Advancing the utilization of real-world data and real-world evidence in clinical pharmacology and translational research-Proceedings from the ASCPT 2023 preconference workshop.

Real-world data (RWD) and real-world evidence (RWE) are now being routinely used in epidemiology, clinical practice, and post-approval regulatory decisions. Despite the increasing utility of the methodology and new regulatory guidelines in recent years, there remains a lack of awareness of how this approach can be applied in clinical pharmacology and translational research settings. Therefore, the American Society of Clinical Pharmacology & Therapeutics (ASCPT) held a workshop on March 21st, 2023 entitled "Advancing the Utilization of Real-World Data (RWD) and Real-World Evidence (RWE) in Clinical Pharmacology and Translational Research." The work described herein is a summary of the workshop proceedings.

A Phase 1a Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7303509, an Anti-TGFß3 Antibody, in Healthy Volunteers.

INTRODUCTION: Transforming growth factor beta (TGFß) cytokines (TGFß1, TGFß2, and TGFß3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFß inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFß3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs). METHODS: This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50 mg, 150 mg, 240 mg) or subcutaneously (SC; 240 mg, 675 mg, 1200 mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations. RESULTS: The study enrolled 49 HVs, with a median age of 39 (range 18-73) years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (Cmax) and area under the concentration-time curve from time 0 to infinity (AUC0-inf) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50 mg IV) tested positive for ADAs at a single time point (day 15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFß3 inhibition. CONCLUSION: RO7303509 was well tolerated at single SC doses up to 1200 mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFß3-specific inhibition may be suitable for development as a chronic antifibrotic therapy. TRIAL REGISTRATION: ISRCTN13175485.

Comparative Pharmacokinetics and Safety Assessment of 1st- and 2nd-Generation Zinpentraxin Alfa Drug Products in Healthy Volunteers: A Randomized Crossover Study.

Zinpentraxin alfa is a recombinant form of the human pentraxin-2 that was studied in idiopathic pulmonary fibrosis (IPF). To improve the purity and yield of the drug material, a 2nd-generation drug product was developed. To characterize and compare the pharmacokinetic (PK) properties of the 1st- and 2nd-generation zinpentraxin alfa, PK studies were conducted in healthy volunteers (HVs). In a phase 1 randomized, double-blind, 2-sequence crossover, sequential 2-stage study (ISRCTN59409907), single intravenous (IV) doses of 1st- and 2nd-generation zinpentraxin alfa at 10 mg/kg were studied with a blinded interim analysis (IA) at the end of stage 1. Bioequivalence (BE) was achieved for the maximum observed plasma concentration (Cmax), but the overall exposure was higher for the 2nd- compared to the 1st-generation zinpentraxin alfa. The study was stopped after stage 1 as the gating criteria were met based on the result of the blinded IA. Safety profiles were similar for the 1st- and 2nd-generation drug products, and antidrug antibody (ADA) was not observed in this study.

Medicaid Expansion and Health Care Use Among Adults With Asthma and Low Incomes: The Adult Asthma Call-Back Survey.

OBJECTIVES: Asthma disproportionately affects Black people and people with low incomes, but Medicaid expansion (hereinafter, expansion) data on these populations are limited. We investigated health care use among adults with asthma, before and after expansion, and examined whether asthma-related health care use after expansion varied by demographic characteristics. METHODS: We analyzed data from the 2011-2013 and 2015-2019 Behavioral Risk Factor Surveillance System Adult Asthma Call-Back Survey on participants aged 18-64 years with current asthma and low incomes in 23 US states. We assessed 5 asthma-related outcomes, including medical visits (routine and emergency) and medication use, for expansion and nonexpansion groups. We used t tests to compare weighted percentages and 95% CIs, then performed adjusted difference-in-differences analyses. Secondary analyses stratified data by race, ethnicity, and sex. RESULTS: Primary analyses (N = 10 796) found no significant associations between expansion and any outcome. Analyses stratified by race and ethnicity found no significant changes (eg, asthma controller medication use among non-Hispanic Black participants in the expansion group was 24.1% [95% CI, 14.4%-37.5%] in 2011-2013 and 35.5% [95% CI, 27.0%-45.1%] in 2015-2019; P = .13). Use of asthma controller medication increased significantly among non-Hispanic Other participants in the nonexpansion group (2011-2013: 16.0% [95% CI, 9.5%-25.5%]; 2015-2019: 40.2% [95% CI, 25.5%-56.8%]; P = .01). Asthma-related hospitalizations decreased significantly among women in the expansion group: 2011-2013 (7.8%; 95% CI, 5.3%-11.3%) and 2015-2019 (3.5%; 95% CI, 2.5%-4.9%) (P = .009). CONCLUSIONS: Investigating factors other than health insurance (eg, social determinants of health) that influence the use of asthma-related health care could advance knowledge of potential strategies to advance health equity for adults with asthma and lower incomes.

Applications of Advanced Natural Language Processing for Clinical Pharmacology.

Natural language processing (NLP) is a branch of artificial intelligence, which combines computational linguistics, machine learning, and deep learning models to process human language. Although there is a surge in NLP usage across various industries in recent years, NLP has not been widely evaluated and utilized to support drug development. To demonstrate how advanced NLP can expedite the extraction and analyses of information to help address clinical pharmacology questions, inform clinical trial designs, and support drug development, three use cases are described in this article: (1) dose optimization strategy in oncology, (2) common covariates on pharmacokinetic (PK) parameters in oncology, and (3) physiologically-based PK (PBPK) analyses for regulatory review and product label. The NLP workflow includes (1) preparation of source files, (2) NLP model building, and (3) automation of data extraction. The Clinical Pharmacology and Biopharmaceutics Summary Basis of Approval (SBA) documents, US package inserts (USPI), and approval letters from the US Food and Drug Administration (FDA) were used as our source data. As demonstrated in the three example use cases, advanced NLP can expedite the extraction and analyses of large amounts of information from regulatory review documents to help address important clinical pharmacology questions. Although this has not been adopted widely, integrating advanced NLP into the clinical pharmacology workflow can increase efficiency in extracting impactful information to advance drug development.

Idiopathic pulmonary fibrosis therapy development: a clinical pharmacology perspective.

Drug development for idiopathic pulmonary fibrosis (IPF) has been challenging due to poorly understood disease etiology, unpredictable disease progression, highly heterogeneous patient populations, and a lack of robust pharmacodynamic biomarkers. Moreover, because lung biopsy is invasive and dangerous, making the extent of fibrosis as a direct longitudinal measurement of IPF disease progression unfeasible, most clinical trials studying IPF can only assess progression of fibrosis indirectly through surrogate measures. This review discusses current state-of-art practices, identifies knowledge gaps, and brainstorms development opportunities for preclinical to clinical translation, clinical populations, pharmacodynamic endpoints, and dose optimization strategies. This article highlights clinical pharmacology perspectives in leveraging real-world data as well as modeling and simulation, special population considerations, and patient-centric approaches for designing future studies.

The Impact of Climate Change on Asthma and Allergic-Immunologic Disease.

PURPOSE OF REVIEW: This review discusses climate change-related impacts on asthma and allergic-immunologic disease, relevant US public health efforts, and healthcare professional resources. RECENT FINDINGS: Climate change can impact people with asthma and allergic-immunologic disease through various pathways, including increased exposure to asthma triggers (e.g., aeroallergens, ground-level ozone). Climate change-related disasters (e.g., wildfires, floods) disrupting healthcare access can complicate management of any allergic-immunologic disease. Climate change disproportionately affects some communities, which can exacerbate disparities in climate-sensitive diseases like asthma. Public health efforts include implementing a national strategic framework to help communities track, prevent, and respond to climate change-related health threats. Healthcare professionals can use resources or tools to help patients with asthma and allergic-immunologic disease prevent climate change-related health impacts. Climate change can affect people with asthma and allergic-immunologic disease and exacerbate health disparities. Resources and tools are available to help prevent climate change-related health impacts at the community and individual level.

Modeling Alzheimer's disease progression utilizing clinical trial and ADNI data to predict longitudinal trajectory of CDR-SB.

There is strong interest in developing predictive models to better understand individual heterogeneity and disease progression in Alzheimer's disease (AD). We have built upon previous longitudinal AD progression models, using a nonlinear, mixed-effect modeling approach to predict Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) progression. Data from the Alzheimer's Disease Neuroimaging Initiative (observational study) and placebo arms from four interventional trials (N = 1093) were used for model building. The placebo arms from two additional interventional trials (N = 805) were used for external model validation. In this modeling framework, CDR-SB progression over the disease trajectory timescale was obtained for each participant by estimating disease onset time (DOT). Disease progression following DOT was described by both global progression rate (RATE) and individual progression rate (α). Baseline Mini-Mental State Examination and CDR-SB scores described the interindividual variabilities in DOT and α well. This model successfully predicted outcomes in the external validation datasets, supporting its suitability for prospective prediction and use in design of future trials. By predicting individual participants' disease progression trajectories using baseline characteristics and comparing these against the observed responses to new agents, the model can help assess treatment effects and support decision making for future trials.

CryoET reveals organelle phenotypes in huntington disease patient iPSC-derived and mouse primary neurons.

Huntington's disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, yielding a Huntingtin protein with an expanded polyglutamine tract. While experiments with patient-derived induced pluripotent stem cells (iPSCs) can help understand disease, defining pathological biomarkers remains challenging. Here, we used cryogenic electron tomography to visualize neurites in HD patient iPSC-derived neurons with varying CAG repeats, and primary cortical neurons from BACHD, deltaN17-BACHD, and wild-type mice. In HD models, we discovered sheet aggregates in double membrane-bound organelles, and mitochondria with distorted cristae and enlarged granules, likely mitochondrial RNA granules. We used artificial intelligence to quantify mitochondrial granules, and proteomics experiments reveal differential protein content in isolated HD mitochondria. Knockdown of Protein Inhibitor of Activated STAT1 ameliorated aberrant phenotypes in iPSC- and BACHD neurons. We show that integrated ultrastructural and proteomic approaches may uncover early HD phenotypes to accelerate diagnostics and the development of targeted therapeutics for HD.

Association between thromboembolic events and COVID-19 infection within 30 days: a case-control study among a large sample of adult hospitalized patients in the United States, March 2020-June 2021.

The association between thromboembolic events (TE) and COVID-19 infection is not completely understood at the population level in the United States. We examined their association using a large US healthcare database. We analyzed data from the Premier Healthcare Database Special COVID-19 Release and conducted a case-control study. The study population consisted of men and non-pregnant women aged ≥ 18 years with (cases) or without (controls) an inpatient ICD-10-CM diagnosis of TE between 3/1/2020 and 6/30/2021. Using multivariable logistic regression, we assessed the association between TE occurrence and COVID-19 diagnosis, adjusting for demographic factors and comorbidities. Among 227,343 cases, 15.2% had a concurrent or prior COVID-19 diagnosis within 30 days of their index TE. Multivariable regression analysis showed a statistically significant association between a COVID-19 diagnosis and TE among cases when compared to controls (adjusted odds ratio [aOR] 1.75, 95% CI 1.72-1.78). The association was more substantial if a COVID-19 diagnosis occurred 1-30 days prior to index hospitalization (aOR 3.00, 95% CI 2.88-3.13) compared to the same encounter as the index hospitalization. Our findings suggest an increased risk of TE among persons within 30 days of being diagnosed COVID-19, highlighting the need for careful consideration of the thrombotic risk among COVID-19 patients, particularly during the first month following diagnosis.

Mortality Risk Among Patients Hospitalized Primarily for COVID-19 During the Omicron and Delta Variant Pandemic Periods - United States, April 2020-June 2022.

The risk for COVID-19-associated mortality increases with age, disability, and underlying medical conditions (1). Early in the emergence of the Omicron variant of SARS-CoV-2, the virus that causes COVID-19, mortality among hospitalized COVID-19 patients was lower than that during previous pandemic peaks (2-5), and some health authorities reported that a substantial proportion of COVID-19 hospitalizations were not primarily for COVID-19-related illness,* which might account for the lower mortality among hospitalized patients. Using a large hospital administrative database, CDC assessed in-hospital mortality risk overall and by demographic and clinical characteristics during the Delta (July-October 2021), early Omicron (January-March 2022), and later Omicron (April-June 2022) variant periods† among patients hospitalized primarily for COVID-19. Model-estimated adjusted mortality risk differences (aMRDs) (measures of absolute risk) and adjusted mortality risk ratios (aMRRs) (measures of relative risk) for in-hospital death were calculated comparing the early and later Omicron periods with the Delta period. Crude mortality risk (cMR) (deaths per 100 patients hospitalized primarily for COVID-19) was lower during the early Omicron (13.1) and later Omicron (4.9) periods than during the Delta (15.1) period (p<0.001). Adjusted mortality risk was lower during the Omicron periods than during the Delta period for patients aged ≥18 years, males and females, all racial and ethnic groups, persons with and without disabilities, and those with one or more underlying medical conditions, as indicated by significant aMRDs and aMRRs (p<0.05). During the later Omicron period, 81.9% of in-hospital deaths occurred among adults aged ≥65 years and 73.4% occurred among persons with three or more underlying medical conditions. Vaccination, early treatment, and appropriate nonpharmaceutical interventions remain important public health priorities for preventing COVID-19 deaths, especially among persons most at risk.

Post-COVID-19 Symptoms and Conditions Among Children and Adolescents - United States, March 1, 2020-January 31, 2022.

Post-COVID-19 (post-COVID) symptoms and conditions* are new, recurring, or ongoing health problems that occur 4 or more weeks after infection with SARS-CoV-2 (the virus that causes COVID-19). Previous studies have characterized and estimated the incidence of post-COVID conditions among adults (1,2), but data among children and adolescents are limited (3-8). Using a large medical claims database, CDC assessed nine potential post-COVID signs and symptoms (symptoms) and 15 potential post-COVID conditions among 781,419 U.S. children and adolescents aged 0-17 years with laboratory-confirmed COVID-19 (patients with COVID-19) compared with 2,344,257 U.S. children and adolescents without recognized COVID-19 (patients without COVID-19) during March 1, 2020-January 31, 2022. The analysis identified several symptoms and conditions with elevated adjusted hazard ratios among patients with COVID-19 (compared with those without). The highest hazard ratios were recorded for acute pulmonary embolism (adjusted hazard ratio [aHR] = 2.01), myocarditis and cardiomyopathy (1.99), venous thromboembolic event (1.87), acute and unspecified renal failure (1.32), and type 1 diabetes (1.23), all of which were rare or uncommon in this study population. Conversely, symptoms and conditions that were most common in this study population had lower aHRs (near or below 1.0). Patients with COVID-19 were less likely than were patients without to experience respiratory signs and symptoms, symptoms of mental conditions, muscle disorders, neurological conditions, anxiety and fear-related disorders, mood disorders, and sleeping disorders. COVID-19 prevention strategies, including vaccination for all eligible children and adolescents, are critical to prevent SARS-CoV-2 infection and subsequent illness, including post-COVID symptoms and conditions (9).

Interim Recommendation of the Advisory Committee on Immunization Practices for Use of the Novavax COVID-19 Vaccine in Persons Aged ≥18 years - United States, July 2022.

The NVX-CoV2373 (Novavax) COVID-19 vaccine is a recombinant spike (rS) protein nanoparticle vaccine with Matrix-M adjuvant to protect against infection with SARS-CoV-2, the virus that causes COVID-19. On July 13, 2022, the Food and Drug Administration (FDA) issued Emergency Use Authorization (EUA) for the Novavax vaccine for primary COVID-19 immunization of unvaccinated adults aged ≥18 years, administered as 2 doses (5 µg rS and 50 µg Matrix-M adjuvant in each dose) 3 weeks apart (1). On July 19, 2022, the Advisory Committee on Immunization Practices (ACIP) issued an interim recommendation for use of the Novavax vaccine in persons aged ≥18 years for the prevention of COVID-19.* In the per-protocol† efficacy analysis, vaccine efficacy (VE) against reverse transcription-polymerase chain reaction (RT-PCR)-confirmed symptomatic COVID-19 was 89.6% (95% CI = 82.4%-93.8%). The Alpha variant (B.1.1.7) of SARS-CoV-2 was the predominant circulating variant during the period of case accrual for VE assessments. Cases of myocarditis or pericarditis were reported in temporal association with vaccination, suggesting a possible causal relationship. The ACIP recommendation for the use of the Novavax COVID-19 vaccine is interim and will be updated as additional information becomes available. The adjuvanted, protein subunit-based Novavax COVID-19 vaccine provides an additional option for unvaccinated adults, increasing flexibility for the public and for vaccine providers. Vaccination is important for protection against COVID-19.

The shifting prevalence of asthma and allergic disease in US children.

BACKGROUND: Asthma is a chronic lung disease that affected 5 million children. Allergy is a common comorbidity of asthma. Having both conditions is associated with unfavorable health outcomes and impaired quality of life. OBJECTIVE: Purpose of this study was to assess allergy and its association with asthma by select characteristics among children to determine differences by populations. METHODS: National Health Interview Survey data (2007-2018) were used to assess asthma and allergy status, trends, and the association between allergy and asthma by select characteristics among US children (aged 0-17 years). RESULTS: Prevalence of asthma decreased among all children (slope [-] P < .001) and among those with allergy (slope [-] P = .002). More children had respiratory allergy (14.7%), followed by skin allergy (12.7%) and food allergy (6.4%). Prevalence of respiratory allergy significantly decreased among White non-Hispanic children (slope [-] P = .002), food allergy increased among White non-Hispanic (slope [+] P < .001) and Hispanic children (slope [+] P = .003), and skin allergy increased among Hispanic children (slope [+] P = .04). Depending on number and type, children with allergy were 2 to 8 times (skin allergy only and having all 3 allergies, respectively) more likely to have current asthma than were children without allergy. Among children with current asthma, having any allergy was significantly associated with missed school days (adjusted prevalence ratio, 1.33 [1.03-1.72]; P = .02) and taking preventive medication daily (adjusted prevalence ratio, 1.89 [1.32-2.71]; P < .001). CONCLUSION: Trends in allergies across years differed by race and ethnicity. Strength of association between asthma and allergy differed by type and number of allergies, being highest among children having all 3 types of allergies. Having both asthma and allergy was associated with unfavorable asthma outcomes.

Mental Health Conditions and Severe COVID-19 Outcomes after Hospitalization, United States.

Among 664,956 hospitalized COVID-19 patients during March 2020-July 2021 in the United States, select mental health conditions (i.e., anxiety, depression, bipolar, schizophrenia) were associated with increased risk for same-hospital readmission and longer length of stay. Anxiety was also associated with increased risk for intensive care unit admission, invasive mechanical ventilation, and death.

Extension of the Alternative Intravenous Dosing Regimens of Atezolizumab into Combination Settings through Modeling and Simulation.

Atezolizumab is approved as an intravenous (IV) infusion for use as a single agent and in combination with other therapies in a number of indications. The objectives of this publication are to characterize atezolizumab pharmacokinetics (PK) across indications with the available clinical data from one phase I and eight phase III studies, to determine the exposure-response (ER) relationships in combination settings across a variety of tumor types, and to provide the clinical safety to support the extension of the 840 mg q2w, 1200 mg q3w, and 1680 mg q4w IV dosing regimens across various indications in combination settings. Across all clinical studies, atezolizumab PK remained in the dose-linear range and were similar across tumor types when used in combination therapy or as a monotherapy. In the combination studies, efficacy was independent of the exposures tested and there was no significant increase in adverse events with increasing atezolizumab exposure (flat ER). The safety profile of atezolizumab in the individual combination studies was generally consistent with the established safety profile of atezolizumab, the combination partners, and the disease under study. The similar atezolizumab PK across monotherapy and combination therapy settings as well as the flat ER in new tumor types and combination therapies support the use of the 3 interchangeable atezolizumab dosing regimens in the combination setting. Atezolizumab is now approved with 3 interchangeable IV dosing regimens of 840 mg q2w, 1200 mg q3w, and 1680 mg q4w for single-agent and combination therapy use in the USA and EU.

Severe Outcomes, Readmission, and Length of Stay Among COVID-19 Patients with Intellectual and Developmental Disabilities.

OBJECTIVES: The aim of this study was to evaluate the association between intellectual and developmental disabilities (IDDs) and severe COVID-19 outcomes, 30-day readmission, and/or increased length of stay (LOS) using a large electronic administrative database. METHODS: Patients hospitalized with COVID-19 were identified between March 2020 and June 2021 from more than 900 hospitals in the United States. IDDs included intellectual disability, cerebral palsy, Down syndrome, autism spectrum disorder (ASD), and other intellectual disabilities. Outcomes included intensive care unit (ICU) admission, invasive mechanical ventilation (IMV), 30-day readmission, mortality, and LOS. RESULTS: Among 643,765 patients with COVID-19, multivariate models showed that patients with any IDD were at a significantly greater risk of at least 1 severe outcome, 30-day readmission, or longer LOS than patients without any IDD. Compared with those without any IDD, patients with Down syndrome had the greatest odds of ICU admission (odds ratio [OR] and 95% confidence interval [CI]: 1.96 [1.73-2.21]), IMV (OR: 2.37 [2.07-2.70]), and mortality (OR: 2.33 [2.00-2.73]). Patients with ASD and those with Down syndrome both had over a 40% longer mean LOS. Patients with intellectual disabilities had a 23% (12-35%) increased odds of 30-day readmission. CONCLUSIONS: Results suggest that patients hospitalized with COVID-19 with IDD have a significantly increased risk of severe outcomes, 30-day readmission, and longer LOS.