Effects Of New Therapies Research Articles

Health technology assessments of new specialized therapies: A typology of key challenges and potential policy solutions

ObjectivesCurrent transformations in the pharmaceutical sector raise pressing questions about what is considered acceptable evidence for the effects of new therapies. This article aims to identifying key challenges in clinical effectiveness evaluation of new therapies and discuss possible policy responses to these challenges. MethodsThe study builds on a systematic review of the 41 appraisals issued in 2019 by the Danish Medicines Council (DMC), which is responsible for the appraisal of new specialized therapies in Denmark. ResultsWhile much political attention currently centers on the use of ‘real-world evidence’, we find that clinical effectiveness evaluation based solely on non-RCT evidence still constitutes an exception in the Danish setting (9% of the evaluations). Yet, challenges of indirectness were prevalent even when evaluations were based on RCT data (54% of the evaluations). Challenges of effect extrapolation arose in about a third of the evaluations. DiscussionAs the identified challenges are likely to increase with the current trend from ‘blockbuster’ to ‘niche’ products in the pharmaceutical sector, we point to a need for regulators and health technology assessment agencies to collaborate about the development of guidance on the use of other study designs than traditional RCTs, methods that can reduce the risk of bias when conducting indirect comparisons, and principles for managed entry agreements.

Assessment of algorithms for identifying patients with triple-class refractory multiple myeloma using real-world data

Objective: Patients with triple-class refractory (TCR) multiple myeloma (MM) have limited treatment options and poor prognoses. This high unmet need has prompted the development of new therapies allowing for improved outcomes for these patients. Recently, new targeted therapies for the treatment of patients with relapsed or refractory MM have been approved based on single-arm clinical trial results. Real-world (RW) data enable a better understanding of the effectiveness of new therapies in clinical practice and provide external controls for single-arm studies. However, using RW data to identify patients with TCR MM is challenging and subject to limitations. Methods: In this retrospective cohort study of an analysis of the COTA electronic health record (EHR) database, we used four algorithms to define refractory status and created four groups of patients with TCR MM initiating post-TCR therapy. Each algorithm relied on slightly different criteria to identify TCR patients, but all were based on the International Myeloma Working Group (IMWG)-derived and/or healthcare provider (HCP)-reported progressions within the database. Results: A total of 3815 patients with newly diagnosed MM met the eligibility criteria for this study. The choice of the algorithm did not impact the characteristics of identified patients with TCR MM (Algorithm 1 [n = 404], Algorithm 2 [n = 123], Algorithm 3 [n = 404], and Algorithm 4 [n = 375]), including their demographic and disease characteristics, MM treatment history, or treatment patterns received after becoming TCR. However, identifying TCR MM using a combination of IMWG-derived and HCP-reported progressions allowed up to a 70% increase in the size of the identified group of patients compared with using only IMWG-derived progressions. Conclusion: In RW settings, progressions from both IMWG-derived data and physician reports may be used to identify patients with TCR MM.

2022-2023 Drug Updates in Solid Tumors.

At JADPRO Live 2023 in Orlando, Lisa M. Holle, PharmD, BCOP, FHOPA, FISOPP, briefed advanced practitioners on key US Food and Drug Administration approvals from late 2022 to late 2023. Dr. Holle described indications, mechanisms of action, and monitoring and management of side effects of new therapies in solid malignancies.

2022-2023 Drug Updates in Hematologic Malignancies.

At JADPRO Live 2023 in Orlando, Rebecca L. Rezac, PharmD, BCOP, summarized key information on US Food and Drug Administration approvals from late 2022 to late 2023. Dr. Rezac described indications, mechanisms of action, and monitoring and management of side effects of new therapies for hematologic malignancies.

Underrepresentation of Hispanics in clinical trials for liver cancer in the United States over the past 20 years.

Accurate representation of racial and ethnic population subgroups in clinical trials is fundamental to ensure universal effectiveness of new therapies as well as to decrease disparities in oncology care. To determine whether Hispanic people are underrepresented in Phase I and II clinical trials for liver cancer in the United States. A database search was performed in clinicaltrials.gov for interventional liver cancer studies based only in the US with reported results from September 1, 2002, to February 1, 2023. A total of 37 trials with 963 total patients met inclusion criteria and were included for further analysis. Proportion of total patients by race/ethnicity was calculated for non-Hispanic white, non-Hispanic black, Asian, Hispanic, and American Indian/Alaska Native subpopulations. The age-adjusted incidence rates of liver and intrahepatic bile duct were acquired from the National Cancer Institute, Surveillance, Epidemiology, and End Results Program. Liver cancer incidence rates (per 100,000 people) were highest in Indians/Alaska Native people (18.8 cases) followed by Hispanic people (15.1 cases), then Asian people (12.5 cases), then non-Hispanic black people (11 cases), and non-Hispanic white people (7.5 cases). From a total of 91 phase I or II clinical trials for liver cancer in the US, 41% reported race/ethnicity enrollment data; among these, 62.8% of patients were non-Hispanic White, 15.9% were non-Hispanic black, 8.8% were Hispanic, 12.7% Asian, and 0.5% American Indian/Alaska Native. Less than half of phase I or II clinical trials for liver cancer in the US in the last 20 years reported race/ethnicity data to clinicaltrials.gov. Compared to the relative incidence rate of liver cancer, non-Hispanic black people and Hispanic people are underrepresented in these clinical trials.

Virtual inpatient continuity visit to reduce readmissions, establish goals of care and engage palliative care: A feasibility pilot.

421 Background: Patients with solid tumors readmitted within 30 days (d) have a median overall survival of less than 90d. Decisions regarding goals of care (GOC), engagement with Palliative Care (PC) and further therapy are often deferred to the outpatient team leading to future readmissions. Methods: A pilot virtual continuity visit (VCV) program was developed using a video platform to arrange meetings with outpatient oncologists, inpatient teams, patients, families and PC providers during a hospital readmission within 30d. The intervention occurred on a single solid tumor oncology service at an academic medical center. Patients were included if discharged from the same hospital within 30d and not readmitted from hospice or SNF. Exclusion criteria included admission for scheduled therapy, curative-intent treatment, or acute side effects of new therapy. Orders were placed at the discretion of the inpatient team. Visits were scheduled only on weekdays. A structured discussion tool was used for prognostic awareness, GOC and availability of PC services. Results: From April 1, 2022 through March 31, 2023, 96 unique patients were eligible for VCVs. This represented 6% admissions to this floor. 15 VCV were completed, 23 were scheduled but not completed, 58 were not scheduled. Reason scheduled visits not completed included: in-person family meeting (7 ), physician unavailable (9), transfer off floor (1), conversation deferred to outpatient visit (4), not clinically necessary (2). Reason visits not scheduled: unable to schedule prior to D/C (37), deferred to outpatient (2) hospice D/C (3), not appropriate (5), in person visit (1). Of the 15 patients who completed VCV, 0% were readmitted within 30d, 100% had documented GOC discussion and 100% had PC engaged in the VCV. Of the 7 patients who had in person visits, 3 of 7 were readmitted, 1 of 7 in person visits had a documented GOC discussion. No PC engagement was present for the in-person meetings. 51/58 patients without scheduled VCV were readmitted, 22 within 30d. Conclusions: VCV are feasible via a video platform with the patient, primary oncologist, inpatient team and PC. The structured discussion provided clear documentation of prognostic awareness, GOC and engagement with PC. No patient who completed a VCV was readmitted.

Determinants and Characterization of Locomotion in Adults with Late-Onset Pompe Disease: New Clinical Biomarkers.

The late-onset form of Pompe disease (LOPD) is characterized by muscle weakness, locomotor limitations and a risk of falls. The mechanisms responsible for altered locomotion in adults with LOPD are unknown. The identification of clinical biomarkers is essential for clinical follow-up and research. To identify muscle determinants of impaired locomotor performance, gait stability and gait pattern, and biomechanical determinants of falls in adults with LOPD. In this cross-sectional, case-control study, LOPD and control participants underwent 3D gait analysis, locomotor performance tests and muscle strength measurements (isokinetic dynamometer). We explored the muscular determinants of locomotor performance (gait speed, 6-minute walk test distance and timed up and go test), gait stability (spatiotemporal gait variables) and the gait pattern. We also explored biomechanical gait determinants of falls. After intergroup comparisons, determinants were sought to use forward stepwise multiple regression. Eighteen participants with LOPD and 20 control participants were included. Locomotor performance, gait stability, and the gait pattern were significantly altered in LOPD compared to control participants. Hip abductor strength was the main common determinant of locomotor performance, gait stability and pelvic instability. Hip flexor strength was the main determinant of abnormal gait kinematics at the hip and knee. Percentage duration of single support phase during the gait cycle was the main determinant of falls. Hip abductor strength and percentage duration of single support during gait were the major determinants of locomotor performance, gait stability, falls and the gait pattern in LOPD. These new clinical biomarkers should therefore be systematically assessed using instrumented tools to improve the follow-up of adults with LOPD. They should also be considered in future studies to accurately assess the effects of new therapies. Hip abductor strength and single support phase should also be priority targets for rehabilitation.

Electrophysiological and Histological Correlations of Optic Neuritis in the Dark Agouti Rat Model of Experimental Autoimmune Encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is an animal model of Inflammatory central nervous system (CNS) disease. Dark agouti (DA) rats immunized with full-length myelin oligodendrocyte glycoprotein (MOG1-125) typically develop a relapsing-remitting EAE form characterized by predominant demyelinating involvement of the spinal cord and optic nerve. Visually evoked potentials (VEP) are a useful objective tool to assess the optic nerve function and monitor electrophysiological changes in optic neuritis (ON). The current study aimed to assess the VEP changes in MOG-EAE DA rats using a minimally invasive recording device and to correlate them with histological findings. Twelve MOG-EAE DA rats and four controls underwent VEP recording at day 0, 7, 14, 21, and 28 post-EAE induction. Tissue samples were obtained on days 14, 21, and 28 from two EAE rats and one control. The median VEP latencies were significantly higher on days 14, 21, and 28 compared to baseline, with maximal latencies observed on day 21. The histological analyses on day 14 demonstrated inflammation with largely preserved myelin and axonal structures. Inflammation and demyelination with largely preserved axons were evident on days 21 and 28, which correlated with prolonged VEP latencies. These findings suggest that VEPs may be a reliable biomarker reflecting the optic nerve involvement in EAE. Moreover, the use of a minimally invasive device enables observation of VEP changes over time in MOG-EAE DA rats. Our findings may have important implications for testing the potential neuroprotective and regenerative effects of new therapies for CNS demyelinating diseases.

Does the Measurement of Ejection Fraction Still Make Sense in the HFpEF Framework? What Recent Trials Suggest.

Left ventricular ejection fraction (LVEF) is universally accepted as a cardiac systolic function index and it provides intuitive interpretation of cardiac performance. Over the last two decades, it has erroneously become the leading feature used by clinicians to characterize the left ventricular function in heart failure (HF). Notably, LVEF sets the basis for structural and functional HF phenotype classification in current guidelines. However, its diagnostic and prognostic role in patients with preserved or mildly reduced contractile function is less clear. This is related to several concerns due to intrinsic technical, methodological and hemodynamic limitations entailed in LVEF measurement that do not describe the chamber's real contractile performance as expressed by pressure volume loop relationship. In patients with HF and preserved ejection fraction (HFpEF), it does not reflect the effective systolic function because it is prone to preload and afterload variability and it does not account for both longitudinal and torsional contraction. Moreover, a repetitive measurement could be assessed over time to better identify HF progression related to natural evolution of disease and to the treatment response. Current gaps may partially explain the causes of negative or neutral effects of traditional medical agents observed in HFpEF. Nevertheless, recent pooled analysis has evidenced the positive effects of new therapies across the LVEF range, suggesting a potential role irrespective of functional status. Additionally, a more detailed analysis of randomized trials suggests that patients with higher LVEF show a risk reduction strictly related to overall cardiovascular (CV) events; on the other hand, patients experiencing lower LVEF values have a decrease in HF-related events. The current paper reports the main limitations and shortcomings in LVEF assessment, with specific focus on patients affected by HFpEF, and it suggests alternative measurements better reflecting the real hemodynamic status. Future investigations may elucidate whether the development of non-invasive stroke volume and longitudinal function measurements could be extensively applied in clinical trials for better phenotyping and screening of HFpEF patients.

A Novel In Vitro Disease Model for Systemic Sclerosis Using Polyisocyanide Hydrogels

AbstractSystemic sclerosis (SSc) is a rare autoimmune disease with limited treatment options that is characterized by fibrosis in various organs. To screen the effectiveness of new therapies, there is an urgent need for reliable in vitro models. Key is that diseased cells' characteristics are maintained, which is challenging in currently used setups. In this study, an in vitro 3D culture system is described using the biocompatible polyisocyanide (PIC‐RGD) hydrogel and SSc patient‐derived fibroblasts from affected (lesional cells) and from healthy‐skin (healthy cells). In contrast to the standard collagen‐coated 2D cultures, the cells in the 3D PIC‐RGD gels maintain the native phenotype and functionality of the primary cells. The functionality of the model is studied in the presence of the fibrosis stimulator transforming growth factor β1 (TGFβ1) and the suppressor tumor necrosis factor (TNFα). In this study, it is observed that lesional cells have a stronger fibrotic character with increased contraction, proliferation, and expression of collagen, and myofibroblast markers α‐smooth muscle actin and fibroblast activation protein. The high tunability of the hydrogel, which can maintain the native functionality of fibroblasts in in vitro cultures, delivers a crucial step in developing these materials into an effective tool for personalized medicine approaches of SSc patients.

HTA45 Uncertainty Regarding the Long-Term Effectiveness of New Therapies in Health Technology Assessment

HTA45 Uncertainty Regarding the Long-Term Effectiveness of New Therapies in Health Technology Assessment

Current Evidence, Limitations and Future Challenges of Survival Prediction for Glioblastoma Based on Advanced Noninvasive Methods: A Narrative Review.

Background and Objectives: Survival estimation for patients diagnosed with Glioblastoma (GBM) is an important information to consider in patient management and communication. Despite some known risk factors, survival estimation remains a major challenge. Novel non-invasive technologies such as radiomics and artificial intelligence (AI) have been implemented to increase the accuracy of these predictions. In this article, we reviewed and discussed the most significant available research on survival estimation for GBM through advanced non-invasive methods. Materials and Methods: PubMed database was queried for articles reporting on survival prognosis for GBM through advanced image and data management methods. Articles including in their title or abstract the following terms were initially screened: ((glioma) AND (survival)) AND ((artificial intelligence) OR (radiomics)). Exclusively English full-text articles, reporting on humans, published as of 1 September 2022 were considered. Articles not reporting on overall survival, evaluating the effects of new therapies or including other tumors were excluded. Research with a radiomics-based methodology were evaluated using the radiomics quality score (RQS). Results: 382 articles were identified. After applying the inclusion criteria, 46 articles remained for further analysis. These articles were thoroughly assessed, summarized and discussed. The results of the RQS revealed some of the limitations of current radiomics investigation on this field. Limitations of analyzed studies included data availability, patient selection and heterogeneity of methodologies. Future challenges on this field are increasing data availability, improving the general understanding of how AI handles data and establishing solid correlations between image features and tumor's biology. Conclusions: Radiomics and AI methods of data processing offer a new paradigm of possibilities to tackle the question of survival prognosis in GBM.

Liver resection of hepatocellular carcinoma in HIV-HCV co-infected patients: a retrospective case series

IntroductionDespite the effectiveness of new therapies and awareness campaigns, the number of seropositive patients is increasing every year. Recently, other causes of death, not directly related to HIV, have emerged, such as chronic liver disease. The risk of hepatocellular carcinoma (HCC) is seven times greater in HIV patients than in noninfected patients, and it is especially attributable to HCV infection. The aim of our study was to evaluate clinical outcomes of HCC in HIV-HCV co-infected patients after liver resection (LR).Materials and methodsThe current study was conducted on a prospective database and reviewed retrospectively. All consecutive patients with HCC treated by LR from January 2013 to March 2019 at the Luigi Sacco University Hospital in Milan were enrolled. We included patients older than 18 years of age with HCV-related HCC, and in this set of patients, we identified two groups based on the presence of HIV infection.ResultsWe identified 16 patients with HCV infection and precisely five with HIV-HCV co-infection and eleven with HCV infection alone. All HIV patients were male against 72.7% in the non-HIV group (p = 0.509). All patients had optimal HIV virologic control and a normal CD4 T-cell count. The mean diagnosis-to-treatment interval was statistically different between the two groups (HIV versus non-HIV: 1.2 ± 0.55 months versus 2.39 ± 1.09 months, p = 0.039).No other significant differences were found between HIV-HCV co-infected patients and HCV-infected patients. Long-term outcomes in terms of OS and RFS were similar between the two groups.ConclusionsWith a multidisciplinary approach and intensive support, LR can be a safe and efficacious procedure in HIV-HCV patients. For these reasons, we should not exclude potential patients merely on the basis of their HIV seropositivity.

Assessing surrogacy using restricted mean survival time ratio for overall survival in liver cancer immunotherapy studies.

e16222 Background: Recently, immunotherapy has played a crucial role in treating liver cancer, one of the major cancers that contributes to global cancer burden. Overall survival (OS) is widely applied in cancer trials to evaluate the treatment effects of new therapies. However, it requires more patients and longer follow-up time comparing with progression-free survival (PFS). In addition, while assessing the treatment effects of cancer immunotherapy, proportional hazard (PH) assumption is often violated due to issues such as delayed treatment effects. Restricted Mean Survival Time (RMST) ratio is increasingly used for treatment effect evaluation when the PH assumption is violated. Such change prompts an important question whether the surrogacy value of PFS will be affected when RMST ratio is used to characterize treatment effect. The aim of this study is to examine the feasibility of using PFS as a surrogate endpoint for OS when the treatment effect is measured using hazard ratio (HR) versus RMST ratio. Methods: The surrogacy of PFS on OS was evaluated through examining the association between PFS and OS using HR and RMST ratio. Seven immunotherapy studies published between 2000 and 2021 were included (Table). Information of examined studies such as treatment arms information, OS and PFS were collected. RMST ratio for PFS and OS were calculated based on the Kaplan-Meier plots extracted from each article using WebPlotDigitizer 4.4. The weighted least square regression lines and R^2 between OS and PFS for HR and RMST ratio were calculated. Results: Among 7 immunotherapy studies, 4 gave placebos to the control arms as treatments. 2 provided Sorafenib and 1 assigned the same drug as treatment arm but with different schedule. All 7 studies had OS and PFS as the endpoints. 2 studies violated the PH assumptions. Based on the data extracted from examined articles, a moderate correlation (0.52) between PFS and OS was observed for HR while low correlation (0.10) was observed for RMST ratio. Conclusions: The R^2 values differ greatly depending on whether HR or RMST ratio was used for assessing surrogacy. Our finding may have important implications for the design of future immunotherapy liver cancer trials. For future work, increasing the number of included studies for a more comprehensive analysis is needed. Moreover, trial-level surrogacy analysis should be conducted to complement the study-level investigation.[Table: see text]

Long-term time trends in incidence, survival, and mortality of malignant melanoma in the United States.

e21599 Background: While there have been newer treatments that were developed in the last decade for metastatic melanoma, there is lack of data that directly looks at survival in melanoma before and after introduction of these new agents. We tried to explore the epidemiology of malignant melanoma including incidence to look at the trends of its incidence, survival and mortality in different groups over the last two decades. Methods: Data was obtained from the Surveillance, Epidemiology, and End Results Program (SEER Research Data, 18 Registries from 2000-2018) and data was cleaned and analyzed in STATA 16. 363,517 records were included in analysis from which baseline characteristics and median were obtained for survival time and survival analysis was done by Cox regression method to compare survival time between different groups. Pearson correlation was calculated to look for association between survival time and Breslow thickness. Results: Mean age group was 55-64 years, with 58% males and 42% females. 95% were White, 0.43% were Black, 0.63% were Asian and 3.79% were other races. 87% were localized, whereas 13% were metastatic. Mean Breslow thickness was 1.27mm (1.26-1.28). Overall median survival time was 62 months for malignant melanoma and 27 months for metastatic malignant melanoma. 42.63% were diagnosed before 2009 and 57.37% were diagnosed from 2009 to 2018. Cumulative incidence rate of melanoma increased from 4.78 to 6.57 per 100,000 persons whereas mortality rate increased from 0.29 to 2.23 per 100,000 persons from years 2000 to 2012 respectively. With contrast to age below 65, patients with age 65 and above had lower survival time (HR 4.78 95% CI 4.71-4.85, p < 0.01). There seemed to be an increase in incidence of melanoma among patients above 65 compared to below 65. When compared to males, females had significantly higher survival time (HR 0.62 95% CI 0.61-0.63, p < 0.01). Similarly, when compared to White population, Black and Asian population had lower survival time (HR 2.27 95% CI 2.11-2.43, p < 0.01 & HR 1.57 95% CI 1.14-1.68, p > 0.01) respectively. Comparing to localized disease, both regional and distant involvement had significantly lower survival time (HR 3.21 95% CI 3.15-3.28, p < 0.01 & HR 11.34 95% CI 11.07-11.61, p < 0.01) respectively. Breslow thickness had a negative correlation with survival months [regression coefficient (R) of -2.21 p < 0.01 (95% CI -2.35 to -2.07)]. Compared to patients who died before 2012, patients who died in 2012 or after had significantly better survival (HR 0.46, 95% CI 0.46-0.47, p < 0.01). Conclusions: Both, the incidence, and mortality of melanoma are rising, with more increase in age above 65 years. There appears to be an improvement in survival among patients who died after 2012, which may be an indirect indicator of the effectiveness of newer therapies. Risk factors for lower survival time were male sex, Black & Asian race, metastatic disease, and higher Breslow thickness.

Progression-free survival at 3 years is a reliable surrogate for 5-year overall survival for patients suffering from locally advanced esophageal squamous cell carcinoma.

BackgroundDespite 3‐year survival being used as a primary endpoint in some randomized controlled trials (RCTs), limited evidence supports the use of intermediate endpoints to evaluate the effect of new therapies in esophageal squamous cell cancer (ESCC). This study aimed to systematically evaluate progression‐free survival at 3 years (3‐year PFS) and overall survival (OS) among patients with ESCC.MethodsWe identified 528 patients newly diagnosed with locally advanced ESCC who received definitive radiotherapy. OS was compared with an age‐ and sex‐matched general Chinese population using the standardized mortality ratio (SMR). Regression analysis was used to validate the correlation between PFS and OS using published data.ResultsThe annual risk of progression decreased to 11.5% after 3 years. Patients who did not achieve 3‐year PFS had a median postprogression survival (PPS) of 7.3 months, with a 5‐year OS rate of 9.6% and a SMR of 15.0 (95% confidence interval [CI], 12.9–17.5). Conversely, the SMR for patients who achieved 3‐year PFS was 0.9 (95% CI, 0.6–1.3). We observed a significant correlation between log hazard ratio (HR) (PFS) and log HR (OS) at the trial level (r = 0.89; 95% CI, 0.88–0.90). The strongest correlation was observed between 3‐year PFS and 5‐year OS in RCTs and retrospective studies.ConclusionsPatients exhibiting progression within 3 years experienced poor survival, whereas patients achieving 3‐year PFS had excellent outcomes. Our study supports 3‐year PFS as a reliable primary endpoint for study design and risk stratification in locally advanced ESCC.

The relation of CD4+CD25+Foxp3+ regulatory T cells concentration with disease activity and damage index in systemic lupus erythematosus.

Regulatory T cells (Treg) deficits, both quantitative and qualitative, are known to be possible triggers for the development of autoimmune disorders by causing T and B cells dysfunction. The contribution of Treg deficiency in the etiology of systemic lupus erythematosus (SLE) is still being debated. The aim of the present study is to evaluate the percentage of circulating CD4+CD25+Foxp3+ Treg cells in a cohort of Egyptian SLE patients and to correlate this value with the activity and damage index of these patients. 50 female patients with SLE together with an equal number of age- and sex-matched healthy controls were enrolled in the study. Flow cytometric determination of peripheral Treg cells was carried out for all participants by detecting the percentage of CD4+CD25+Foxp3+ cells to compare cases with the control group. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), while disease damage was assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR DI). Both indices were correlated with the percentage of CD4+CD25+Foxp3 T regulatory cells. CD4+CD25+Foxp3+ Treg cells percentage was significantly decreased in patients with SLE as compared to healthy controls. On correlating CD4+CD25+Foxp3+ Treg percentage with SLEDAI-2K, a significantly negative correlation was found. Also, there was a negative significant correlation between CD4+CD25+Foxp3+ Treg cells percentage and SLICC/ACR DI. On correlating SLEDAI-2K with damage index (SLICC/ACR DI), we found highly significant positive correlation. Our study showed impaired production of CD4+CD25+Foxp3+ Tregs in SLE patients, which can play a reciprocal role with some cytokines to affect the activity of the disease and organ damage. CD4+CD25+Foxp3+ Tregs cells should be the target to determine the clinical effectiveness of new therapy to modulate Tregs besides the traditional treatments.

Bilateral visual acuity decline in males with choroideremia: a pooled, cross-sectional meta-analysis

BackgroundChoroideremia is a rare inherited retinal disease that leads to blindness. Visual acuity (VA) is a key outcome measure in choroideremia treatment studies, but VA decline rates change with age. An accurate understanding of the natural deterioration of VA in choroideremia is important to assess the treatment effect of new therapies in which VA is the primary outcome measure. We conducted a meta-analysis of data on individuals with choroideremia to determine the rate of VA deterioration between the better- and worse-seeing eye (BSE and WSE, respectively).MethodsData were collected from the prospective Natural History of the Progression of Choroideremia (NIGHT) study (613 eyes, baseline data only), studies included in a recent meta-analysis, and studies identified in a targeted literature search performed on March 25, 2020, including individual best-corrected VA (BCVA) and age data in male individuals with choroideremia. Best-corrected VA decline rates (measured by logMAR units) by age and trends in BCVA decline rates in the BSE and WSE were evaluated. ResultsData from 1037 males (1602 eyes; mean age, 41.8 years) were included. Before and after an age cutoff of 33.8 years, BCVA decline rates for the WSE were 0.0086 and 0.0219 logMAR per year, respectively. Before and after an age cutoff of 39.1 years, BCVA decline rates for the BSE were 0.00001 and 0.0203 logMAR per year, respectively. Differences in absolute BCVA and decline rates increased between the 2 eyes until age ~ 40; thereafter, differences in absolute BCVA and decline rates were similar between eyes.ConclusionsUsing the largest choroideremia data set to date, this analysis demonstrates accelerated BCVA decline beginning between 30 and 40 years of age. Disparate interocular progression rates were observed before the transition age, with similar interocular progression rates after the transition age.

An overview of real-world data sources for oncology and considerations for research.

Generating evidence on the use, effectiveness, and safety of new cancer therapies is a priority for researchers, health care providers, payers, and regulators given the rapid pace of change in cancer diagnosis and treatments. The use of real-world data (RWD) is integral to understanding the utilization patterns and outcomes of these new treatments among patients with cancer who are treated in clinical practice and community settings. An initial step in the use of RWD is careful study design to assess the suitability of an RWD source. This pivotal process can be guided by using a conceptual model that encourages predesign conceptualization. The primary types of RWD included are electronic health records, administrative claims data, cancer registries, and specialty data providers and networks. Careful consideration of each data type is necessary because they are collected for a specific purpose, capturing a set of data elements within a certain population for that purpose, and they vary by population coverage and longitudinality. In this review, the authors provide a high-level assessment of the strengths and limitations of each data category to inform data source selection appropriate to the study question. Overall, the development and accessibility of RWD sources for cancer research are rapidly increasing, and the use of these data requires careful consideration of composition and utility to assess important questions in understanding the use and effectiveness of new therapies.

Abstract 13569: A Composite Score Summarizing Use And Dosing Of Evidence-based Medical Therapies In Heart Failure: Application To The DAPA-HF Trial

Introduction: The Heart Failure Collaboratory consortium (HFC) has developed a score to quantify background guideline-directed medical therapy (GDMT) in patients with heart failure and reduced ejection fraction (HFrEF). One potential use of this score is to test the incremental value of new therapies. We evaluated the effect of dapagliflozin according to a modified HFC score in the DAPA-HF trial. Methods: The key inclusion criteria in DAPA-HF were: 1) NYHA class II-IV, 2) LVEF ≤40%, and 3) elevated plasma NT-proBNP and 4) eGFR ≥30 ml/min/1.73m2. The primary outcome was a composite of a first episode of worsening HF (hospitalization for HF or an urgent HF visit requiring iv therapy) or cardiovascular death. The HFC score is calculated based on the use of GDMT and dose of GDMT. The modified HFC score used here also accounted for race (Black/non-Black) and ECG rhythm/rate with a maximum possible score of 100 (percent) for any patient (Panel A). Results: Among the 4744 patients (mean age 66 years; 23% women) randomized, an ACEi/ARB was used in 84%, beta-blocker 96%, MRA 71%, ARNI 11%, ivabradine 4.8%, and hydralazine 4.3%. During a median follow-up of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and 502 of 2371 patients (21.2%) in the placebo group (HR, 0.74; 95%CI 0.65 to 0.85; P<0.001). The benefit of dapagliflozin on the primary outcome was consistent across the range of baseline treatment score (Panel B). Examination of the effect of dapagliflozin on the primary outcome by score tertile (T1 ≤40, T2 41-60 and T3 >60) gave HRs for the effect of dapagliflozin, compared with placebo, of 0.75 (0.61-0.93), 0.77 (0.61-0.98), and 0.71 (0.55-0.90), respectively (P-interaction 0.87). Conclusions: A composite score for GDMT of the type developed by the HFC can be easily calculated in clinical trials and used to evaluate the incremental effect of new therapies.