Exclusion Criterion In Clinical Trials Research Articles

Abstract PO3-17-07: Real-world experience with trastuzumab deruxtecan in patients with breast cancer: 6 month-interim analysis of an all-patient postmarketing surveillance in Japan

Abstract Background: Trastuzumab deruxtecan (T-DXd) is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate. T-DXd has shown great efficacy in HER2-positive breast cancer, hence receiving approval in Japan in March 2020. In Japan, all-patient postmarketing surveillance (PMS) is underway to evaluate the risk of interstitial lung disease/pneumonitis (ILD/p) in patients with breast cancer treated with T-DXd. Due to the limited generalizability of results from clinical trials, there is a need for more information about ILD/p in a real-world setting. Herein we present an interim analysis of the large-scale all-patient PMS. Methods: This is an observational, multicenter, all-patient PMS (jRCT1080225197) with an observation period of 18 months that enrolled all patients treated with T-DXd for recurrent/advanced HER2-positive breast cancer. Patients who initiated T-DXd treatment between May 2020 (launch date of T-DXd) and May 2021 were included in the interim analysis to ensure the observation period of 6 months from the initial treatment of T-DXd. This interim analysis is based on safety data from the first 6 months of 1204 patients. Data collected includes baseline characteristics and information on ILD/p. All potential ILD/p (identified based on the AE terms) reported by physicians were adjudicated by an independent ILD adjudication committee. The incidence of ILD/p was calculated from adjudicated drug-related ILD/p. Results: The interim analysis set included 1204 patients with median age of 60 years. Three of the 1204 patients (0.2%) received T-DXd as a first-line treatment, 30 (2.5%) as second-line, 1159 (96.3%) as third- line or later treatment. At baseline, 105 (8.7%) of patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) 2 or greater, 8 (0.7%) had severe renal impairment (15≤ creatinine clearance (CLcr) < 30 mL/min), 4 (0.3%) had end-stage renal disease (CLcr < 15 mL/min), 5 (0.4%) had severe liver impairment (total bilirubin >4.5 mg/dL), and 32 (2.7%) had comorbid ILD/radiation pneumonitis. Those were defined as exclusion criteria in clinical trials of T-DXd. The median dose at the start of administration of T-DXd was 5.4 mg/kg (range:2.7-5.4). During the first 6 months from the initial treatment, T-DXd was discontinued in 403 (33.5%) of the 1204 patients. The most common reasons for discontinuation were disease progression in 232 (57.6%) of the discontinued 403 patients followed by ILD/p in 97 (24.1%) of the 403 patients. In the first 6 months, the incidence of all grade, grade ≥3, and grade 5 ILD/p were 8.2% (n=99), 1.7% (n=20) and 0.4% (n=5), respectively. The incidence of ILD/p stratified by baseline characteristics identified as potential risk factors of drug-related ILD/p is shown in Table. Conclusion: This is the first report demonstrating real-world experience with T-DXd in Japan. The interim analysis revealed useful information including patient and treatment profiles of T-DXd and the incidence of ILD/p during the first 6 months from the initial treatment in a real-world setting in Japan. The final analysis of the ongoing PMS is warranted for further evaluation. Incidence of interstitial lung disease/pneumonitis by patient baseline characteristics XX XX ILD/p: interstitial lung disease/pneumonitis, 95% CI: 95% confidence interval, CLCr: creatinine clearance using the Cockcroft-Gault equation * includes ILD/p, pulmonary fibrosis, radiation pneumonitis, chronic obstructive pulmonary disease, emphysema, and Asthma (Source: Powell CA, Modi S, Iwata H, et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open 2022;7(4):100554) Citation Format: Junji Tsurutani, Hideki Mizutani, Ayumi Tanabe. Real-world experience with trastuzumab deruxtecan in patients with breast cancer: 6 month-interim analysis of an all-patient postmarketing surveillance in Japan [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-17-07.

Abstract PS11-01: Brain metastases in metastatic breast cancer: prevalence per line of treatment and cumulative incidence in a cohort of 18075 real-world patients

Abstract BACKGROUND Historic data suggest that incidence of brain metastasis (BM) is relatively distributed over time in HER2-positive (HER2+) breast cancer (BC), occurs early in triple negative BC (TNBC), and occurs late in hormone receptor-positive (HR+) metastatic BC (mBC). However, the timing of BM relative to line of therapy has not been well described. We describe the prevalence per line of therapy and cumulative incidence of BM in a large real-world cohort of patients (pts) with mBC, by BC subtype and line of therapy. METHODS This analysis used data from the longitudinal US Flatiron Health de-identified database, which provides unstructured and structured electronic health record-derived data from >2.6 million pts with cancer in ~800 unique sites of care. Eligible pts had initiated a first line of treatment (index data) for mBC up to March 1, 2021, to allow for ≥2 years potential follow-up time. Baseline characteristics were assessed, and pts categorized by HER2 and HR status: 1) HR+, HER2+; 2) HR+, HER2–, 3) HR–, HER2+ and 4) TNBC (i.e., negative for HR and HER2). For the last two categories, HER2-low subsets were defined based on immunohistochemistry results (1+, 2+, or equivocal). Lines of therapy were derived using both treatment regimens and progression data. The primary outcome was the first diagnosis of BM. The prevalence of BM was evaluated by subtype, at the index date, and by the line of therapy. The cumulative incidence function (CIF) of BM was used to estimate the risk of BM in pts free of BM at the index date, and death was treated as a competing event. RESULTS Overall, 18075 pts were included (HR+, HER2+: 3062 pts [16.9%]; HR–, HER2+: 902 pts [5.0%]; HR+, HER2–: 12331 pts [68.2%] [HR+, HER2-low: 7062 (39.1%)]; TNBC: 1780 pts [9.8%] [HR–, HER2-low: 725 pts (4.0%)]). Median age at the index date was 64 years (interquartile range: 54, 73) and 10271pts (56.8%) had visceral metastasis. In total, 5951 pts (32.9%) had de novo disease, 12090 (66.9%) had recurrent disease, and 34 (0.2%) did not have available data for mBC type. The table shows the number of pts by line of therapy, prevalence of BM, and cumulative incidence of BM from the index date. Of the included pts, 1306 (7.2%) had a BM at the index date; the CIF was run on the remaining 16973 pts. Overall, 2248 pts (13.2%) had an incident BM event during follow-up (HR+, HER2+: 578 events; HR–, HER2+: 237 events; HR+, HER2–: 1119 events [HR+, HER2-low: 619 events]; TNBC: 314 events [HR–, HER2-low: 124 events]), 9314 had a competing event, and 5411 were censored. By fourth-line therapy, the prevalence of BM was 26.1% in HR+, HER2+; 37.1% in HR–, HER2+; 24.7% in TNBC (HR–, HER2-low: 27.9%); but remained low at 7.2% in HR+, HER2– (HR+, HER2-low: 9.4%). The cumulative incidence of BM at 60 months was 23% in HR+, HER2+, 34% in HR–, HER2+, 10% in HR+, HER2–, and, 22% in TNBC. Overall, the HER2-low subsets had BM prevalence and cumulative incidence that were very close to those that were HER2–. CONCLUSIONS This large analysis of real-world data demonstrates that the prevalence of BM across pts with mBC differs by tumor subtype and by line of therapy. Conversely, HER2-low status may have limited impact. The cumulative incidence of BM was highest in the HR–, HER2+ and TNBC subgroups, and lowest in the HR+, HER2– subgroup; despite this, due to the high proportion of HER2–, HR+ mBC cases, the HR+, HER2– group represented the largest number of BM events. These data emphasize the need for clinical and biologic predictors of BM and for strategies to prevent their onset, and provide information on the impact of BM inclusion and exclusion criteria in clinical trials for pts with mBC. Number of patients by line of therapy, prevalence of BM, and cumulative incidence of BM from the index date BM, brain metastasis; HR, hormone receptor, pts, patients; TNBC, triple negative breast cancer. Citation Format: Sarah Sammons, Jose Leone, Thibaut Sanglier, Peter Lambert, Filippo Montemurro, Raf Poppe, Eleonora Restuccia, Sara Tolaney, Nancy Lin. Brain metastases in metastatic breast cancer: prevalence per line of treatment and cumulative incidence in a cohort of 18075 real-world patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS11-01.

Abstract PO1-05-14: Outcomes of first-line chemotherapy for visceral crisis in metastatic breast cancer

Abstract Background: Visceral crisis (VC) in metastatic breast cancer (BC) is defined as severe organ dysfunction, as assessed by signs and symptoms, laboratory tests, and rapid disease progression. The management of this condition is currently based on limited retrospective evidence and expert opinions, since VC has been a common exclusion criterion in clinical trials. There is a paucity of real-world data regarding the management of BC VC. We aim to evaluate the survival outcomes and prognostic factors of first-line palliative chemotherapy for VC in a tertiary cancer center in Brazil. Methods: Data were retrospectively collected from patients with metastatic BC diagnosed with VC between 2017 and 2022 in a single cancer center. Our analysis focused on patients receiving first-line chemotherapy for VC. Patients with hormone receptor-positive BC could have been previously treated with endocrine therapy for metastatic disease. CDK4/6 inhibitors were not available in the cancer center during the study period. Prognostic factors associated with survival were evaluated through univariate and multivariable analyses, using the Cox regression model. Results: A total of 106 patients with VC were evaluated. Among them, 58.5% (62 patients) had not received any previous line of chemotherapy in the metastatic setting before the diagnosis of VC (1st line cohort). Median overall survival (mOS) in the total population was 1.7 months, significantly distinct from the 1st line cohort, which had a mOS of 4.9 months (p < 0.001). Focusing on the 1st line cohort, the most common type of VC was pulmonary (40.3%), followed by hepatic (24.2%), and medullary infiltration (21%). 66.1% of patients had HR+HER2- (mOS 9.3 months), 19.3% HER2+ (mOS 4.5 months), and 11.3% triple-negative BC (TNBC) (mOS 1.5 months). Most patients were treated for VC based on systemic therapy combinations (59.7%), while 32.2% received monochemotherapy, and 8.1% were managed with best supportive care (BSC) alone. In the population receiving multidrug therapy, the mOS was 9.3 months, compared to 4.9 months with monochemotherapy and 0.7 months in patients undergoing BSC. Nevertheless, the type of treatment received was not associated with OS in the multivariable analysis. In the multivariable analysis, the prognostic factors associated with worse mOS were TNBC subtype, hepatic VC), and ECOG-PS > 2. (Table). Among patients with hepatic VC, 73.7% died during the same hospitalization and 60.5% received chemotherapy within 30 days prior to death. Conclusions: Patients with VC due to BC have a poor prognosis, even in the context of first-line chemotherapy. Factors such as ECOG-PS, BC subtype, and VC type should be taken into account when discussing the expected outcomes of this life-threatening condition. Taking these factors into account can help physicians to differentiate patients who are more likely to benefit from systemic oncologic treatment from those for whom such therapy would be futile or potentially harmful. Median overall survival according to baseline characteristics and multivariable analysis (1st line cohort, n=62) Citation Format: Matheus de Oliveira Andrade, Vitor Hugo Felix, Renata Colombo Bonadio, Laura Testa. Outcomes of first-line chemotherapy for visceral crisis in metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-14.

Evaluation of covariate effects in item response theory models.

Item response theory (IRT) models are usually the best way to analyze composite or rating scale data. Standard methods to evaluate covariate or treatment effects in IRT models do not allow to identify item-specific effects. Finding subgroups of patients who respond differently to certain items could be very important when designing inclusion or exclusion criteria for clinical trials, and aid in understanding different treatment responses in varying disease manifestations. We present a new method to investigate item-specific effects in IRT models, which is based on inspection of residuals. The method was investigated in a simulation exercise with a model for the Epworth Sleepiness Scale. We also provide a detailed discussion as a guidance on how to build a robust covariate IRT model.

Clinical Trials Studying Suicide Risk Reduction: Who is Excluded From Participation

Objective The use of exclusion criteria in clinical trials can cause research participants to differ markedly from clinical populations, which negatively impacts generalizability of results. This study identifies and quantifies common and recurring exclusion criteria in clinical trials studying suicide risk reduction, and estimates their impact on eligibility among a clinical sample of adults in an emergency department with high suicide risk. Method Recent trials were identified by searching PubMed (terms suicide, efficacy, effectiveness, limited to clinical trials in prior 5 years). Common exclusion criteria were identified using Qualitative Content Analysis. A retrospective chart review examined a one-month sample of all adults receiving psychiatric evaluation in a large urban academic emergency department. Results The search yielded 27 unique clinical trials studying suicide risk reduction as a primary or secondary outcome. After research fundamentals (e.g. informed consent, language fluency), the most common exclusion criteria involved psychosis (77.8%), cognitive problems (66.7%), and substance use (63.0%). In the clinical sample of adults with high suicide risk (N = 232), psychosis exclusions would exclude 53.0% of patients and substance use exclusions would exclude 67.2% of patients. Overall, 5.6% of emergency psychiatry patients would be eligible for clinical trials that use common exclusion criteria. Conclusions Recent clinical trials studying suicide risk reduction have low generalizability to emergency psychiatry patients with high suicide risk. Trials enrolling persons with psychosis and substance use in particular are needed to improve generalizability to this clinical population.

Real-world experience with trastuzumab deruxtecan among patients with gastric cancer: 4 month-interim analysis of an all-patient post-marketing surveillance study in Japan.

273 Background: Interstitial lung disease (ILD) is an important identified risk in the Japanese risk management plan of trastuzumab deruxtecan (T-DXd). In Japan, all-patient post-marketing surveillance (PMS) is underway to investigate the risk of ILD among patients with gastric cancer treated with T-DXd in a real-world setting. We present an interim analysis of the large-scale all-patient PMS. Methods: This is an observational, multicenter, all-patient PMS (jRCT2001200001) with an observation period of 12 months that enrolled all patients treated with T-DXd for HER2-positive unresectable advanced or recurrent gastric cancer between Sep 2020 and Dec 2021. This interim analysis is based on safety data from the first 4 months of all enrolled patients. All potential ILD (identified based on the pre-specified list of AE terms) reported by physicians were adjudicated by an independent ILD adjudication committee (ILD-AC). The incidence of ILD was calculated from adjudicated drug-related ILD. Results: The interim analysis set included 1074 patients with median age of 70 years (range: 23-100). Of the 1074 patients, 1051 (97.9%) received T-DXd as third-line or later treatment. One hundred and eight patients (10.1%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) 2 or greater, and 32 (3.0%), 3 (0.3%), and 23 (2.1%) patients had severe renal impairment (15≤ creatinine clearance (CL) <30 mL/min), end-stage renal disease (CL <15 mL/min), and ILD/radiation pneumonitis at baseline, respectively (all of which were defined as exclusion criteria in clinical trials of T-DXd). Median initial dose of T-DXd was 6.4 mg/kg (range: 3.1-6.4). Median treatment duration of T-DXd was 4.0 months (range: 0.7-4.0). During the first 4 months from the initial treatment, T-DXd was discontinued in 50.9% (547/1074) of patients. The most common reasons for treatment discontinuation were disease progression (n=390, 71.3%), adverse events other than ILD (n=76, 13.9%), and ILD (n=56, 10.2%). All potential ILD that occurred during the first 4 months were adjudicated by ILD-AC, and the incidence of all grades, grade ≥3, and grade 5 adjudicated drug-related ILD were 5.2% (n=56), 1.5% (n=16) and 0.7% (n=7), respectively. Of the 56 patients with adjudicated drug-related ILD, 54 (96.4%) discontinued T-DXd. The incidence of adjudicated drug-related ILD by time from initial treatment of T-DXd were 0.7% (7/1074) at ≤ 1 month, 2.0% (19/949) at 1-2 months, 2.7% (22/829) at 2-3 months, and 1.2% (8/652) at 3-4 months. Conclusions: The interim analysis revealed patient experiences and treatment profiles of T-DXd and the incidence of ILD during the first 4 months since initial treatment in a real-world setting in Japan. The final analysis including a risk factor analysis for ILD of the ongoing PMS is planned.

‘Being disabled’ as an exclusion criterion for clinical trials: a scoping review

BackgroundPeople with disabilities (PWDs) are often excluded from biomedical research, but comprehensive data regarding their participation in clinical trials are not available. The objective of this study was to assess...

Elevated serum transaminases in patients with acute coronary syndromes: Do we need a revision of exclusion criteria for clinical trials?

Elevations of hepatic transaminase (serum alanine transaminase [ALT] and serum aspartate aminotransferase [AST]) levels in patients with acute coronary syndrome (ACS), although transient, may result in exclusions from clinical efficacy trials due to suspected liver disease. The aim of this study was to evaluate the concentrations of serum transaminases in ACS and relate these to currently accepted AST/ALT exclusion criteria from clinical trials. One hundred consecutive patients with ACS were prospectively examined. Blood samples for AST, ALT, total bilirubin and troponin I concentration were obtained at the time of admission and after 6, 12 and 24 hours. Eighty percent of patients had elevated AST, and 47% ALT; 43% of patients characterized AST concentration > 3 × upper limit of normal (ULN) in at least one measurement, while 8% of patients presented ALT concentration > 3 × ULN. AST presented higher concentrations when compared to ALT, resulting in a high De-Ritis ratio at every time point. No significant or high correlations were found between the concentrations of serum transaminases, De-Ritis ratio and troponin I. Two different cut-off values of troponin I were adopted to define the amount of infarcted myocardium that distinguished 28-31% of individuals with "large infarction". Among these patients, approximately 93% presented AST concentrations > 3 × ULN. Hepatic transaminases are often elevated in ACS, with the majority of patients with more extensive myocardial injury presenting high concentrations of AST. In the setting of ACS, current transaminase thresholds for liver dysfunction used in clinical trials may lead to excessive and inadequate exclusions of patients with larger infarcts from such trials.

WS08.02 Change in hepatobiliary ultrasound measures, incl. shear wave elastography, after introduction of elexacaftor/tezacaftor/ivacaftor: results from 12-month follow-up in the Danish cystic fibrosis cohort

Objectives: A new era in cystic fibrosis (CF) since the introduction of CF transmembrane conductance regulator modulators with elexacaftor/tezacaftor/ivacaftor (ETI) is marked by significantly improved lung function and nutritional status. However, the impact of ETI on the liver remains poorly characterized, as advanced liver disease was an exclusion criterion in clinical trials. Clinical experience from the Danish CF cohort has shown ETI to be generally well-tolerated in term of liver biomarkers. The objective of this study is to assess hepatobiliary ultrasonographic changes before and twelve months after the initiation of ETI.

Eligibility for Anti-Amyloid Treatment in a Population-Based Cohort Study of Aging (P5-6.006)

Eligibility for Anti-Amyloid Treatment in a Population-Based Cohort Study of Aging (P5-6.006)

A Gap of Patients with Infective Endocarditis between Clinical Trials and the Real World.

Introduction: A randomized control trial (RCT) is considered to be the highest level in the Evidence-Based Medicine (EBM) pyramid. While EBM is essential to make a practical tool such as a prognostic guideline, it has been unclear how many patients in the real world can be eligible for a randomized control trial (RCT). Patients and method: This study was performed to clarify if there is a difference in patients' profiles and clinical outcomes between the patients eligible and not eligible for any RCT. We reviewed all IE patients at our institute between 2007 and 2019. The patients were divided into two groups: those eligible for RCTs (RCT appropriate group) and those who were not (RCT inappropriate group). Exclusion criteria for clinical trials were set based on previous clinical trials. Results: A total of 66 patients were enrolled in the study. The median age was 70 years (range 18 to 87 years), and 46 (70%) were male. Seventeen (26%) of the patients were eligible for RCTs. Comparing the two groups, patients in the RCT appropriate group were younger and had fewer comorbidities. The disease severity was milder in the RCT appropriate groups than in the RCT inappropriate groups. Patients in the RCT appropriate group showed significantly longer overall survival times than those in the RCT inappropriate group (Log-Rank test, p < 0.001). Conclusions: We found a significant gap in patients' characteristics and clinical outcomes between the groups. Physicians should be aware that RCT can never reflect the real-world population.

Abstract WMP5: How Do Clinical Trial Exclusion Criteria Impact The Inclusivity Of Clinical Trials?

Intro: Enrolling women and under-represented minorities into clinical trials is a top priority for the stroke community. Common trial exclusions for medical conditions or demographics may negatively impact enrollment for these groups. We sought to describe the potential impact that various exclusion criteria have on trial eligibility of ischemic stroke (IS) patients by race and sex within the large, biracial Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS) population. Methods: The GCNKSS is a population-based study of 1.3 million people living in a 5-county area of southern Ohio/ Northern Kentucky. During 7/1/14-12/31/15 for blacks, and 2015 for whites, we captured all hospitalized ischemic strokes by screening ICD-9 codes 430-436 and ICD10 codes I60-I68, and G45-46. Commonly used exclusion criteria from stroke clinical trials were applied to the GCNKSS IS population, and were compared by sex and race. All comparisons were evaluated with chi-square test and corrected for multiple comparisons, as necessary. Results: In 2014-2015, there were 2806 ischemic stroke patients, which were 53% female, and 30% black. Table 1 presents common clinical trial exclusion criteria and the % excluded among IS patients, stratified by sex and race. Every trial exclusion evaluated had significant differences by sex, race, or both. Discussion: Within our population, we found that commonly-used age and disability clinical trial exclusion criteria exclude more women than men, and exclusion of milder strokes affects more men than women. Blood pressure, renal function, and early arrival time criteria exclude more blacks than whites, while older age exclude more whites than blacks. Optimal clinical trial design should be informed by epidemiology data to ensure representation of underrepresented populations in clinical trials. We will continue to provide epidemiology feedback on acute trial exclusion criteria to NIH StrokeNet proposals in the future.

A scoping review protocol to elucidate outcomes following abiraterone versus enzalutamide for prostate cancer.

IntroductionAbiraterone acetate and enzalutamide are commonly employed in prostate cancer therapy in an interchangeable manner. These drugs are highly efficacious in androgen antagonism to improve patient outcomes, but they also carry noteworthy risk of adverse effects. Common toxicities vary amongst the two drugs and may have differential interactions with patient co-morbidities, but these patterns are unclear as co-morbidities typically serve as exclusion criteria in clinical trials. Hence, there is no existing guidance on how clinicians may tailor treatment based on patient-specific factors. Analysis of differential patient outcomes between these two drugs can inform future systematic reviews, new clinical studies, and clinical decision making.Method and analysisThe framework for this methodology was informed by the Joanna Briggs Institute methodology for scoping reviews. Title and abstract screening will be performed by two independent researchers to create an initial study inventory. This will be followed by full-text screening for study inclusion. Population-based studies describing patient outcomes, common toxicities, and associations with patient co-morbidities following abiraterone or enzalutamide therapy will be included. After data is extracted, it will be summarized for presentation.Ethics and disseminationThe findings of this scoping review will be published in a peer-reviewed journal. The results will be used to inform future studies on patient-specific factors informing treatment choice between abiraterone and enzalutamide for castration-resistant prostate cancer. All data are from published openly accessible sources, and therefore, no ethical clearance is necessary. The protocol is also registered at https://doi.org/10.6084/m9.figshare.19149227.

Predicting immune checkpoint inhibitor-related hepatitis using electronic health records of patients.

e13564 Background: Immune checkpoint inhibitor (ICI) therapies have shown impressive results in treating oncology patients. However, some patients exhibit immune-related adverse events (irAE-s), one significant irAE is autoimmune hepatitis. Oncologists routinely screen for hepatic toxicity with a complete metabolic panel prior to each ICI administration. Predictive modeling of irAE-s based on patient factors has the potential to help guide treatment selection and monitoring protocols. We have developed a widely usable model based on patient history and routinely collected standard blood panels that can predict whether a patient will experience hepatitis with ICI administration. Methods: We defined irAE hepatitis as any single value of AST, ALT, or alkaline phosphatase three-times the upper limit of normal (ULN) as following ICI treatment. The goal was to determine whether the level of the biomarkers exceed this threshold within certain, pre-defined time-windows, as determined by medical experts. We used feature engineering to compress the time-series of lab panels into single meaningful statistical descriptors, such as mean or maximum of these vectors. The dataset was highly unbalanced with many more negative cases (out of the 3231 patients, depending on the window length used for feature generation, 100-400 positives were found), which warranted the application of synthetic resampling methods. Finally, we trained various ensemble models ( e.g., random forest, gradient boosting), on both the resampled and original dataset, to obtain the final, predictive model for the likelihood of irAE hepatitis. Models were tuned to favor high recall and lower precision (identification of patients for increased monitoring) or moderate recall and moderate precision (maximizing F1-score). Results: We explored several modelling methods, such as KNN, Logistic Regression, Random Forests (RF), Gradient Boosting (GB), and stacking. GB without resampling produced the best model with the moderate recall and precision. To achieve high recall with low precision, we needed to resample the dataset with random majority class under sampling and then use RF (see table below for exact results). Conclusions: In this study, we show contemporary machine learning methods can be used as a screening tool for patients at risk for irAE hepatitis. This method could be used to identify patients who would benefit from additional laboratory monitoring between ICI administrations or guide clinical decisions about therapy cessation in advance of toxicity. Additionally, these methods may be further developed and adapted to improve clinical trial exclusion criteria for patients most likely to develop irAE hepatitis.[Table: see text]

Effect of sponsor on enrollment criteria in non-small cell lung cancer clinical trials

BackgroundInclusion and exclusion criteria in clinical trials are used to mitigate the effects of confounding variables on study outcomes. In 2017 and 2021, ASCO and the Friends of Cancer Research published recommendations to loosen enrollment criteria in cancer clinical trials to improve generalizability. The purpose of this study is to determine if the source of funding influences the degree of transparency and selection of inclusion and exclusion criteria. MethodsPhase 2 and 3 non-small cell lung cancer (NSCLC) drug trials on clinicaltrials.gov were grouped into one of three sponsor categories: industry, government/cooperative group, and academic. Strictness of specific criteria and the level of transparency in listing organ function requirements were analyzed using Fisher Exact tests. Independent sample t-tests were used to assess the variability in total number of criteria. ResultsOrgan function requirements listed on clinicaltrials.gov are more often vague or incomplete in industry sponsored trials compared to government/cooperative group (p = 2.3 × 10−10, α = 0.01) and academic (p = 1.8 × 10−4, α = 0.01) sponsored trials. Industry sponsored trials more often excluded patients with worse performance status scores compared to government/cooperative group sponsored trials (p = 5.7 × 10−6, α = 0.01). ConclusionIndustry sponsored NSCLC drug trials are more likely to exclude patients with worse performance status and are less transparent in listing complete study requirements on clinicaltrials.gov. Policy summaryUnnecessarily strict enrollment criteria are increasingly seen in clinical trials sponsored by industry. Regulators responsible for drug approvals should note when studies deviate from ASCO and Friends of Cancer Research framework and question the external validity of study findings with overly narrow enrollment criteria when making decisions on drug approvals.

A Large Gap in Patients' Characteristics and Outcomes between the Real-World and Clinical Trial Settings in Community-Acquired Pneumonia and Healthcare-Associated Pneumonia.

(1) Introduction: Evidence-based medicine (EBM) is necessary to standardize treatments for infections because EBM has been established based on the results of clinical trials. Since entry criteria for clinical trials are very strict, it may cause skepticism or questions on whether the results of clinical trials reflect the real world of medical practice. (2) Methods: To examine how many patients could join any randomized clinical trials for the treatment of community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP). We reviewed all the pneumonia patients in our institute during 2014–2017. The patients were divided into two groups: patients who were eligible for clinical trials (participation-possible group), and those who were not (participation-impossible group). Exclusion criteria for clinical trials were set based on previous clinical trials. (3) Results: A total of 406 patients were enrolled in the present study. Fifty-seven (14%) patients were categorized into the participation-possible group, while 86% of patients belonged to the participation-impossible group. Patients in the participation-possible group had less comorbidities and more favorable outcomes than those with the participation-impossible group. As for the outcomes, there were significant differences in the 30-day and in-hospital mortality rates between the two groups. In addition, the participation-possible group showed a longer overall survival time than the participation-impossible group (p < 0.001 by Log-Rank test). (4) Conclusion: There is a difference in patients’ profile and outcomes between clinical trials and the real world. Though EBM is essential to advance medicine, we should acknowledge the facts and the limits of the clinical trials.

PREVALCENCE OF MR‐DECTED CARTILAGE DAMAGE IN KNEES WITH KELLGREN-LAWRENCE 2 & 3 OSTEOARTHRITIS AND IMPLICATIONS FOR CLINICAL TRIALS

Many potential disease-modifying osteoarthritis drugs (DMOADs) have been investigated, but to date no DMOADs that slow or stop disease progression have been approved by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA). A potential reason for the lack of demonstrated efficacy may be reliance on radiographs for defining structural inclusion and exclusion criteria for clinical trials, such as use of joint space width and Kellgren-Lawrence (KL) grade as surrogates for cartilage damage. To estimate the distribution of cartilage damage seen on knee MRI in a sample of knees with radiographic KL 2 and 3 OA that would potentially qualify for a DMOAD trial. We selected knees from the Osteoarthritis Initiative (OAI) that met common structural inclusion criteria for DMOAD trial enrollment at OAI baseline: knees with radiographs centrally graded as KL 2 or 3 and medial minimum joint space width (mJSW) ≥ 1.5mm. A musculoskeletal radiologist with 10 years of experience in semi-quantitative MRI assessment scored knee cartilage damage in the medial and lateral tibiofemoral and patellofemoral compartments using WORMS (Whole-Organ Magnetic Resonance Imaging Score). Coronal intermediate weighted (IW) TSE and sagittal fat-suppressed IW TSE sequences on 3T MRI were used. The WORMS cartilage scores, which are based on both the extent and depth of cartilage damage, were collapsed into 4 categories: no cartilage damage (WORMS 0 and 1), focal partial or full-thickness (PT/FT) cartilage damage (WORMS 2 and 2.5), diffuse partial thickness (PT) cartilage damage (WORMS 3 and 4), and diffuse full-thickness (FT) cartilage damage (WORMS 5 and 6). We estimated the prevalence of each category of cartilage damage in KL2 and KL3 knees; 95% confidence intervals (CI) accounted for clustering at the participant-level since some participants contributed two knees to the analysis. We identified 2,372 participants contributing 3,446 knees with radiographic OA (KL 2 and 3) and medial mJSW ≥ 1.5mm. There were 2,318 KL2 knees and 1,128 KL3 knees. We found no cartilage damage in any compartments in 9.8% (95%CI: 8.5, 11.1) of KL2 knees and 2.0% (95%CI: 1.1, 2.9) of KL3 knees. Cartilage damage was absent in the medial tibiofemoral compartment in 52.4% (95%CI: 50.1, 54.6) of KL2 knees, and 14.4% (95%CI: 12.2, 16.6) of KL3 knees, versus 61% (95%CI: 58.8, 63.2) of KL2 knees and 53.6% (95%CI: 50.4, 56.7) of KL3 knees in the lateral compartment. When medial and lateral compartments were combined, cartilage damage was absent in 34.8% (95%CI: 32.7, 36.9) of the KL2 knees, and 4.3% (95%CI: 3.0, 5.5) of the KL3 knees. Diffuse FT cartilage lesions in the medial compartment were found in 6.1% (95%CI: 5.0, 7.1) of KL2 knees and 42.5% (95%CI: 39.4, 45.6) of KL3 knees. MRI screening prior to clinical trial enrollment may identify a substantial percentage of knees with normal cartilage, as well as knees with diffuse FT cartilage lesions that may not be responsive to DMOADs, depending on the mode of action of a given pharmacological compound. AG has received consultancies fees from Pfizer, Novartis, AstraZeneca, Merck Serono, Regeneron and TissueGene and is shareholder of Boston Imaging Core Lab (BICL), LLC a company providing image assessment services. FWR is shareholder of BICL, LLC and has received consultancies fees from Calibr–California Institute of Biomedical Research and Grünenthal, GmbH. DH receives publication royalties from Wolters-Kluwer. CKK has received consultancy fees from Thuasne, Regeneron, Novartis, Kolon Tissue Gene, Taiwan Liposome, Amzell AZ, LG Chem, Express Scripts, and has received grants from Lilly, Pfizer GSK, Cumberland CORRESPONDENCE ADDRESS: mjarraya@mgh.harvard.edu .

Investigation of the Differences between Clinical Trial Exclusion Criteria and Contraindications at the Time of Marketing of Monoclonal Antibody Drugs

Investigation of the Differences between Clinical Trial Exclusion Criteria and Contraindications at the Time of Marketing of Monoclonal Antibody Drugs

Risk Mitigation of Immunogenicity: A Key to Personalized Retinal Gene Therapy.

Gene therapy (GT) for ocular disorders has advanced the most among adeno-associated virus (AAV)-mediated therapies, with one product already approved in the market. The bank of retinal gene mutations carefully compiled over 30 years, the small retinal surface that does not require high clinical vector stocks, and the relatively immune-privileged environment of the eye explain such success. However, adverse effects due to AAV-delivery, though rare in the retina have led to the interruption of clinical trials. Risk mitigation, as the key to safe and efficient GT, has become the focus of ‘bedside-back-to-bench’ studies. Herein, we overview the inflammatory adverse events described in retinal GT trials and analyze which components of the retinal immunological environment might be the most involved in these immune responses, with a focus on the innate immune system composed of microglial surveillance. We consider the factors that can influence inflammation in the retina after GT such as viral sensors in the retinal tissue and CpG content in promoters or transgene sequences. Finally, we consider options to reduce the immunological risk, including dose, modified capsids or exclusion criteria for clinical trials. A better understanding and mitigation of immune risk factors inducing host immunity in AAV-mediated retinal GT is the key to achieving safe and efficient GT.

Liver and kidney function in patients with Covid-19 treated with remdesivir.

For the treatment of Covid‐19 patients with remdesivir, poor renal and liver function were both exclusion criteria in randomized clinical trials and contraindication for treatment. Also, nephrotoxicity and hepatotoxicity are reported as adverse events. We retrospectively reviewed renal and liver functions of Covid‐19 103 patients who received remdesivir in the 15 days after treatment initiation. Approximately 20% of the patient population met randomized clinical trial exclusion criteria. In total, 11% of the patients had a decrease in estimated glomerular filtration rate >10 mL/min/1.73m2. Also, 25 and 35% had increased alanine transaminase and aspartate transaminase levels, respectively. However, serious adverse events were limited. Therefore, based on these preliminary results, contraindications based on kidney and liver function should not be absolute for remdesivir treatment in patients with Covid‐19 if these functions are monitored regularly. A larger patient cohort is warranted to confirm our results.