Adopting a Framework for Rapid Real-World Data Analyses in Safety Signal Assessment.

The expanding availability of real-world data (RWD) has led to an increase in both the interest and possibilities for using this information in postmarketing safety analyses and signal management. While there is enormous potential value from the safety insights generated through RWD, the analysis preparation, execution, and communication required to reliably deliver the evidence can be time consuming. Since the safety signal assessment process is a regulated and timebound process, any supporting RWD analyses require a rapid turnaround of well-designed and informative results. To address this challenge, a TransCelerate BioPharma working group was formed and developed a framework to help teams responsible for safety signal assessment overcome the challenges of working with RWD rapidly to deliver analyses within regulatory timelines. Here, a previously performed safety assessment was evaluated within the context of the developed framework to illustrate how the framework may be adopted in practice.

Data quality and timeliness analysis for post-vaccination adverse event cases reported through healthcare data exchange to FDA BEST pilot platform.

Introduction: This study is part of the U.S. Food and Drug Administration (FDA)'s Biologics Effectiveness and Safety (BEST) initiative, which aims to improve the FDA's postmarket surveillance capabilities by using real-world data (RWD). In the United States, using RWD for postmarket surveillance has been hindered by the inability to exchange clinical data between healthcare providers and public health organizations in an interoperable format. However, the Office of the National Coordinator for Health Information Technology (ONC) has recently enacted regulation requiring all healthcare providers to support seamless access, exchange, and use of electronic health information through the interoperable HL7 Fast Healthcare Interoperability Resources (FHIR) standard. To leverage the recent ONC changes, BEST designed a pilot platform to query and receive the clinical information necessary to analyze suspected AEs. This study assessed the feasibility of using the RWD received through the data exchange of FHIR resources to study post-vaccination AE cases by evaluating the data volume, query response time, and data quality. Materials and methods: The study used RWD from 283 post-vaccination AE cases, which were received through the platform. We used descriptive statistics to report results and apply 322 data quality tests based on a data quality framework for EHR. Results: The volume analysis indicated the average clinical resources for a post-vaccination AE case was 983.9 for the median partner. The query response time analysis indicated that cases could be received by the platform at a median of 3 min and 30 s. The quality analysis indicated that most of the data elements and conformance requirements useful for postmarket surveillance were met. Discussion: This study describes the platform's data volume, data query response time, and data quality results from the queried postvaccination adverse event cases and identified updates to current standards to close data quality gaps.

The real-world treatment characteristic and efficacy of immune checkpoint inhibitors in non-small cell lung cancer: Data from a retrospective cohort study.

BACKGROUND: The efficacy and prognosis of immune checkpoint inhibitors (ICIs) remain unresolved issues. Here, we assessed the treatment characteristics and efficacy of ICIs in non-small cell lung cancer (NSCLC) using real-world data and evaluated the predictive value of factors, including programmed death-ligand 1 (PD-L1) expression, for the clinical outcome of ICIs in NSCLC. METHODS: Analyzed data was collected from hospitalized patients in the West China Hospital of Sichuan University between January 2017 and March 2023. The Kaplan-Meier method was utilized for analyzing real-world progression-free survival (rwPFS), while Cox regression models was employed to access the correlation between the efficacy of immunotherapy and sociodemographic characteristics, disease information, and characteristics of ICI treatment. RESULTS: A total of 545 patients were included in the retrospective study and characteristics of immunotherapy varied significantly among PD-L1 expression groups. The median rwPFS for the entire population was 9.76 months. Subgroup analyses revealed that patients with high PD-L1 expression, early TNM stage, first-line immunotherapy, EGFR wild-type and those who have not received radiotherapy and targeted therapy previously were more likely to have better rwPFS. Furthermore, multivariate Cox regression analyses identified PD-L1 expression, EGFR mutation status and previous radiotherapy as the most influential predictors of the response to ICI treatment. CONCLUSIONS: This study presents the real-world experience of Chinese NSCLC patients undergoing ICI treatment, offering guidance for clinical decision-making based on various patient conditions, preferences, and indications for ICIs, through the evaluation of immunotherapy efficacy and predictors in NSCLC patients.

Application of multiple validated algorithms for identifying incident breast cancer among individuals with atopic dermatitis.

PURPOSE: Validated algorithms (VAs) in insurance claims databases are often used to estimate the prevalence and incidence of comorbidities and evaluate safety signals. However, although they are then used in different data sources or subpopulations from those in which they were developed the replicability of these VAs are rarely tested, making their application and performance in these settings potentially unknown. This paper describes testing multiple VAs used to identify incident breast cancer cases in a general population and in an indication-specific population, patients with atopic dermatitis (AD). METHODS: Two algorithms were tested in multiple insurance claims databases and four cohorts were created. Modifications were made to account for the US insurance setting. The resulting incidence rates (IRs) were then compared across algorithms and against surveillance, epidemiology, and end results (SEER) estimates to assess reliability. RESULTS: Algorithm 1 produced low IRs compared to Algorithm 2. Algorithm 2 provided similar estimates to those of SEER. Individuals in the AD cohorts experienced lower incident breast cancer cases than those in the general population cohorts. CONCLUSION: Regardless of an algorithm's reported accuracy, the original study setting and targeted population for the VAs may matter when attempting to replicate the algorithm in an indication-specific subpopulation or varying data sources. Investigators should use caution and conduct sensitivity analyses or use multiple algorithms when attempting to calculate incidence or prevalence estimates using VAs.

Quantitative evaluation of the impact of relaxing eligibility criteria on the risk-benefit profile of drugs for lung cancer based on real-world data.

INTRODUCTION: Restrictive eligibility criteria in cancer drug trials result in low enrollment rates and limited population diversity. Relaxed eligibility criteria (REC) based on solid evidence is becoming necessary for stakeholders worldwide. However, the absence of high-quality, favorable evidence remains a major challenge. This study presents a protocol to quantitatively evaluate the impact of relaxing eligibility criteria in common non-small cell lung cancer (NSCLC) protocols in China, on the risk-benefit profile. This involves a detailed explanation of the rationale, framework, and design of REC. METHODS: To evaluate our REC in NSCLC drug trials, we will first construct a structured, cross-dimensional real-world NSCLC database using deep learning methods. We will then establish randomized virtual cohorts and perform benefit-risk assessment using Monte Carlo simulation and propensity matching. Shapley value will be utilized to quantitatively measure the effect of the change of each eligibility criterion on patient volume, clinical efficacy and safety. DISCUSSION: This study is one of the few that focuses on the problem of overly stringent eligibility criteria cancer drug clinical trials, providing quantitative evaluation of the effect of relaxing each NSCLC eligibility criterion. This study will not only provide scientific evidence for the rational design of population inclusion in lung cancer clinical trials, but also establish a data governance system, as well as a REC evaluation framework that can be generalized to other cancer studies.

Incorporating external real-world data (RWD) in confirmatory adaptive design.

Adaptive designs, such as group sequential designs (and the ones with additional adaptive features) or adaptive platform trials, have been quintessential efficient design strategies in trials of unmet medical needs, especially for generating evidence from global regions. Such designs allow interim decision making and making adjustment to study design when necessary, meanwhile maintaining study integrity and operating characteristics. However, driven by the heightened competitive landscape and the desire to bring effective treatment to patients faster, innovation in the already functional designs is still germane to further propel drug development to a more efficient path. One way to achieve this is by leveraging external real-world data (RWD) in the adaptive designs to support interim or final decision making. In this paper, we propose a novel framework of incorporating external RWD in adaptive design to improve interim and/or final analysis decision making. Within this framework, researchers can prespecify the decision process and choose the timing and amount of borrowing while maintaining objectivity and controlling of type I error. Simulation studies in various scenarios are provided to describe power, type I error, and other performance metrics for interim/final decision making. A case study in non-small cell lung cancer is used for illustration on proposed design framework.

The Amager Project IV: suicidal behavior and aftercare: real world data (RWD) from a prospective observational project.

BACKGROUND: In an RCT study, OPAC (outreach, problem solving, adherence, continuity) approach to aftercare after suicide attempts had an effect. The present study used the OPAC method in a clinical setting on Amager Copenhagen to patients after suicide attempt (Group 1) and patients with suicide ideation (Group 2) in a real-world data (RWD) study. AIM: To study whether the OPAC method could provide real world evidence (RWE) for results from the RCT study and long-time prospects. METHOD: This RWD study included 506 patients and followed them for 5 years. Kaplan-Meyer showed 5 years results. Risk factors for 5 years were calculated. RESULTS: 206 males (mean age 37.9) and 300 females (mean age 35.2) participated. A decline in survival accelerated after 3 years. After a 2-year follow-up, Group 1 had an attempted suicide rate of 12,2% and Group 2 5,4%. After 5 years the numbers were 18% and 10%. There were 3 completed suicides. Risk factors were: earlier suicide attempts, one or both parents or they themselves were alcohol/drug abusers, and a poor social network. Group 1 showed the same result as the intervention group in our earlier RCT study. Group 2 did better. Both groups did better than the control group from our RCT study. CONCLUSION: The OPAC effect was translated into the daily clinic. Risk factors were previous suicide attempts, alcohol and drug abuse and poor social networks. More specific therapy is needed for some patients to prevent relapse. Focus on enhancing a sense of belongingness and/or treating substance abuse.

Measuring the impact of monoclonal antibody therapies.

Objective: Monoclonal antibody (Mab) treatments have significantly improved the quality and quantity of life, but they are some of the most expensive treatments, resulting in a degree of hesitancy to introduce new Mab agents. A system for estimating the effect of Mab drugs, in general, would optimally inform health strategy and fully realize how a single scientific discovery can deliver health benefits. We evaluated such a method with several well-established Mab regimens. Methods: We selected five different Mab regimens in oncology and rheumatology in England. We carried out two systematic literature reviews and meta-analyses to assess health outcomes (Health Assessment Questionnaire-Disability Index for rheumatoid arthritis; overall mortality for melanoma) from real-world data and compared them to the outcomes from randomized control trials (RCTs). We applied economic modeling to estimate the net monetary benefits for health outcomes for the estimated patient population size for each Mab regimen. Results: Meta-analyses of 27 eligible real-world data (RWD) sets and 26 randomized controlled trial (RCT) sets found close agreement between the observed and expected health outcomes. A Markov model showed the net positive monetary benefit in three Mab regimens and the negative benefit in two regimens. However, because of limited access to NHS data, the economic model made several assumptions about the number of treated patients and the cost of treatment to the NHS, the accuracy of which may affect the estimation of the net monetary benefit. Conclusion: RCT results reliably inform the real-world experience of Mab treatments. Calculation of the net monetary benefit by the algorithm described provides a valuable overall measure of the health impact, subject to the accuracy of data inputs. This study provides a compelling case for building a comprehensive, systematized, and accessible database and related analytics, on all Mab treatments within health services.

A blueprint for success in real-world evidence: "glocal" approach to building capabilities and generating impactful evidence.

The past decade has seen the increasing influence and relevance of real-world data (RWD) and real-world evidence (RWE) in healthcare decision making. The value added by RWD/RWE has prompted the pharmaceutical industry to develop high performing systems and practices to harness the power of evidence generated at the global level. However, this worldwide transformation provides outstanding opportunities to support capability building within local affiliates and to impact key country-level stakeholders through resulting evidence. Therefore, we present an Evidence Blueprint Initiative, which links the global and local ("glocal") skills, and furthermore addresses the opportunities and gaps in evidence generation capabilities at the local level. Cross-functional experts were recruited at the local, regional, and global level to define best practices. A framework was developed to characterize the foundational expertise needed and to assess markets' existing capabilities. Subsequently, targeted roadmaps were developed and implemented to build capabilities in specific areas within each affiliate. The impact from the Blueprint is encouraging, resulting in improved local evidence plans, established evidence teams, enhanced RWD use and strategic implementation of patient centric science in local affiliates. The success of the Blueprint resides in empowering affiliates to realise their local evidence generation ambitions and to match them to their local context. It strengthens and expands the ties between various parts of the organisation and the external environment while building fit-for-future evidence capabilities from local affiliates.

Analyzing factors affecting risk aversion: Case of life insurance data in Korea.

This research employs machine learning analysis on extensive data from a prominent Korean life insurance company to substantiate the insurance demand theory, which posits that insurance demand increases with risk aversion. We quantitatively delineate the traits of risk-averse individuals. Our study focuses on a cohort of 94,306 individuals who have filed insurance claims due to illness. To forecast prospective insurance consumers inclined toward additional purchases, we construct a predictive model using a machine learning algorithm. This model incorporates 19 demographic and socioeconomic factors as independent variables, with additional insurance acquisition as the dependent variable. Consequently, we uncover the distinctive characteristics of consumers predicted to acquire supplementary insurance products. Our findings reveal a significant association between the independent variables and the likelihood of purchasing additional insurance. Notably, 10 out of the 19 independent variables exert a substantial influence on additional insurance acquisitions. These characteristics encompass residence in rural areas, a higher likelihood of being female, advanced age, increased assets, a higher likelihood of being blue-collar workers, lower education levels, a greater likelihood of being married or divorced/separated, a history of cancer, and a predisposition for existing policyholders with prior subscriptions to actual loss insurance or substantial insurance contract amounts. Our study holds academic significance by addressing limitations observed in prior research, which predominantly relied on questionnaires to qualitatively assess risk aversion. Instead, we offer specific insights into individual characteristics associated with risk aversion. Moreover, we anticipate that Korean insurance companies can leverage these insights to attract new clientele while retaining existing members through predictive risk aversion analysis. These findings also offer valuable insights across a spectrum of disciplines, including business administration, psychology, education, sociology, and sales/marketing, related to individuals' risk preferences and behaviors.

Efficacy and safety of turoctocog alfa in patients with hemophilia A requiring surgical procedures: A multicentre retrospective study.

BACKGROUND: Turoctocog alfa is a recombinant Factor VIII used in patients with hemophilia A. The aim is to assess the real-life evidence of turoctocog alfa in surgery. STUDY DESIGN AND METHODS: Data were extracted from a national database. RESULTS: Turoctocog alfa was used for 86 surgeries (49 major and 37 minor) in 56 patients. The results are expressed as medians (interquartile range). Six (10.7%) patients had severe hemophilia A, four (7.1%) moderate, and 46 (82.2%) mild. For patients who underwent major surgeries, basal plasma FVIII coagulant activity (FVIII:C) levels were 15 IU.dL-1 (8-22). Eight (5-14) infusions were given, at a preoperative loading dose of 40.0 (35.0-45.5) IU.kg-1 and a total dose of 253.3 (125.0-507.0) IU.kg-1 . In patients who underwent minor surgeries, basal FVIII:C levels were 18 IU.dL-1 (9-31). Two (1-3) infusions were required, at a preoperative loading dose of 34.0 (28.8-38.5) IU.kg-1 and a total dose of 73.7 (37.6-122.1) IU.kg-1 . The overall clinical efficacy was judged excellent/good in 77 procedures (89.5%) and fair/poor in nine (10.5%). The fair/poor efficacy concerned seven patients (six mild hemophilia and one severe), for four urological surgeries, two dermatological procedures, one heart surgery, one ear-nose-throat procedure, and one dental avulsion in the patient with severe hemophilia. Three out of those seven patients received antiplatelet therapy. No thromboembolic events, anti-FVIII antibodies, or adverse events were reported. DISCUSSION: The efficacy and safety of turoctocog alfa were confirmed for the management of surgery in patients with hemophilia A. No adverse events were observed and overall efficacy was good.

Innovative thinking of clinical investigation for rare disease drug development.

For the development of a test treatment or drug product, it is necessary to conduct composite hypothesis testing to test for effectiveness and safety simultaneously, since some approved drug products have been recalled due to safety concerns. One of the major issues in conducting a composite hypothesis testing for effectiveness and safety is the requirement of a huge sample size to achieve the desired power for detecting clinically meaningful differences in both safety and effectiveness. Situation can be much difficult in orphan drug development. In this article, a generalized two-stage innovative approach to test for effectiveness and safety simultaneously is proposed. Additionally, to alleviate the requirement of a large randomized clinical trial (RCT) and revealing effectiveness, real-world data is suggested to use in conjunction with RCT data for orphan drug development. The proposed approach can help investigators test for effectiveness and safety at the same time without worrying about the sample size. It also helps reduce the probability of approving a drug product with safety concerns.

Use of Real-World Evidence for Drug Regulatory Decisions in China: Current Status and Future Directions.

Real-world data (RWD) and real-world evidence (RWE) have garnered great interest for supporting drug research and development (R&D) by medical researchers and regulators in recent years. The application and development of RWD/E in drug regulatory decision-making have been vigorously promoted in China. This study seeks to provide a broad overview of how RWE has been contributing to drug regulatory decisions in China. In this paper, we review the development of RWD and RWE, summarize key elements that promote application of RWE, introduce relevant methods and guidelines, elaborate on the opportunities and challenges of RWE in regulatory decision-making in China, and put forward suggestions to promote the application of RWE in China's regulatory decision-making and to further facilitate innovative drug evaluation and regulation.

[Real world data in radiotherapy: A data farming project by Unitrad]. / Données de vie réelle en radiothérapie : le data farming du groupe Unitrad.

The aim of the data farming project by the Unitrad group is to produce and use large quantities of structured real-life data throughout radiotherapy treatment. Starting in 2016, target real world data were selected at expert consensus conferences and regularly updated, then captured in MOSAIQ© as the patient was treated. For each partner institution, the data was then stored in a relational database, then extracted and used by researchers to create real world knowledge. This production was carried out in a multicentre, coordinated fashion. When necessary, the raw data was shared according to the research projects, in compliance with regulations. Feedack was provided at each stage, enabling the system to evolve flexibly and rapidly, using the "agile" method. This work, which is constantly evolving, has led to the creation of health data warehouses focused on data of interest in radiotherapy, and the publication of numerous academic studies. It forms part of the wider context of the exploitation of real-life data in cancerology. Unitrad data farming is a collaborative project for creating knowledge from real-life radiotherapy data, based on an active network of clinicians and researchers.

HPV infection and breast cancer risk: insights from a nationwide population study in Taiwan.

Background: The prevalence of cancer, specifically breast cancer, has raised globally. The etiology of breast cancer has been attributed to age, genetic mutations, reproductive history, hormone therapy, lifestyle factors, and viral infections. The human papillomavirus (HPV) has been one of the most widespread sexually transmitted infection in the United States. The role of HPV in breast oncogenesis was hypothesized before, yet the association remained unclear. Methods: In this study, we employed a nationwide population study using centralized patient data managed by the Ministry of Health and Welfare in Taiwan and the Taiwan Cancer Registry database. The breast cancer incidence rates of the 467,454 HPV patients were compared to twice as many non-HPV patients with matching sex and age. Cumulative breast cancer incidence rates were presented by a Kaplan-Meier curve, and the relative risk of breast cancer for HPV and non-HPV patients were calculated using Cox-regression model. Results: Our results indicated a crude hazard ratio (HR) and an adjusted hazard ratio (aHR) of 2.336 and 2.271, respectively, when comparing the risk of breast cancer in the HPV and non-HPV group. The risk of breast cancer was comparable or higher than those of head and neck cancer (aHR=1.595) and cervical cancer (aHR=2.225), which both were found to have causal relationships with HPV. The Kaplan-Meier curve further illustrated a higher cumulative risk across 84 months for HPV patients (p<.0001). Besides HPV, age (p<.0001), insurance providers (p<.001), and comorbidities such as abnormal liver function (aHR=1.191, p=.0069) and hyperlipidemia (aHR=1.218, p=.0002) were found to be correlated with higher risks of breast cancer. Conclusion: A correlation between HPV and breast cancer can be inferred using national health databases. More molecular studies are required to understand the mechanism of the virus-induced oncogenesis of the breast.

Unresectable stage III non-small cell lung cancer: could durvalumab be safe and effective in real-life clinical scenarios? Results of a single-center experience.

Introduction: The standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) followed by consolidation durvalumab as shown in the PACIFIC trial. The purpose of this study is to evaluate clinical outcomes and toxicities regarding the use of durvalumab in a real clinical scenario. Methods: A single-center retrospective study was conducted on patients with a diagnosis of unresectable stage III NSCLC who underwent radical CRT followed or not by durvalumab. Tumor response after CRT, pattern of relapse, overall survival (OS) and progression-free survival (PFS), and toxicity profile were investigated. Results: Eighty-five patients met the inclusion criteria. The median age was 67 years (range 45-82 years). Fifty-two patients (61.2%) started sequential therapy with durvalumab. The main reason for excluding patients from the durvalumab treatment was the expression of PD-L1 < 1%. Only two patients presented a grade 4 or 5 pneumonitis. A median follow-up (FU) of 20 months has been reached. Forty-five patients (52.9%) had disease progression, and 21 (24.7%) had a distant progression. The addition of maintenance immunotherapy confirmed a clinical benefit in terms of OS and PFS. Two-year OS and PFS were respectively 69.4% and 54.4% in the durvalumab group and 47.9% and 24.2% in the no-durvalumab group (p = 0.015, p = 0.007). Conclusion: In this real-world study, patients treated with CRT plus durvalumab showed clinical outcomes and toxicities similar to the PACIFIC results. Maintenance immunotherapy after CRT has been shown to be safe and has increased the survival of patients in clinical practice.

A feasibility assessment of real-world data capabilities for monitoring vaccine safety and effectiveness in China: Human papillomavirus vaccination in the Yinzhou district as a use case.

BACKGROUND: Real-world data (RWD) are increasingly used to generate real-world evidence (RWE) of vaccine safety and effectiveness for regulatory purposes. Assessing feasibility of using RWD sources prior to implementing observational studies is recommended. As a use case, we described the process and findings of a feasibility assessment to identify reliable and relevant data sources for monitoring the safety and effectiveness of the AS04-HPV-16/18 human papillomavirus (HPV) vaccine in China. METHODS: Iterative multi-step process: (1) targeted literature review and data source mapping; (2) expert opinion from national RWD experts; (3) survey to evaluate the identified data source operational infrastructure; and (4) continuous appraisal of published studies using the identified data source. RESULTS: The Yinzhou Regional Health Information Platform (YRHIP) was identified as a data source of main interest, based on its large population coverage, high cervical cancer screening rates, and availability of adult electronic immunization records. Field meetings with national RWD experts confirmed its suitability for post-authorization vaccine studies. Survey results showed that exposure data and relevant safety and effectiveness endpoints were recorded and linkable at the individual level across the platform. Iterative appraisal of emerging evidence from the literature corroborated these findings. CONCLUSIONS: This feasibility assessment indicates that the YRHIP has the capacity to capture demographic, exposure, outcome and other data required to generate RWE on HPV vaccine safety and effectiveness in China. Studies using the YRHIP to monitor the AS04-HPV-16/18 vaccine in routine use building on this feasibility assessment are ongoing.

The role of Real-World Data and evidence in oncology medicines approved in EU in 2018-2019.

Use of Real-World Data (RWD) has gained the interest of different stakeholders in cancer care. The aim of this study was to identify and describe the use of RWD/RWE during the pre-authorization phase of products authorized by the EMA in 2018 and 2019 (n = 111), with the focus on oncology medicines (n = 24). Information was extracted from the European Public Assessment Report (EPAR) summaries and recorded for 5 stages (11 categories) of the drug development lifecycle (discovery, early development, clinical development, registration/market launch, lifecycle management). Specific chapters of full EPAR were reviewed to substantiate the findings on RWD/RWE use in clinical trial design, efficacy, safety, and effectiveness evaluation. RWD/RWE is present in all stages of the oncology drug development; 100.0 % in discovery, 37.5 % early development, 58.3 % in clinical development, 62.5 % in registration decision and 100.0 % in post-authorization lifecycle management. Examples showed that trial design supported by RWD/RWE included use of open label/single arm studies; efficacy was about using either comparison of results to historical controls, supplying survey data obtained outside the clinical trial or utilizing expert panel advice; safety about including literature findings in evidence; and effectiveness on comparison of trial results of the given product to historical data or existing standard of care. The findings of this study provide specific insights into how RWD/RWE is used in development of cancer therapeutics, how it contributes to regulatory decision making and can guide further policy developments in this field.