Publications

BACKGROUND: Statistical testing in phase III clinical trials is subject to chance errors, which can lead to false conclusions with substantial clinical and economic consequences for patients and society.

METHODS: We collected summary data for the primary endpoints of overall survival (OS) and progression-related survival (PRS) (eg, time to other type of event) for industry-sponsored, randomized, phase III superiority oncology trials from 2008 through 2017. Using an empirical Bayes methodology, we estimated the number of false-positive and false-negative errors in these trials and the errors under alternative P value thresholds and/or sample sizes.

RESULTS: We analyzed 187 OS and 216 PRS endpoints from 362 trials. Among 56 OS endpoints that achieved statistical significance, the true efficacy of experimental therapies failed to reach the projected effect size in 33 cases (58.4% false-positives). Among 131 OS endpoints that did not achieve statistical significance, the true efficacy of experimental therapies reached the projected effect size in 1 case (0.9% false-negatives). For PRS endpoints, there were 34 (24.5%) false-positives and 3 (4.2%) false-negatives. Applying an alternative P value threshold and/or sample size could reduce false-positive errors and slightly increase false-negative errors.

CONCLUSIONS: Current statistical approaches detect almost all truly effective oncologic therapies studied in phase III trials, but they generate many false-positives. Adjusting testing procedures in phase III trials is numerically favorable but practically infeasible. The root of the problem is the large number of ineffective therapies being studied in phase III trials. Innovative strategies are needed to efficiently identify which new therapies merit phase III testing.

Feasibility, safety, and utility of brain MRI for patients with non-MRI-conditioned cardiac implantable electrical devices (CIEDs) remains controversial. While a growing number of studies have shown safe employment in select patients under strict protocols, there is an increasing clinical need for further off-label investigations. To assess the feasibility and utility of brain MRI in neurological and neurosurgical patients with non-MRI-conditioned CIEDs using off-label protocol. We retrospectively evaluated 126 patients with non-MRI-conditioned CIEDs referred to our hospital between 2014 to 2018 for MRI under an IRB-approved protocol. A total of 126 off-label brain MRI scans were performed. The mean age was 67.5 ± 13.0. Seventy percent of scans were performed on female patients. Indications for MRI are neurosurgical (45.2%), neurological (51.6%), and others (3.2%). MRI utilization for tumor cases was highest for tumor cases (68.3%), but employment was valuable for vascular (12.7%), deep brain stimulators (3.2%), and other cases (15.9%). In the tumor category, (37.2%) of the scans were performed for initial diagnosis and pre-surgical planning, (47.7%) for post-intervention evaluation/surveillance, (15.1%) for stereotactic radiosurgery treatment (CyberKnife). No clinical complications were encountered. No functional device complications of the CIED were identified during and after the MRI in 96.9% of the studies. A 49.6% of the off-label brain MRI scans performed led to a clinically significant decision and/or intervention for the patients. A 42.9% of obtained MRI studies did not change the plan of care. A 7.9% of post-scan decision-making data was not available. We demonstrate that off-label brain MRI scans performed on select patients under a strict protocol is feasible, safe, and relevant. Almost 50% of scans provided critical information resulting in clinical intervention of the patients.

Shared decision making (SDM) facilitates delivery of medical therapies that are in alignment with patients' goals and values. Medicare national coverage decision for several interventions now includes SDM mandates, but few have been evaluated in nationwide studies. Based upon a detailed needs assessment with diverse stakeholders, we developed pamphlet and video patient decision aids (PtDAs) for implantable cardioverter/defibrillator (ICD) implantation, ICD replacement, and cardiac resynchronization therapy with defibrillation to help patients contemplate, forecast, and deliberate their options. These PtDAs are the foundation of the Multicenter Trial of a Shared Decision Support Intervention for Patients Offered Implantable Cardioverter-Defibrillators (DECIDE-ICD), a multicenter, randomized trial sponsored by the National Heart, Lung, and Blood Institute aimed at understanding the effectiveness and implementation of an SDM support intervention for patients considering ICDs. Finalization of a Medicare coverage decision mandating the inclusion of SDM for new ICD implantation occurred shortly after trial initiation, raising novel practical and statistical considerations for evaluating study end points. METHODS/DESIGN: A stepped-wedge randomized controlled trial was designed, guided by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) planning and evaluation framework using an effectiveness-implementation hybrid type II design. Six electrophysiology programs from across the United States will participate. The primary effectiveness outcome is decision quality (defined by knowledge and values-treatment concordance). Patients with heart failure who are clinically eligible for an ICD are eligible for the study. Target enrollment is 900 participants. DISCUSSION: Study findings will provide a foundation for implementing decision support interventions, including PtDAs, with patients who have chronic progressive illness and are facing decisions involving invasive, preference-sensitive therapy options.

UNLABELLED: Policy Points Millions of life-sustaining implantable devices collect and relay massive amounts of digital health data, increasingly by using user-downloaded smartphone applications to facilitate data relay to clinicians via manufacturer servers. Our analysis of health privacy laws indicates that most US patients may have little access to their own digital health data in the United States under the Health Insurance Portability and Accountability Act Privacy Rule, whereas the EU General Data Protection Regulation and the California Consumer Privacy Act grant greater access to device-collected data. Our normative analysis argues for consistently granting patients access to the raw data collected by their implantable devices.

CONTEXT: Millions of life-sustaining implantable devices collect and relay massive amounts of digital health data, increasingly by using user-downloaded smartphone applications to facilitate data relay to clinicians via manufacturer servers. Whether patients have either legal or normative claims to data collected by these devices, particularly in the raw, granular format beyond that summarized in their medical records, remains incompletely explored.

METHODS: Using pacemakers and implantable cardioverter-defibrillators (ICDs) as a clinical model, we outline the clinical ecosystem of data collection, relay, retrieval, and documentation. We consider the legal implications of US and European privacy regulations for patient access to either summary or raw device data. Lastly, we evaluate ethical arguments for or against providing patients access to data beyond the summaries presented in medical records.

FINDINGS: Our analysis of applicable health privacy laws indicates that US patients may have little access to their raw data collected and held by device manufacturers in the United States under the Health Insurance Portability and Accountability Act Privacy Rule, whereas the EU General Data Protection Regulation (GDPR) grants greater access to device-collected data when the processing of personal data falls under the GDPR's territorial scope. The California Consumer Privacy Act, the "little sister" of the GDPR, also grants greater rights to California residents. By contrast, our normative analysis argues for consistently granting patients access to the raw data collected by their implantable devices. Smartphone applications are increasingly involved in the collection, relay, retrieval, and documentation of these data. Therefore, we argue that smartphone user agreements are an emerging but potentially underutilized opportunity for clarifying both legal and ethical claims for device-derived data.

CONCLUSIONS: Current health privacy legislation incompletely supports patients' normative claims for access to digital health data.

Randomized trials inform the use of implantable cardioverter-defibrillators (ICDs) for prevention of sudden cardiac death, yet management of patients considering ICD generator replacement procedures remains largely dependent on clinical judgment. Thus, we performed a systematic review of all studies evaluating outcomes associated with ICD generator replacement. We queried PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews for relevant studies with a prespecified search and adjudication strategy (PROSPERO registration number CRD42018100818) to evaluate outcomes including (1) survival; (2) clinical complications (eg, infection, hematoma); or (3) incidence of ICD therapy. From 1607 unique titles, 37 studies met inclusion criteria, describing outcomes for 238,949 patients. Procedural mortality was rare, but complications including reoperation (median 4.57%; range 0.38%-10.31%), infections (median 2.01%; range 0.03%-9.27%), and hematoma (median 1.22%, range 0.17%-2.53%) were observed in a small fraction of patients. Appropriate ICD therapy after generator replacement was common (median rate 23.03%; range 10.9%-31.4%), with an overall annualized event rate of 8.52% at median duration of follow-up of 32.4 months. Appropriate ICD therapy continued to occur at a significant annual rate even in patients who no longer met implantation criteria (5.27%) and in patients who never previously received ICD therapy (4.87%). This analysis of published observational data regarding ICD generator replacement procedures identifies relatively low risks of procedural complications and clinically meaningful rates of appropriate ICD therapies. These estimates may guide clinical decisions and inform the design of definitive trials.