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Perspectives in Clinical Research 2023
PubMed: 37325573
DOI: 10.4103/picr.picr_69_23 -
JAMA Network Open Feb 2021The cohort size of phase 1 clinical trials and thus the timing of the interim decisions are typically prespecified in the trial protocol. During trial implementation,...
IMPORTANCE
The cohort size of phase 1 clinical trials and thus the timing of the interim decisions are typically prespecified in the trial protocol. During trial implementation, however, the cohort size often deviates from the planned one, which shifts the schedule of the interims. Despite its pervasiveness in phase 1 trials, the association of cohort size deviation with the operating characteristics of these trials is not clear.
OBJECTIVE
To explore the association between cohort size deviation and the operating characteristics of phase 1 clinical trials.
DESIGN, SETTING, AND PARTICIPANTS
In this cross-sectional simulation study, a review was conducted of 102 phase 1 dose-escalation trials published between January 2017 and May 2018 in 3 peer-reviewed journals (Journal of Clinical Oncology, Clinical Cancer Research, and Cancer). After exclusion of studies that did not report the cohort size, 45 trials remained for analysis. Based on the analysis results, a simulation study was performed to systematically investigate the association of cohort size deviation with the operating characteristics of the trials.
MAIN OUTCOMES AND MEASURES
The prevalence of cohort size deviation and the percentage of correct selection of the maximum tolerated dose.
RESULTS
Of the 45 reviewed trials, 10 (22.2%) adhered strictly to the planned cohort size. The simulation study showed that when cohort size deviation was random, it had little association with the performance of novel model-based and model-assisted designs (mean reduction in the percentage of correct selection of the maximum tolerated dose was 0.87 percentage point for the continual reassessment method and 0.84 percentage point for the bayesian optimal interval design). When the cohort size deviation was informative and made based on the observed data on toxicity (eg, if dose-limiting toxicity was observed, the size of the next or current cohort was reduced or expanded), the variation of the design performance increased. The range of the change in the percentage of correct selection was -3.7 to 1.3 percentage points for the continual reassessment method and -4.5 to 0 percentage points for the bayesian optimal interval design.
CONCLUSIONS AND RELEVANCE
The findings suggest that when novel phase 1 clinical trial designs are used, some cohort size deviation is acceptable and has little association with the performance of the designs. These deviations may be used by expert investigators to properly interpret the data, ensure safety, and leverage flexibility in the protocol.
Topics: Antineoplastic Agents; Bayes Theorem; Clinical Trial Protocols as Topic; Clinical Trials, Phase I as Topic; Computer Simulation; Cross-Sectional Studies; Humans; Maximum Tolerated Dose; Neoplasms; Research Design; Sample Size
PubMed: 33595664
DOI: 10.1001/jamanetworkopen.2020.37563 -
Trials Dec 2023Retention to trials is important to ensure the results of the trial are valid and reliable. The SPIRIT guidelines (18b) require "plans to promote participant retention... (Review)
Review
BACKGROUND
Retention to trials is important to ensure the results of the trial are valid and reliable. The SPIRIT guidelines (18b) require "plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols" be included in trial protocols. It is unknown how often protocols report this retention information. The purpose of our scoping review is to establish if, and how, trial teams report plans for retention during the design stage of the trial.
MATERIALS AND METHODS
A scoping review with searches in key databases (PubMed, Scopus, EMBASE, CINAHL (EBSCO), and Web of Science from 2014 to 2019 inclusive) to identify randomised controlled trial protocols. We produced descriptive statistics on the characteristics of the trial protocols and also on those adhering to SPIRIT item 18b. A narrative synthesis of the retention strategies was also conducted.
RESULTS
Eight-hundred and twenty-four protocols met our inclusion criteria. RCTs (n = 722) and pilot and feasibility trial protocols (n = 102) reported using the SPIRIT guidelines during protocol development 35% and 34.3% of the time respectively. Of these protocols, only 9.5% and 11.4% respectively reported all aspects of SPIRIT item 18b "plans to promote participant retention and to complete follow-up, including list of any outcome data for participants who discontinue or deviate from intervention protocols". Of the RCT protocols, 36.8% included proactive "plans to promote participant retention" regardless of whether they reported using SPIRIT guidelines or not. Most protocols planned "combined strategies" (48.1%). Of these, the joint most commonly reported were "reminders and data collection location and method" and "reminders and monetary incentives". The most popular individual retention strategy was "reminders" (14.7%) followed by "monetary incentives- conditional" (10.2%). Of the pilot and feasibility protocols, 40.2% included proactive "plans to promote participant retention" with the use of "combined strategies" being most frequent (46.3%). The use of "monetary incentives - conditional" (22%) was the most popular individual reported retention strategy.
CONCLUSION
There is a lack of reporting of plans to promote participant retention in trial protocols. Proactive planning of retention strategies during the trial design stage is preferable to the reactive implementation of retention strategies. Prospective retention planning and clear communication in protocols may inform more suitable choice, costing and implementation of retention strategies and improve transparency in trial conduct.
Topics: Humans; Randomized Controlled Trials as Topic; Retention in Care; Research Design
PubMed: 38049833
DOI: 10.1186/s13063-023-07775-2 -
Evidence-based Complementary and... 2015In the 1960s Bong Han Kim discovered and characterized a new vascular system. He was able to differentiate it clearly from vascular blood and lymph systems by the use of... (Review)
Review
In the 1960s Bong Han Kim discovered and characterized a new vascular system. He was able to differentiate it clearly from vascular blood and lymph systems by the use of a variety of methods, which were available to him in the mid-20th century. He gave detailed characterization of the system and created comprehensive diagrams and photographs in his publications. He demonstrated that this system is composed of nodes and vessels, and it was responsible for tissue regeneration. However, he did not disclose in detail his methods. Consequently, his results are relatively obscure from the vantage point of contemporary scientists. The stains that Kim used had been perfected and had been in use for more than 100 years. Therefore, the names of the stains were directed to the explicit protocols for the usage with the particular cells or molecules. Traditionally, it was not normally necessary to describe the method used unless it is significantly deviated from the original method. In this present work, we have been able to disclose staining methods used by Kim.
PubMed: 26379743
DOI: 10.1155/2015/361974 -
Open Heart Dec 2023Targeted temperature management (TTM) is a recommended therapy for postcardiac arrest patients. Hyperthermia worsened the patient outcome, and overcooling increased the... (Observational Study)
Observational Study
BACKGROUND
Targeted temperature management (TTM) is a recommended therapy for postcardiac arrest patients. Hyperthermia worsened the patient outcome, and overcooling increased the incidence of complications; therefore, a high-quality TTM is required. The target temperature tended to be modified worldwide after the TTM trial in 2013. Our institute modified the target temperature to 35°C in 2017. This study aimed to compare the conventional and modified protocols, assess the relationship between target temperature deviation and patient outcomes, and identify the factors influencing temperature deviation.
METHODS
This single-centre, retrospective, observational study included adult out-of-hospital cardiac arrest patients who underwent TTM between April 2013 and October 2019. We compared the conventional and modified protocol groups to evaluate the difference in the background characteristics and details on TTM. Subsequently, we assessed the relationship of deviation (>±0.5°C, >37°C, or<33°C) rates from the target temperature with mortality and neurological outcomes. We assessed the factors that influenced the deviation from the target temperature.
RESULTS
Temperature deviation was frequently observed in the conventional protocol group (p=0.012), and the modified protocol group required higher doses of neuromuscular blocking agents (NMBAs) during TTM (p=0.016). Other background data, completion of protocol, incidence of complications, mortality and rate of favourable neurological outcomes were not significantly different. The performance rate of TTM was significantly higher in the modified group than in the conventional protocol group (p<0.001). Temperature deviation did not have an impact on the outcomes. Age, sex, body surface area, NMBA doses and type of cooling device were the factors influencing temperature deviation.
CONCLUSIONS
A target temperature of 35°C might be acceptable and easily attainable if shivering of the patients was well controlled using NMBAs. Temperature deviation did not have an impact on outcomes. The identified factors influencing deviation from target temperature might be useful for ensuring a high-quality TTM.
Topics: Adult; Humans; Body Temperature; Hypothermia, Induced; Retrospective Studies; Temperature; Treatment Outcome; Male; Female
PubMed: 38101858
DOI: 10.1136/openhrt-2023-002459 -
Mutation Research. Genetic Toxicology... Jan 2023Several trials have attempted to identify sources of inter-laboratory variability in comet assay results, aiming at achieving more equal responses. Ionising radiation...
Several trials have attempted to identify sources of inter-laboratory variability in comet assay results, aiming at achieving more equal responses. Ionising radiation induces a defined level of DNA single-strand breaks (per dose/base pairs) and is used as a reference when comparing comet results but relies on accurately determined radiation doses. In this ring test we studied the significance of dose calibrations and comet assay protocol differences, with the object of identifying causes of variability and how to deal with them. Eight participating laboratories, using either x-ray or gamma radiation units, measured dose rates using alanine pellet dosimeters that were subsequently sent to a specialised laboratory for analysis. We found substantial deviations between calibrated and nominal (uncalibrated) dose rates, with up to 46% difference comparing highest and lowest values. Three additional dosimetry systems were employed in some laboratories: thermoluminescence detectors and two aqueous chemical dosimeters. Fricke's and Benzoic Acid dosimetry solutions gave reliable quantitative dose estimations using local equipment. Mononuclear cells from fresh human blood or mammalian cell lines were irradiated locally with calibrated (alanine) radiation doses and analysed for DNA damage using a standardised comet assay protocol and a lab-specific protocol. The dose response of eight laboratories, calculated against calibrated radiation doses, was linear with slope variance CV= 29% with the lab-specific protocol, reduced to CV= 16% with the standard protocol. Variation between laboratories indicate post-irradiation repair differences. Intra-laboratory variation was very low judging from the dose response of 8 donors (CV=4%). Electrophoresis conditions were different in the lab-specific protocols explaining some dose response variations which were reduced by systematic corrections for electrophoresis conditions. The study shows that comet assay data obtained in different laboratories can be compared quantitatively using calibrated radiation doses and that systematic corrections for electrophoresis conditions are useful.
Topics: Animals; Humans; Comet Assay; Calibration; DNA Damage; Radiation, Ionizing; Gamma Rays; Dose-Response Relationship, Radiation; Mammals
PubMed: 36669811
DOI: 10.1016/j.mrgentox.2022.503560 -
Journal of Clinical Pharmacy and... Mar 2022Paediatric intensive care patients are at high risk for prescription errors due to the more complex process of medication prescribing. Clinical decision support systems... (Observational Study)
Observational Study
WHAT IS KNOWN AND OBJECTIVE
Paediatric intensive care patients are at high risk for prescription errors due to the more complex process of medication prescribing. Clinical decision support systems (CDSS) have shown good results in effectively reducing prescription errors. A specific dosing CDSS was developed that can check and suggest normal dose, dose limits and administration frequencies. This study aimed to assess the effect of this CDSS on protocol deviation (as measure of prescription error) types and frequency in a paediatric intensive care unit (PICU).
METHODS
A retrospective observational study was conducted evaluating 9342 prescriptions in a 4-month period before and after the implementation of a CDSS in the PICU of the University Medical Center Utrecht. Medication forms were reviewed to identify protocol deviations (and therefore possible prescription errors). The incidence and nature of deviations from evidence-based protocols that were unintended and needed to be adjusted, were determined.
RESULTS AND DISCUSSION
In the period before the dosing CDSS, we identified 45 protocol deviations in 5034 prescriptions (0.89%), 28 of which could not be justified (0.56%) and 11 needed to be adjusted (0.22%). In the period after the implementation of the CDSS, there were 21 protocol deviations in 4308 prescriptions (0.49%) of which ten without a valid reason (0.23%) of which two were adjusted (0.05%).
WHAT IS NEW AND CONCLUSION
The specific dosing CDSS was able to significantly reduce unintentional prescription dose deviations and the number of prescriptions that needed to be adjusted, in an existing low incidence situation.
Topics: Child; Decision Support Systems, Clinical; Drug Prescriptions; Humans; Incidence; Intensive Care Units, Pediatric; Medication Errors
PubMed: 34734650
DOI: 10.1111/jcpt.13562 -
Asia-Pacific Journal of Oncology Nursing Oct 2022This study aimed to construct evidence-based anticancer drug clinical trial nursing management norms to ensure the safety and quality of clinical trial nursing.
OBJECTIVE
This study aimed to construct evidence-based anticancer drug clinical trial nursing management norms to ensure the safety and quality of clinical trial nursing.
METHODS
This before-after study was carried out to complete the evidence implementation in a cancer hospital in Shanghai, China. Seven review indicators were developed and reviewed in one phase I clinical trial center and two oncology wards. The corresponding evidence-based intervention program was formulated, and the completion rate of good clinical practice certification, protocol training, delegation of duties, qualification rate of administration, sampling and document recording in anticancer drug clinical trials before and after implementation were compared.
RESULTS
After implementation, the completion rate of protocol training, delegation of duties, and the qualification rate of document recording were significantly higher than those of the baseline review, whereas the completion rate of good clinical practice certification and the qualification rate of sampling did not significantly differ from those observed at the baseline review. There was no administration or infusion device-related protocol deviation during the baseline and post reviews.
CONCLUSIONS
Anticancer drug clinical trial nursing management norms and relevant standard operating procedures were constructed. The results showed that the implementation of this intervention improved the standardization of nurse qualification procedures and the nursing original document recording in anticancer drug clinical trials, and nursing-related protocol deviation could be reduced to a certain extent.
PubMed: 36105794
DOI: 10.1016/j.apjon.2022.100114 -
Journal of the American Dental... Nov 2022Dental health care personnel (DHCP) may be at increased risk of exposure to severe acute respiratory syndrome coronavirus 2, the virus that causes COVID-19, as well as...
BACKGROUND
Dental health care personnel (DHCP) may be at increased risk of exposure to severe acute respiratory syndrome coronavirus 2, the virus that causes COVID-19, as well as other clinically important pathogens. Proper use of personal protective equipment (PPE) reduces occupational exposure to pathogens. The authors performed an assessment of PPE donning and doffing practices among DHCP, using a fluorescent marker as a surrogate for pathogen transmission.
METHODS
Participants donned PPE (that is, disposable gown, gloves, face mask, and eye protection) and the fluorescent marker was applied to their palms and abdomen. DHCP then doffed PPE according to their usual practices. The donning and doffing processes were video recorded, areas of fluorescence were noted, and protocol deviations were assessed. Statistical analyses included frequency, type, and descriptions of protocol deviations and factors associated with fluorescence.
RESULTS
Seventy DHCP were enrolled. The donning and doffing steps with the highest frequency of protocol deviations were hand hygiene (66% of donning and 78% of doffing observations involved a deviation) and disposable gown use (63% of donning and 60% of doffing observations involved a deviation). Fluorescence was detected on 69% of DHCP after doffing, most frequently on hands. An increasing number of protocol deviations was significantly associated with increased risk of fluorescence. DHCP with a gown doffing deviation, excluding doffing out of order, were more likely to have fluorescence detected.
CONCLUSIONS
DHCP self-contamination was common with both donning and doffing PPE.
PRACTICAL IMPLICATIONS
Proper use of PPE is an important component of occupational health.
Topics: Humans; Personal Protective Equipment; COVID-19; Health Personnel; SARS-CoV-2; Delivery of Health Care
PubMed: 36175202
DOI: 10.1016/j.adaj.2022.08.004 -
Clinical Trials (London, England) Feb 2019Intention-to-treat comparisons of randomized trials provide asymptotically consistent estimators of the effect of treatment assignment, without regard to compliance....
BACKGROUND
Intention-to-treat comparisons of randomized trials provide asymptotically consistent estimators of the effect of treatment assignment, without regard to compliance. However, decision makers often wish to know the effect of a per-protocol comparison. Moreover, decision makers may also wish to know the effect of treatment assignment or treatment protocol in a user-specified target population other than the sample in which the trial was fielded. Here, we aimed to generalize results from the ACTG A5095 trial to the US recently HIV-diagnosed target population.
METHODS
We first replicated the published conventional intention-to-treat estimate (2-year risk difference and hazard ratio) comparing a four-drug antiretroviral regimen to a three-drug regimen in the A5095 trial. We then estimated the intention-to-treat effect that accounted for informative dropout and the per-protocol effect that additionally accounted for protocol deviations by constructing inverse probability weights. Furthermore, we employed inverse odds of sampling weights to generalize both intention-to-treat and per-protocol effects to a target population comprising US individuals with HIV diagnosed during 2008-2014.
RESULTS
Of 761 subjects in the analysis, 82 dropouts (36 in the three-drug arm and 46 in the four-drug arm) and 59 protocol deviations (25 in the three-drug arm and 34 in the four-drug arm) occurred during the first 2 years of follow-up. A total of 169 subjects incurred virologic failure or death. The 2-year risks were similar both in the trial and in the US HIV-diagnosed target population for estimates from the conventional intention-to-treat, dropout-weighted intention-to-treat, and per-protocol analyses. In the US target population, the 2-year conventional intention-to-treat risk difference (unit: %) for virologic failure or death comparing the four-drug arm to the three-drug arm was -0.4 (95% confidence interval: -6.2, 5.1), while the hazard ratio was 0.97 (95% confidence interval: 0.70, 1.34); the 2-year risk difference was -0.9 (95% confidence interval: -6.9, 5.3) for the dropout-weighted intention-to-treat comparison (hazard ratio = 0.95, 95% confidence interval: 0.68, 1.32) and -0.7 (95% confidence interval: -6.7, 5.5) for the per-protocol comparison (hazard ratio = 0.96, 95% confidence interval: 0.69, 1.34).
CONCLUSION
No benefit of four-drug antiretroviral regimen over three-drug regimen was found from the conventional intention-to-treat, dropout-weighted intention-to-treat or per-protocol estimates in the trial sample or target population.
Topics: Adult; Anti-Retroviral Agents; Clinical Protocols; Female; HIV Infections; Humans; Intention to Treat Analysis; Male; Middle Aged; Sustained Virologic Response; Viral Load
PubMed: 30326736
DOI: 10.1177/1740774518806311