Use of Sensitivity Analyses to Assess Uncontrolled Confounding from Unmeasured Variables in Observational, Active Comparator Pharmacoepidemiologic Studies: A Systematic Review.

Understanding the potential for, direction, and magnitude of uncontrolled confounding is critical for generating informative real-world evidence. Many sensitivity analyses are available to assess robustness of study results to residual confounding, but it is unclear how researchers are using these methods. We conducted a systematic review of published active comparator cohort studies of drugs or biologics to summarize use of sensitivity analyses aimed at assessing uncontrolled confounding from an unmeasured variable.

Qualitative Analysis of Inquiries Received by FDA Regarding Conduct of Clinical Trials during the Covid-19 Public Health Emergency.

Background: This report describes the U.S. Food and Drug Administration (FDA) experience in establishing a dedicated mailbox, and in publishing related guidance, to address concerns among interested parties regarding the conduct of clinical trials during the COVID-19 public health emergency (PHE).

Clinical Interviewing: An Essential but Neglected Method of Medicine.

Clinical interviewing is the basic method to understand how a person feels and what are the presenting complaints, obtain medical history, evaluate personal attitudes and behavior related to health and disease, give the patient information about diagnosis, prognosis, and treatment, and establish a bond between patient and physician that is crucial for shared decision making and self-management. However, the value of this basic skill is threatened by time pressures and emphasis on technology. Current health care trends privilege expensive tests and procedures and tag the time devoted to interaction with the patient as lacking cost-effectiveness.

The Million Veteran Program 1990-1991 Gulf War Era Survey: An Evaluation of Veteran Response, Characteristics, and Representativeness of the Gulf War Era Veteran Population.

To address gaps in understanding the pathophysiology of Gulf War Illness (GWI), the VA Million Veteran Program (MVP) developed and implemented a survey to MVP enrollees who served in the U.S. military during the 1990-1991 Persian Gulf War (GW).

Comparison of two assessments of real-world data and real-world evidence for regulatory decision-making.

Real-world data (RWD) and real-world evidence (RWE) are increasingly used to support regulatory decision making, but regulatory agencies and stakeholders may apply different definitions for RWD and use different criteria to determine when analysis of such data are considered RWE in decisions on drug approvals. To explore this issue, we reviewed two prominent publications that operationalized the definitions of RWD and RWE when describing the use of RWE in drug approvals by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Both publications considered noninterventional (observational) studies, RWD as a comparator arm for a single-arm trial, product-related literature reviews, and RWD to support clinical trial implementation (e.

Decisions on Non-oncology Breakthrough Therapy Designation Requests in 2017-2019.

Background: The US Food and Drug Administration's Breakthrough Therapy Designation (BTD) program is intended to facilitate and expedite development of investigational drugs to address unmet medical needs. The objective of this study is to provide an update on FDA's process for review of BTD requests.

Methods: We reviewed Center for Drug Evaluation and Research (CDER) decisions to grant or deny breakthrough therapy designation requests for non-oncology drugs or biological products ("drugs") from January 1, 2017, through December 31, 2019.

Metformin prescription for U.S. veterans with prediabetes, 2010-2019.

Affecting an estimated 88 million Americans, prediabetes increases the risk for developing type 2 diabetes mellitus (T2DM), and independently, cardiovascular disease, retinopathy, nephropathy, and neuropathy. Nevertheless, little is known about the use of metformin for diabetes prevention among patients in the Veterans Health Administration, the largest integrated healthcare system in the U.S.

Early predictors of chronic posttraumatic stress disorder symptom trajectories in U.S. Army soldiers deployed to the Iraq war zone.

The course of posttraumatic stress disorder (PTSD) symptoms varies among veterans of war zones, but sources of variation in long-term symptom course remain poorly understood. Modeling of symptom growth trajectories facilitates the understanding of predictors of individual outcomes over time. Although growth mixture modeling (GMM) has been applied to military populations, few studies have incorporated both predeployment and follow-up measurements over an extended time.

Use of Real-World Evidence in Neuroscience-Related New Drug and Biologics License Applications for Novel Therapeutics.

The US Food and Drug Administration (FDA) is evaluating the potential use of real-world evidence (RWE) in regulatory decision making. Some groups have evaluated the use of RWE in regulatory submissions in the United States and abroad, reporting that reliance on RWE to support new product approvals is relatively common. Confusion regarding the use of RWE in drug-approval decisions may arise, however, based on different application of the terms real-world data (RWD) and RWE.

Evaluating and improving real-world evidence with Targeted Learning.

Background: The Targeted Learning roadmap provides a systematic guide for generating and evaluating real-world evidence (RWE). From a regulatory perspective, RWE arises from diverse sources such as randomized controlled trials that make use of real-world data, observational studies, and other study designs. This paper illustrates a principled approach to assessing the validity and interpretability of RWE.

Emulation of Randomized Clinical Trials With Nonrandomized Database Analyses: Results of 32 Clinical Trials.

Importance: Nonrandomized studies using insurance claims databases can be analyzed to produce real-world evidence on the effectiveness of medical products. Given the lack of baseline randomization and measurement issues, concerns exist about whether such studies produce unbiased treatment effect estimates.

Objective: To emulate the design of 30 completed and 2 ongoing randomized clinical trials (RCTs) of medications with database studies using observational analogues of the RCT design parameters (population, intervention, comparator, outcome, time [PICOT]) and to quantify agreement in RCT-database study pairs.

Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia, Bipolar Disorder, and Depression Among Adults in the US Veterans Affairs Health Care System.

Importance: Serious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide.

Objective: To benchmark the penetrance of current neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration health care system and to explore associations between PRS and broad categories of human disease via phenome-wide association studies.

Design, Setting, And Participants: Extensive Veterans Health Administration's electronic health records were assessed from October 1999 to January 2021, and an embedded cohort of 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder were found.

Real-World Evidence Prediction of a Phase IV Oncology Trial: Comparative Degarelix vs Leuprolide Safety.

Background: Medical and regulatory communities are increasingly interested in the utility of real-world evidence (RWE) for answering questions pertaining to drug safety and effectiveness but concerns about validity remain. A principled approach to conducting RWE studies may alleviate concerns and increase confidence in findings. This study sought to predict the findings from the PRONOUNCE trial using a principled approach to generating RWE.

Genomics of Gulf War Illness in U.S. Veterans Who Served during the 1990-1991 Persian Gulf War: Methods and Rationale for Veterans Affairs Cooperative Study #2006.

Background: Approximately 697,000 members of the U.S. Armed Forces were deployed to the Persian Gulf in support of the 1990-1991 Persian Gulf War (GW).

Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions.

Major depressive disorder is the most common neuropsychiatric disorder, affecting 11% of veterans. Here we report results of a large meta-analysis of depression using data from the Million Veteran Program, 23andMe, UK Biobank and FinnGen, including individuals of European ancestry (n = 1,154,267; 340,591 cases) and African ancestry (n = 59,600; 25,843 cases). Transcriptome-wide association study analyses revealed significant associations with expression of NEGR1 in the hypothalamus and DRD2 in the nucleus accumbens, among others.

Clinimetric Criteria for Patient-Reported Outcome Measures.

Patient-reported outcome measures (PROMs) are self-rated scales and indices developed to improve the detection of the patients' subjective experience. Given that a considerable number of PROMs are available, it is important to evaluate their validity and usefulness in a specific research or clinical setting. Published guidelines, based on psychometric criteria, do not fit in with the complexity of clinical challenges, because of their quest for homogeneity of components and inadequate attention to sensitivity.

Deintensification or No Statin Treatment Is Associated With Higher Mortality in Patients With Ischemic Stroke or Transient Ischemic Attack.

Background And Purpose: Practice guidelines recommend that most patients receive moderate- or high-potency statins after ischemic stroke or transient ischemic attack (TIA) of atherosclerotic origin. We tested the association of different patterns of potency for prescribed statin therapy—assessed before admission and at hospital discharge for ischemic stroke or TIA—on mortality in a large, nationwide sample of US Veterans.

Methods: The study population included patients with an ischemic stroke or TIA occurring during 2011 at any of the 134 Veterans Health Administration facilities.