SURF: A Screening Tool (for Sponsors) to Evaluate Whether Using Real-World Data to Support an Effectiveness Claim in an FDA Application Has Regulatory Feasibility.

Based on recent guidance and publicly available approvals, the US Food and Drug Administration (FDA) has demonstrated its openness to considering evidence of effectiveness from real-world data (RWD) and nonrandomized studies (or "real-world evidence (RWE)") in its decision making. Through analysis of the FDA approvals, several authors have identified methodologic issues commonly discussed by FDA reviewers. However, in our analysis of FDA guidance and use cases, acceptability of RWE also critically depends on whether the characteristics of the clinical development program align with circumstances in which the FDA may have flexibility in considering evidence from real-world study designs relative to more robust designs.

A Descriptive Cohort Study of Drug Utilization Patterns Among Patients Hospitalized With Coronavirus Disease 2019 in the United States, January 2021-February 2022.

Background: There is a dearth of drug utilization studies for coronavirus disease 2019 (COVID-19) treatments in 2021 and beyond after the introduction of vaccines and updated guidelines; such studies are needed to contextualize ongoing COVID-19 treatment effectiveness studies during these time periods. This study describes utilization patterns for corticosteroids, interleukin-6 (IL-6) inhibitors, Janus kinase inhibitors, and remdesivir among hospitalized adults with COVID-19, over the entire hospitalization, and within hospitalization periods categorized by respiratory support requirements.

Methods: This descriptive cohort study included United States adults hospitalized with COVID-19 admitted from 1 January 2021 through 1 February 2022; data included HealthVerity claims and hospital chargemaster.

A Structured Process to Identify Fit-for-Purpose Study Design and Data to Generate Valid and Transparent Real-World Evidence for Regulatory Uses.

Generating evidence from real-world data requires fit-for-purpose study design and data. In addition to validity, decision makers require transparency in the reasoning that underlies study design and data source decisions. The 2019 Structured Preapproval and Postapproval Comparative Study Design Framework to Generate Valid and Transparent Real-World Evidence (SPACE) and the 2021 Structured Process to Identify Fit-For-Purpose Data (SPIFD)-intended to be used together-provide a step-by-step guide to identify decision grade, fit-for-purpose study design and data.

Real-world comparative effectiveness of mRNA-1273 and BNT162b2 vaccines among immunocompromised adults identified in administrative claims data in the United States.

Introduction: Head-to-head studies comparing COVID-19 mRNA vaccine effectiveness in immunocompromised individuals, who are vulnerable to severe disease are lacking, as large sample sizes are required to make meaningful inferences.

Methods: This observational comparative effectiveness study was conducted in closed administrative claims data from the US HealthVerity database (December 11, 2020-January 10, 2022, before omicron). A 2-dose mRNA-1273 versus BNT162b2 regimen was assessed for preventing medically-attended breakthrough COVID-19 diagnosis and hospitalizations among immunocompromised adults.

Describing characteristics and treatment patterns of patients hospitalized with COVID-19 by race and ethnicity in a national RWD during the early months of the pandemic.

Objective: To describe differences by race and ethnicity in treatment patterns among hospitalized COVID-19 patients in the US from March-August 2020.

Methods: Among patients in de-identified Optum electronic health record data hospitalized with COVID-19 (March-August 2020), we estimated odds ratios of receiving COVID-19 treatments of interest (azithromycin, dexamethasone, hydroxychloroquine, remdesivir, and other steroids) at hospital admission, by race and ethnicity, after adjusting for key covariates of interest.

Results: After adjusting for key covariates, Black/African American patients were less likely to receive dexamethasone (adj.

Visualizations throughout pharmacoepidemiology study planning, implementation, and reporting.

Transparency is increasingly promoted to instill trust in nonrandomized studies using real-world data. Graphics and data visualizations support transparency by aiding communication and understanding, and can inform study design and analysis decisions. However, other than graphical representation of a study design and flow diagrams (e.

Treatment effectiveness in a rare oncology indication: Lessons from an external control cohort study.

Real-world data (RWD) reflecting patient treatment in routine clinical practice can be used to develop external control groups for single-arm trials. External controls can provide valuable benchmark results on potential comparator drug effectiveness, particularly in rare indications when randomized controlled trials are either infeasible or unethical. This paper describes lessons learned from a descriptive real-world external control cohort study conducted to provide benchmark data for a single-arm clinical trial in a rare oncology biomarker driven disease.

Categorization of COVID-19 severity to determine mortality risk.

Purpose: Algorithms for classification of inpatient COVID-19 severity are necessary for confounding control in studies using real-world data.

Methods: Using Healthverity chargemaster and claims data, we selected patients hospitalized with COVID-19 between April 2020 and February 2021, and classified them by severity at admission using an algorithm we developed based on respiratory support requirements (supplemental oxygen or non-invasive ventilation, O2/NIV, invasive mechanical ventilation, IMV, or NEITHER). To evaluate the utility of the algorithm, patients were followed from admission until death, discharge, or a 28-day maximum to report mortality risks and rates overall and by stratified by severity.

The Structured Process to Identify Fit-For-Purpose Data: A Data Feasibility Assessment Framework.

To complement real-world evidence (RWE) guidelines, the 2019 Structured Preapproval and Postapproval Comparative study design framework to generate valid and transparent real-world Evidence (SPACE) framework elucidated a process for designing valid and transparent real-world studies. As an extension to SPACE, here, we provide a structured framework for conducting feasibility assessments-a step-by-step guide to identify decision grade, fit-for-purpose data, which complements the United States Food and Drug Administration (FDA)'s framework for a RWE program. The process was informed by our collective experience conducting systematic feasibility assessments of existing data sources for pharmacoepidemiology studies to support regulatory decisions.

Organized structure of real-world evidence best practices: moving from fragmented recommendations to comprehensive guidance.

Decision-makers have become increasingly interested in incorporating real-world evidence (RWE) into their decision-making process. Due to concerns regarding the reliability and quality of RWE, stakeholders have issued numerous recommendation documents to assist in setting RWE standards. The fragmented nature of these documents poses a challenge to researchers and decision-makers looking for guidance on what is 'high-quality' RWE and how it can be used in decision-making.

Real-World Evidence for Assessing Pharmaceutical Treatments in the Context of COVID-19.

The emergence and global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an urgent need for evidence on medical interventions and outcomes of the resulting disease, coronavirus disease 2019 (COVID-19). Although many randomized controlled trials (RCTs) evaluating treatments and vaccines for COVID-19 are already in progress, the number of clinical questions of interest greatly outpaces the available resources to conduct RCTs. Therefore, there is growing interest in whether nonrandomized real-world evidence (RWE) can be used to supplement RCT evidence and aid in clinical decision making, but concerns about nonrandomized RWE have been highlighted by a proliferation of RWE studies on medications and COVID-19 outcomes with widely varying conclusions.

Determining the Suitability of Registries for Embedding Clinical Trials in the United States: A Project of the Clinical Trials Transformation Initiative.

Background: Patient registries are organized systems that use observational methods to collect uniform data on specified outcomes in a population defined by a particular disease, condition, or exposure. Data collected in registries often coincide with data that could support clinical trials. Integrating clinical trials within registries to create registry-embedded clinical trials offers opportunities to reduce duplicative data collection, identify and recruit patients more efficiently, decrease time to database lock, accelerate time to regulatory decision-making, and reduce clinical trial costs.

Pulmonary and cardiovascular safety of inhaled insulin in routine practice: The Exubera Large Simple Trial (VOLUME).

Objective: VOLUME is a randomized, open-label, post-approval pragmatic trial aiming to evaluate long-term pulmonary and cardiovascular safety of Exubera® (EXU; insulin human [rDNA origin] Inhalation Powder) in routine clinical practice. The primary study objective is to compare risk of persistent decline in forced expiratory volume in 1 second (FEV) among patients treated with and without EXU.

Research Design And Methods: Patients eligible to take EXU per approved local label were randomized to EXU or routine care and followed per usual care, with scheduled FEV tests at baseline, 6 months, and yearly.

Implications of product withdrawal on a post-approval pragmatic trial: The VOLUME study experience.

Introduction: Many clinical trials terminate early due to safety and efficacy concerns, and less often due to unexpected "positive" findings. However, early termination of post-approval (Phase IV) pragmatic randomized trials for commercial reasons is less frequent, may be more complex, and may require added flexibility in closure methods, including short term follow-up. VOLUME was a randomized, open-label, post-approval pragmatic clinical trial (PCT) or large simple trial that terminated early due to product withdrawal.

Lung Cancer-Related Mortality With Inhaled Insulin or a Comparator: Follow-Up Study of patients previously enrolled in Exubera Controlled Clinical Trials (FUSE) Final Results.

Objective: The Follow-Up Study of patients previously enrolled in Exubera controlled clinical trials (FUSE) was designed to evaluate whether patients previously treated with Exubera (EXU; insulin human [rDNA origin], inhaled powder) in controlled clinical trials died because of incident primary lung cancer at a substantially higher rate than patients treated with a comparator.

Research Design And Methods: FUSE is a hybrid, randomized, controlled trial/cohort study including participants of 17 prior EXU clinical trials. Pooled patient data from these trials were used, and the subset of patients enrolled in the follow-up cohort study was followed prospectively for 2 years in order to evaluate the incidence of fatal and nonfatal primary lung cancers and all-cause mortality.

A Structured Preapproval and Postapproval Comparative Study Design Framework to Generate Valid and Transparent Real-World Evidence for Regulatory Decisions.

Real-world evidence provides important information about the effects of medicines in routine clinical practice. To engender trust that evidence generated for regulatory purposes is sufficiently valid, transparency in the reasoning that underlies study design decisions is critical. Building on existing guidance and frameworks, we developed the Structured Preapproval and Postapproval Comparative study design framework to generate valid and transparent real-world Evidence (SPACE) as a process for identifying design elements and minimal criteria for feasibility and validity concerns, and for documenting decisions.

Causal identification: a charge of epidemiology in danger of marginalization.

The requirement for framing all causal questions as well-defined interventions is being promoted in the causal inference literature within epidemiology. One can consider this perspective as an intervention on the field which requires a refocusing of epidemiologic questions and retooling of epidemiologic methods. Although this intervention has produced many positive results, we think that its underlying assumptions and the possibilities of unintended consequences warrant examination.

Consensus of recommendations guiding comparative effectiveness research methods.

Purpose: Because of an increasing demand for quality comparative effectiveness research (CER), methods guidance documents have been published, such as those from the Agency for Healthcare Research and Quality (AHRQ) and the Patient-Centered Outcomes Research Institute (PCORI). Our objective was to identify CER methods guidance documents and compare them to produce a summary of important recommendations which could serve as a consensus of CER method recommendations.

Methods: We conducted a systematic literature review to identify CER methods guidance documents published through 2014.

Methodological comparison of marginal structural model, time-varying Cox regression, and propensity score methods: the example of antidepressant use and the risk of hip fracture.

Background: Observational studies including time-varying treatments are prone to confounding. We compared time-varying Cox regression analysis, propensity score (PS) methods, and marginal structural models (MSMs) in a study of antidepressant [selective serotonin reuptake inhibitors (SSRIs)] use and the risk of hip fracture.

Methods: A cohort of patients with a first prescription for antidepressants (SSRI or tricyclic antidepressants) was extracted from the Dutch Mondriaan and Spanish Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) general practice databases for the period 2001-2009.

Epidemiology's continuing contribution to public health: The power of "Then and Now".

The 47th annual meeting of the Society for Epidemiologic Research hosted 17 invited speakers charged by the Executive Committee with presenting some of the many ways that epidemiologists have improved the health of the general population. There were 9 "Then and Now" sessions that were structured to focus on how early epidemiologists overcame research hurdles and advanced health through innovative strategies. For most topics, a longstanding expert was paired with an excellent contemporary epidemiologist working in the area, and both were given the freedom to deliver an integrated story about epidemiology's temporal role in protecting and promoting public health.

Toward a clarification of the taxonomy of "bias" in epidemiology textbooks.

Epidemiology textbooks typically divide biases into 3 general categories-confounding, selection bias, and information bias. Despite the ubiquity of this categorization, authors often use these terms to mean different things. This hinders communication among epidemiologists and confuses students who are just learning about the field.