Remote Cardiac Safety Monitoring through the Lens of the FDA Biomarker Qualification Evidentiary Criteria Framework: A Case Study Analysis

Clinical safety findings remain one of the reasons for attrition of drug candidates during clinical development. Cardiovascular liabilities are not consistently detected in early-stage clinical trials and often become apparent when drugs are administered chronically for extended periods of time. Vital sign data collection outside of the clinic offers an opportunity for deeper physiological characterization of drug candidates and earlier safety signal detection. A working group representing expertise from biopharmaceutical and technology sectors, US Food and Drug Administration (FDA) public-private partnerships, academia, and regulators discussed and presented a remote cardiac monitoring case study at the FNIH Biomarkers Consortium Remote Digital Monitoring for Medical Product Development workshop to examine applicability of the biomarker qualification evidentiary framework by the FDA. This use case examined the components of the framework, including the statement of need, the context of use, the state of the evidence, and the benefit/risk profile. Examination of results from 2 clinical trials deploying 510(k)-cleared devices for remote cardiac data collection demonstrated the need for analytical and clinical validity irrespectively of the regulatory status of a device of interest, emphasizing the importance of data collection method assessment in the context of intended use. Additionally, collection of large amounts of ambulatory data also highlighted the need for new statistical methods and contextual information to enable data interpretation. A wider adoption of this approach for drug development purposes will require collaborations across industry, academia, and regulatory agencies to establish methodologies and supportive data sets to enable data interpretation and decision-making.

COVID-19 and Cancer: A Review of the Registry-Based Pandemic Response.

Importance: The COVID-19 pandemic has had consequences for patients with cancer worldwide and has been associated with delays in diagnosis, interruption of treatment and follow-up care, and increases in overall infection rates and premature mortality. Observations: Despite the challenges experienced during the pandemic, the global oncology community has responded with an unprecedented level of investigation, collaboration, and technological innovation through the rapid development of COVID-19 registries that have allowed an increased understanding of the natural history, risk factors, and outcomes of patients with cancer who are diagnosed with COVID-19. This review describes 14 major registries comprising more than 28 500 patients with cancer and COVID-19; these ongoing registry efforts have provided an improved understanding of the impact and outcomes of COVID-19 among patients with cancer. Conclusions and Relevance: An initiative is needed to promote active collaboration between different registries to improve the quality and consistency of information. Well-designed prospective and randomized clinical trials are needed to collect high-level evidence to guide long-term epidemiologic, behavioral, and clinical decision-making for this and future pandemics.

COVID-19 and Hematopoietic Cell Transplantation Center-Specific Survival Analysis: Can We Adjust for the Impact of the Pandemic? Recommendations of the COVID-19 Task Force of the 2020 Center for International Blood and Marrow Transplantation Research Center Outcomes Forum.

COVID-19 has significantly impacted the practice of hematopoietic cell transplantation (HCT) and likely affected outcomes of HCT recipients. Early reports document substantially higher case fatality rates for HCT recipients than seen in faced by the general population. Currently we do not have a clear picture of how much of this threat is present within the first year after HCT and how infection rates and outcomes vary with time after HCT. There are important because center-specific survival estimates for reporting purposes focus on 1-year post-HCT mortality. Transplantation centers have dramatically changed their practices in response to the pandemic. At many centers, quality assurance processes and procedures were disrupted, changes that likely affected team performance. Centers have been affected unevenly by the pandemic through time, location, and COVID-19 burdens. Assessment of center-specific survival depends on the ability to adjust for risk factors, such as COVID-19, that are outside center control using consistent methods so that team performance based on controllable risk factors can be ascertained. The Center for International Blood and Marrow Transplantation Research (CIBMTR) convened a working group for the 2020 Center Outcomes Forum to assess the impact of COVID-19 on both patient-specific risks and center-specific performance. This committee reviewed the factors at play and developed recommendations for a process to determine whether adjustments in the methodology to assess center-specific performance are needed.

A toolkit for the collection of thrombosis-related data elements in COVID-19 clinical studies.

Thrombosis has emerged as an important complication of coronavirus disease 2019 (COVID-19), particularly among individuals with severe illness. However, the precise incidence of thrombotic events remains uncertain due to differences in study design, patient populations, outcome ascertainment, event definitions, and reporting. In an effort to overcome some of these challenges and promote standardized data collection and reporting in clinical studies, the American Society of Hematology Research Collaborative COVID-19 Non-Malignant Hematology Task Force, in collaboration with the International Society on Thrombosis and Haemostasis COVID-19 Task Force, developed sets of data elements in the following domains: venous thromboembolism, myocardial infarction, stroke/transient ischemic attack, peripheral arterial thrombosis, bleeding, laboratory investigations, and antithrombotic therapy. Data elements in each of these domains were developed with 3 levels of detail to facilitate their incorporation into studies evaluating a range of interventions and outcomes. Previously published data elements were included where possible. The use of standardized variables in a range of clinical studies can enhance the quality of data collection, create efficiency, enhance comparison of results across studies, and facilitate future pooling of data sets.

Outcomes of patients with hematologic malignancies and COVID-19: a report from the ASH Research Collaborative Data Hub.

Coronavirus disease 2019 (COVID-19) is an illness resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in late 2019. Patients with cancer, and especially those with hematologic malignancies, may be at especially high risk of adverse outcomes, including mortality resulting from COVID-19 infection. The ASH Research Collaborative COVID-19 Registry for Hematology was developed to study features and outcomes of COVID-19 infection in patients with underlying blood disorders, such as hematologic malignancies. At the time of this report, data from 250 patients with blood cancers from 74 sites around the world had been entered into the registry. The most commonly represented malignancies were acute leukemia (33%), non-Hodgkin lymphoma (27%), and myeloma or amyloidosis (16%). Patients presented with a myriad of symptoms, most frequently fever (73%), cough (67%), dyspnea (50%), and fatigue (40%). Use of COVID-19-directed therapies, such as hydroxychloroquine (n = 76) or azithromycin (n = 59), was common. Overall mortality was 28%. Patients with a physician-estimated prognosis from the underlying hematologic malignancy of <12 months at the time of COVID-19 diagnosis and those with relapsed/refractory disease experienced a higher proportion of moderate/severe COVID-19 disease and death. In some instances, death occurred after a decision was made to forgo intensive care unit admission in favor of a palliative approach. Taken together, these data support the emerging consensus that patients with hematologic malignancies experience significant morbidity and mortality resulting from COVID-19 infection. Batch submissions from sites with high incidence of COVID-19 infection are planned to support future analyses.

Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta-analysis of 3377 patients.

Outcomes for patients with hematologic malignancy infected with COVID-19 have not been aggregated. The objective of this study was to perform a systematic review and meta-analysis to estimate the risk of death and other important outcomes for these patients. We searched PubMed and EMBASE up to 20 August 2020 to identify reports of patients with hematologic malignancy and COVID-19. The primary outcome was a pooled mortality estimate, considering all patients and only hospitalized patients. Secondary outcomes included risk of intensive care unit admission and ventilation in hospitalized patients. Subgroup analyses included mortality stratified by age, treatment status, and malignancy subtype. Pooled prevalence, risk ratios (RRs), and 95% confidence intervals (CIs) were calculated using a random-effects model. Thirty-four adult and 5 pediatric studies (3377 patients) from Asia, Europe, and North America were included (14 of 34 adult studies included only hospitalized patients). Risk of death among adult patients was 34% (95% CI, 28-39; N = 3240) in this sample of predominantly hospitalized patients. Patients aged ≥60 years had a significantly higher risk of death than patients <60 years (RR, 1.82; 95% CI, 1.45-2.27; N = 1169). The risk of death in pediatric patients was 4% (95% CI, 1-9; N = 102). RR of death comparing patients with recent systemic anticancer therapy to no treatment was 1.17 (95% CI, 0.83-1.64; N = 736). Adult patients with hematologic malignancy and COVID-19, especially hospitalized patients, have a high risk of dying. Patients ≥60 years have significantly higher mortality; pediatric patients appear to be relatively spared. Recent cancer treatment does not appear to significantly increase the risk of death.

Real-World Issues and Potential Solutions in Hematopoietic Cell Transplantation during the COVID-19 Pandemic: Perspectives from the Worldwide Network for Blood and Marrow Transplantation and Center for International Blood and Marrow Transplant Research Health Services and International Studies Committee.

The current COVID-19 pandemic, caused by SARS-CoV-2, has impacted many facets of hematopoietic cell transplantation (HCT) in both developed and developing countries. Realizing the challenges as a result of this pandemic affecting the daily practice of the HCT centers and the recognition of the variability in practice worldwide, the Worldwide Network for Blood and Marrow Transplantation (WBMT) and the Center for International Blood and Marrow Transplant Research's (CIBMTR) Health Services and International Studies Committee have jointly produced an expert opinion statement as a general guide to deal with certain aspects of HCT, including diagnostics for SARS-CoV-2 in HCT recipient, pre- and post-HCT management, donor issues, medical tourism, and facilities management. During these crucial times, which may last for months or years, the HCT community must reorganize to proceed with transplantation activity in those patients who urgently require it, albeit with extreme caution. This shared knowledge may be of value to the HCT community in the absence of high-quality evidence-based medicine. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.