rottenberg , Rose Adam 
Published: June 2024

e23030 Background: During the last decades, there have been many crises in the world, including COVID-19, the Ukraine-Russia war and major tsunamis and earthquakes. These situations create challenges for providing appropriate care for cancer patients. It remains an important research priority to understand how to improve care delivery for cancer patients under conditions of stress or emergency. Methods: Israel has one of the highest-quality healthcare systems in the world. Strengths of the health system include advanced technology, universal health insurance, and four strong health maintenance organizations. Israel’s health system recently performed relatively well during the COVID-19 pandemic. Here, we report on system efforts to continue providing care despite the massive terrorist attack by Hamas of October 7, 2023, the ongoing rocket fire, and the mobilization of young and middle-aged adults to the army, which led to staff shortages. Our report focuses in particular on efforts to maintain continuity and quality of care for cancer patients. Results: There have been three main pillars of Israel’s efforts to maintain care for cancer patients despite the challenges. 1) We activated strategies learned from previous events, including the COVID-19 pandemic and other wars. This enabled continuing treatment of cancer patients, including those who had been evacuated from border-adjacent areas, in oncology departments that are either missile-proof or adjacent to a protected area. 2) The existence of universal health insurance, together with strong health maintenance organizations, enabled us to fill in gaps in social needs and ensure that no patient is “left behind”. This, in turn, allowed patients and their care teams to continue their cancer care without reimbursement barriers or other interruptions, despite the challenges. 3) There was a massive groundswell of volunteerism and lay-led social service initiatives. Almost half (48.6%) of the Israeli population engaged in some volunteer activity during the first two weeks of the war. This included volunteers who provided transportation for patients to and from treatments, donation of medications aimed at helping evacuees from border areas, and volunteer medical staff, such as recent retirees. These civil initiatives played a critical role in providing the initial response to the urgent needs that were left unaddressed by the government. Conclusions: We identified three main pillars that enabled continuity and high quality of care for cancer patients to continue despite a major crisis. A rapid response due to having similar, previous experiences and ready plans. A high-performance and resilient health delivery system, and lay volunteerism in times of crisis. While Israel’s challenges in the present period are unique, nevertheless lessons can be learned by health systems that wish to become more resilient and able to provide adequate care in times of crisis.