Time burden and logistical intensity of early-phase clinical trials (EP-CTs).

84 Background: EP-CTs are increasingly important options for patients with cancer and often involve intensive monitoring. Thus, characterizing the time burden and logistical intensity of EP-CTs could help patients and clinicians make informed decisions regarding trial participation. Methods: We retrospectively reviewed the electronic health records of consecutive patients enrolled in EP-CTs at Massachusetts General Hospital from 2017-2019 to obtain baseline characteristics (demographics and clinical factors), EP-CT investigational agent (immunomodulatory therapy [IM], targeted inhibitor(s) [TI], antibody drug conjugate [ADC]/chemotherapy prodrug), and logistical intensity (trial visit frequency, presence of extended visits, distance traveled in one direction from home zip code to trial site). We defined visit frequency as the number of visits per protocol within the first 28 days on trial. We defined an extended visit as six or more hours in clinic on at least one day during the first 28 days on study. We investigated associations among patient characteristics, investigational agent, and logistical intensity. Results: Among 421 patients (median age=60.6 years, 55.8% female, 97.4% metastatic disease), most (73.6%) had two or more sites of metastatic disease. EP-CTs included 43.2% IM, 43.0% TI, and 13.8% ADC/chemotherapy prodrug. Patients enrolled in ADC/prodrug trials had the highest burden of metastatic disease (mean sites: 2.8 [ADC] vs 2.4 [TI] vs 2.3 [IM], p = 0.007) and oldest age (mean years: 64.0 [ADC] vs 61.7 [IM] vs 58.5 [TI], p = 0.003). Patients enrolled on TI trials had the highest visit frequency compared with those enrolled on other trials (mean visits: 5.5 [TI] vs 5.3 [ADC] vs 5.0 [IM], p = 0.027) and the fewest days spent on trial (mean days: 78.3 [TI] vs 102.2 [IM] vs 131.8 [ADC], p = 0.003). Patients enrolled on TI trials were also most likely to have an extended visit (82.3% [TI] vs 58.2% [IM] vs 29.3% [ADC], p < 0.001) and least likely to receive first in human therapy (38.1% [TI] vs 74.1% [ADC] vs 74.2% [IM], p < 0.001). Distance traveled from home to clinic did not significantly differ across trial type (median miles traveled: 35.1 [TI] vs 34.1 [IM] vs 33.2 [ADC], p = 0.884). Conclusions: In this cohort of patients participating in EP-CTs, we found that a plurality enrolled in IM studies. Those receiving ADC/prodrug regimens were older and had a higher burden of disease. On average, patients participating in EP-CTs had over five visits in the first month, with those enrolled on TI trials having the highest visit frequency and greatest likelihood of extended visits. Patients on TI trials also spent the fewest total days on trial. Despite the lack of significant differences in distance traveled, most patients were still traveling over 30 miles to get to the trial site. These data highlight the time burden and logistical intensity of various EP-CTs, which may help inform patient-clinician discussions about trial participation.

Clinical trial site identification practices and the use of electronic health records in feasibility evaluations: An interview study in the Nordic countries

Introduction: Feasibility evaluations are performed to create the best possible starting point for the set-up and execution of a clinical trial, and to identify any obstacles for successful trial conduct. New digital technologies can provide various types of data for use in feasibility evaluations. There is a need to identify and compare such data sources for trial site identification and for evaluating the sites’ patient recruitment potential. Especially, information is needed on the use of electronic health records. We investigated how different data sources are used by pharmaceutical companies operating in the Nordic countries for identifying trial sites and for evaluating their potential to recruit trial participants. Methods: This was a semi-structured qualitative interview study with 21 participants from pharmaceutical companies and contract research organizations operating in Finland, Sweden, Denmark and Norway. Qualitative content analysis was applied. Results: For identifying countries and trial sites on a global level, the trial sponsors mostly used databases on previous trial performance. The use of electronic health record data was very limited. Sites’ and investigators’ visibility in various databases was seen as fundamental for their countries becoming selected into new clinical trials. For estimating the sites’ recruitment projections, most sites were seen to base their patient count estimates solely on their previous experience. Some sites had reviewed their electronic health record data, which was considered to increase the accuracy of their recruitment estimates and these sites’ attractivity. Along with dialogs with investigators, the sponsors used various data sources to validate the investigators’ estimates. Legislative obstacles were seen to hinder the use of electronic health record queries for estimation of patient counts. Conclusion: Visibility in the databases used by trial sponsors is crucial for the countries and sites to be identified. Site selection appears to be based on trust and relationships built from experience, but electronic data provide the support upon which the trust is based. Estimation of the number of potential trial participants is a complex and time-consuming process for both investigators and sponsors. Sponsors seem to favour sites who could support their patient count estimates with electronic health record data as they were quicker in providing the estimates and more reliable than sites with no electronic health record evidence. The patient count evaluation process could be simplified, accelerated and made more reliable with more systematic use of electronic health record evidence in the feasibility evaluation phase. This would increase the accuracy of the patient count estimates and, on its part, contribute to improved recruitment success.

Analysis of Genetic Diversity in the Traditional Chinese Medicine Plant ‘Kushen’ (Sophora flavescens Ait.)

Kushen root, from the woody legume Sophora flavescens, is a traditional Chinese medicine that is a key ingredient in several promising cancer treatments. This activity is attributed in part to two quinolizidine alkaloids (QAs), oxymatrine and matrine, that have a variety of therapeutic activities in vitro. Genetic selection is needed to adapt S. flavescens for cultivation and to improve productivity and product quality. Genetic diversity of S. flavescens was investigated using genotyping-by-sequencing (GBS) on 85 plants grown from seeds collected from 9 provinces of China. DArTSeq provided over 10,000 single nucleotide polymorphism (SNP) markers, 1636 of which were used in phylogenetic analysis to reveal clear regional differences for S. flavescens. One accession from each region was selected for PCR-sequencing to identify gene-specific SNPs in the first two QA pathway genes, lysine decarboxylase (LDC) and copper amine oxidase (CAO). To obtain SfCAO sequence for primer design we used a targeted transcript capture and assembly strategy using publicly available RNA sequencing data. Partial gene sequence analysis of SfCAO revealed two recently duplicated genes, SfCAO1 and SfCAO2, in contrast to the single gene found in the QA-producing legume Lupinus angustifolius. We demonstrate high efficiency converting SNPs to Kompetitive Allele Specific PCR (KASP) markers developing 27 new KASP markers, 17 from DArTSeq data, 7 for SfLDC, and 3 for SfCAO1. To complement this genetic diversity analysis a field trial site has been established in South Australia, providing access to diverse S. flavescens material for morphological, transcriptomic, and QA metabolite analysis. Analysis of dissected flower buds revealed that anthesis occurs before buds fully open suggesting a potential for S. flavescens to be an inbreeding species, however this is not supported by the relatively high level of heterozygosity observed. Two plants from the field trial site were analysed by quantitative real-time PCR and levels of matrine and oxymatrine were assessed in a variety of tissues. We are now in a strong position to select diverse plants for crosses to accelerate the process of genetic selection needed to adapt kushen to cultivation and improve productivity and product quality.

Pengaruh faktor lingkungan terhadap pertumbuhan beberapa aksesi Dioscorea alata L terpilih koleksi kebun raya purwodadi

Uwi (Dioscorea alata L.) merupakan jenis tanaman umbi-umbian berpotensi nutrisi. Namun pemanfaatannya sebagai bahan pangan alternatif masih jarang, karena keterbatasan informasi potensi nutrisi dan sistem budidaya. Penelitian ini bertujuan untuk menentukan faktor-faktor lingkungan yang berpengaruh terhadap pertumbuhan uwi. Penelitian dilakukan di lahan percobaan di Kabupaten Pasuruan, pada tujuh aksesi yang dipilih berdasarkan hasil penelitian sebelumnya, yaitu aksesi nomor 28, 36, dan 86 (Pasuruan), 42 dan 43 (Nganjuk), 57 dan 66 (Malang). Parameter lingkungan yang diamati meliputi suhu udara, kelembaban udara, intensitas cahaya, pH tanah, kelembaban tanah, jumlah dan jenis gulma. Hasil pengamatan dianalisis secara deskriptif dan statistik dengan uji Biplot menggunakan software Past 3. Hasil penelitian menunjukkan bahwa intensitas cahaya dan jumlah jenis gulma merupakan faktor lingkungan yang paling berpengaruh pada pertumbuhan tanaman uwi. Terdapat tiga grup aksesi tanaman uwi berdasarkan perbedaan faktor lingkungan yang mempengaruhi pertumbuhannya. Aksesi 42, 43 dan 57 dipengaruhi oleh suhu dan kelembaban udara, aksesi 28, 36 dan 66 dipengaruhi oleh intensitas cahaya dan aksesi 86 dipengaruhi oleh pH tanah. Analisis deskriptif menunjukkan bahwa sebagian besar gulma yang tumbuh merupakan tanaman invasif yang mempengaruhi pertumbuhan tanaman komoditas. Aksesi nomor 42, 43 dan 57 direkomendasikan untuk dibudidayakan di lahan sub optimal dengan kondisi pH asam dan minim air.AbstractWater yam (Dioscorea alataL.) is one of the tubers potentially as nutrition source. However, its utilization as the source of food alternative is still rare causes by limited information about its nutritional content and cultivation. The research aimed to determine the environmental factors effects the growth of water yam. The study was conducted in the trial site at Pasuruan with seven selected accessions of water yam based on previous research i.e. accessions number 28, 36 and 86 (Pasuruan), 42 and 43 (Nganjuk), 57 and 66 (Malang). The observed environmental parameters were the number and type of weeds, temperature, humidity, light intensity, soil pH, and soil moisture. The observations were descriptive and statistically analyzed using Biplot test with Past 3 software. The results showed that the light intensity and the number of weed species are the environmental factors that have the most affected on the growth of water yam plants. Accessions 28, 36 and 66 are affected by light intensity, accession 86 is affected by soil pH, and accessions 42, 43 and 57 are affected by air temperature and humidity. Most of the weeds grown in the study area are invasive species, which affect the growth of cultivated crops, so weeding is needed. Accession number 42, 43 and 57 adaptively grow in sub-optimum land with acidic pH conditions and minimum water capacity.

Clinical trials site recruitment optimisation: Guidance from Clinical Trials: Impact and Quality

Background/Aims: Participants are integral to the success of any clinical research study, yet participant recruitment into clinical trials poses ongoing and complex challenges. It is widely accepted and recognised that clinical trial sites often find it difficult to meet recruitment goals, both in terms of accrual targets and timelines. This can impact the validity of trials or cause major delays for research. There are very few frameworks available to clinical trial sites to improve recruitment. The GREET project (Guidance to Recruitment: Examining Experiences at clinical Trial sites) sought to identify barriers to recruitment and produce formal guidance to optimise recruitment outcomes. Methods: Clinical Trials: Impact and Quality, a collaborative of sector stakeholders, convened a project team with comprehensive knowledge of the Australian clinical trials sector to undertake the GREET project. The project scope included exploration of recruitment issues at a site level across all phases of clinical trials and all types of trial sites. The scope excluded upstream issues such as protocol design and general public clinical trial awareness, participant retention and elements of recruitment outside a site’s capacity to directly influence or control. The project team’s extensive knowledge and experience conducting clinical trials in Australia was used to collaboratively identify a list of 24 key barriers and 12 enablers to site recruitment which formed the basis of the project. Key stakeholder groups were surveyed to challenge project team assumptions. A national and international environmental scan and literature review was conducted to identify best-practice recruitment solutions. Results: A total of 343 people responded to a survey sent to sites, sponsors, and contract research organisations, and 162 people responded to a survey sent to consumers via consumer networks. The key barriers and enablers initially identified by the project team aligned with the key outcomes of the surveys, which in turn assisted in the development of best-practice recommendations in the form of a Clinical Trial Site Recruitment Guide. Recommendations were grouped into four key themes; conducting accurate study feasibility; proactive planning during start-up; selecting optimal recruitment methods; and participant involvement. Early intervention was identified as a key facilitator in maximising improved recruitment outcomes. The GREET Clinical Trial Site Recruitment Guide is publicly accessible on the Clinical Trials: Impact and Quality website. Conclusion: Participant recruitment challenges experienced at a site level are widespread and varied, and there is no universal recruitment solution. However, this project identified that there are interventions and assessments that can be proactively implemented and selectively applied to facilitate improved recruitment outcomes.

Social vulnerability and clinical trial access for older adults with myeloma in North Carolina.

e18540 Background: Multiple myeloma (MM) is a disease of aging, associated with one of the greatest black-white disparities in incidence and mortality among all US cancer types. Clinical trials provide the critical evidence-base to inform clinical management in all cancers, including MM. However, clinical trial participants are often younger (age < 65 years) and white, limiting the generalizability of published data to real-world MM care. Although geographical and financial barriers to clinical trial participation are well recognized, less is known about the association of county-level social vulnerability with MM trial availability. We examined county-level variation in the number of registered myeloma trials per 10,000 North Carolina (NC) residents age ≥ 65 years as a function of social vulnerability and the presence of a National Cancer Institute Comprehensive Cancer Center (CCC). Methods: We conducted a cross-sectional study using data from ClinicalTrials.gov to identify all registered interventional myeloma trials involving adults age ≥ 65 years with sites in NC. Records were downloaded on January 24th, 2021. This strategy yielded 456 non-unique NC sites for 223 trials. We obtained county locations for all trial sites by matching city, zip code, or institution name. We obtained NC population data for residents age ≥ 65 years (in 2019) from the American Community Survey. The four themes (socioeconomic status, household composition, ethnic and racial minority status/language, housing/transportation) within the Centers for Disease Control Social Vulnerability Index (CDC SVI) (composite score: 0-1, with a higher number indicating more vulnerability) were used to characterize county-level social vulnerability. We performed negative binomial regression and tabulations using R, version 3.6.1. A p-value < 0.05 was considered statistically significant. Results: Across 100 counties in NC, trial site counts by county per 10,000 residents age ≥ 65 years ranged from 0 to 23.2 (mean: 1.5, median: 0; IQR, 0-0.7). Controlling for the 4 SVI themes, counties with CCCs (Durham, Forsyth, Orange) had 77% more trials than those without CCCs [Incidence Rate Ratio (IRR): 7.74; p = 0.05]. We observed a 3.3% reduction in trial counts with each percentile increase in socioeconomic vulnerability (IRR: 0.97; p = 0.008). Counties with higher representation by racial and ethnic minorities had similar trial site counts to counties with lower minority populations (IRR: 1.01; p = 0.08). Sub-group analyses of early-stage studies (phase 1/2 and phase 2; n = 268) and late-stage studies (phase 2/3 and phase 3; n = 168) were similar. Conclusions: Our preliminary results suggest county-level socioeconomic status is associated with the distribution of MM clinical trial sites across NC. Further work is planned to explore whether additional variances in trial distribution could be explained by site- and study-specific characteristics.

Regulatory delays in a multinational clinical stroke trial

Introduction The initiation and conduct of randomised clinical trials are complicated by multiple barriers, including delays in obtaining regulatory approvals. Quantitative data on the extent of the delays due to national or local review in randomised clinical trials is scarce. Materials and methods We assessed the times needed to obtain regulatory approval and to initiate a trial site for an academic, EU-funded, phase III, randomised clinical trial of pharmacological prevention of complications in patients with acute stroke in over 80 sites in nine European countries. The primary outcome was the time from the first submission to a regulatory authority to initiation of a trial site. Secondary outcomes included time needed to complete each individual preparatory requirement and the number of patients recruited by each site in the first 6 and 12 months. Results The median time from the first submission to a regulatory authority to initiation of a trial site was 784 days (IQR: 586–1102). The single most time-consuming step was the conclusion of a clinical trial agreement between the national coordinator and the trial site, which took a median of 194 days (IQR: 93–293). A longer time to site initiation was associated with a lower patient recruitment rate in the first six months after initiation (B = –0.002; p = 0.02). Discussion Conclusion In this EU-funded clinical trial, approximately 26 months were needed to initiate a trial site for patient recruitment. The conclusion of a contract with a trial site was the most time-consuming activity. To simplify and speed up the process, we suggest that the level of detail of contracts for academic trials should be proportional to the risks and commercial interests of these trials.

Assessing the impact made by groundwater processes and undermining on coal pit wall stability

Introduction. The reliability of geomechanical prediction depends on the level of detail of databases covering geological structure, geometry and physical properties of the rock mass under investigation. In order to improve the accuracy of coal pit wall stability prediction, following the generalization of databases containing geological survey, groundwater monitoring, geophysical sounding and mine surveying, it is advisable to construct three-dimensional geological-geophysical models accounting for the main adverse factors, and thereafter search for the most hazardous section. Research aim is to predict wall stability according to the developed algorithm based on the threedimensional geological-geophysical model. Research methodology includes a search for the most hazardous rock mass site section by the ratio between shear and retaining forces within the established zones with anomalous physical characteristics. Results. By generalizing databases containing geological studies, groundwater monitoring, geophysical sounding by the method of electrical resistivity tomography, and mine surveying, a three-dimensional geological- geophysical model has been constructed of a wall loaded with “heap of dry rock atop of the hydraulic dump” man-made structure and undermined by underground works. The trial site stability has been predicted for the true state of mining. Comparative analysis of the obtained data has been carried out. Summary. The combination of natural and man-made factors, including hydrogeological conditions of the territory, seasonal and climatic behavior, tectonic faulting of the deposit and shear zones connected with undermining result in the development of a rather complex geological structure of the wall which includes local deconsolidated and waterlogged zones significantly reducing the stability of the pit slope. At the trial site of Kedrovsky pit due to spatial and temporal alternation of properties and state of rock within the landslide hazardous zone, the variation range of the factor of safety in six typical sections amounts n = 1.06–2.39. For that reason the objective prediction of slope stability in similar conditions (in addition to geological survey and hydrogeological observations data analysis) should include geophysical monitoring of anomalous zones origination and development, hereupon creation of a treedimensional geological-physical model, and the automated calculation of the factor of safety including repeated selection of the most hazardous section.

Effects of Different Rates of Nitrogen and Phosphorus Fertilizers on Growth and Yield of Potato (Solanum tuberosum) under Mechanized and Traditional Cultivation

In the present study, half of the land was cultivated mechanically by tractor using a two-bladed mould board plough and nine tine harrow. The other half was cultivated by a local farmer who used a bullock and wooden plough. A single seed variety (Marabel) was sown across the entire trial site. Four separate identical fertilizer treatments were used across both the mechanized and traditionally cultivated sites. Phosphorous was applied in the form of diammonium phosphate. Nitrogen was applied in the form of Urea. FAO’s recommended rates for phosphorus (220kg/ha) and nitrogen (330kg/ha) were applied. In addition, additional rates below and above the FAO’s recommendations were also applied, with phosphorous being applied at 0 kg/ha, 110 kg/ha (50% of recommendation) and 440 kg/ha (200% of recommendation). Nitrogen was applied at 0 kg/ha, 165 kg/ha (50% of recommendation) and 660 kg/ha (200% of recommendation). Results on average revealed that across all four fertilizer rates, mechanized cultivation produced 60% higher crop yields (average 32.83mt/ha) compared with traditional cultivation (average 20.5 mt/ha) which resulted in an average of 12.33mt/ha higher yield for mechanized cultivation over traditional cultivation. This yield difference was highly statistically significant (P =0.99(. Additionally, the average gross margin per hectare was 74% higher across the mechanized plots (US$6,552/ha or 373,464AFN/ha) compared with the traditional plots (US$3,772/ha or 215,004 AFN/ha). These figures confirm that use of mechanized cultivation and the application of phosphorus at 440 kg/ha and nitrogen at 660 kg/ha will increase the potato yield and produce a higher cash value and a higher gross margin per hectare.