Simultaneous Global Drug Development and Multiregional Clinical Trials (MRCT): 5 Years After Implementation of ICH E17 Guidelines.

The ICH E17 guidelines (2014-2017) on Multiregional Clinical Trials (MRCT) was a joint effort by the regulators and industry to facilitate simultaneous global drug development and registration through taking a strategic approach for clinical trials. In other words, the objective was to reduce the time it takes to bringing medications to patients around the world through minimizing unnecessary duplication of local or regional studies, which may add the regulatory burden to cost and time of bringing new therapies to patients. Under the auspices of ICH, training materials were created and provided to various stakeholders. Despite the successful promotion of the benefits of ICH E17 MRCT guidelines across the different regions, the uptake of some concepts (e.g., pooling strategy) in the ICH E17 guidelines has been slow. This paper describes various factors which could affect the conduct of MRCT at a global level, including ambiguity in definition of "region" (in MRCT), new regulatory requirements to enroll a diverse patient population, the use of decentralized clinical trials, use of data sources other than randomized clinical trials (e.g., use of Real Word Data), and the impact of the COVID-19 pandemic on the conduct of MRCT.

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. The number and distribution of patients were reported for the first 3 drug regimen lines initiated. Results: The cohort included 51 066 patients; the most common initial drug regimens were corticosteroids (23.4%), corticosteroids plus remdesivir (25.1%), and remdesivir (4.4%). IL-6 inhibitors and Janus kinase inhibitors were included in later drug regimens and were more commonly administered with both corticosteroids and remdesivir than with corticosteroids alone. IL-6 inhibitors were more commonly administered than Janus kinase inhibitors when patients received high-flow oxygen or ventilation. Conclusions: These findings provide important context for comparative studies of COVID-19 treatments with study periods extending into 2021 and later. While prescribing generally aligned with National Institutes of Health COVID-19 treatment guidelines during this period, these findings suggest that prescribing preference, potential confounding by indication, and confounding by prior/concomitant use of other therapeutics should be considered in the design and interpretation of comparative studies.

Improving data capture of race and ethnicity for the Food and Drug Administration Sentinel database: a narrative review.

PURPOSE: The U.S. Food and Drug Administration's Sentinel System is a national medical product safety surveillance system consisting of a large multisite distributed database of administrative claims supplemented by electronic health-care record data. The program seeks to improve data capture of race and ethnicity for pharmacoepidemiology studies. METHODS: We conducted a narrative literature review of published research on data augmentation and imputation methods to improve race and ethnicity capture in U.S. health-care systems databases. We focused on methods with limited (five-digit ZIP codes only) or full patient identifiers available to link to external sources of self-reported data. We organized the literature by themes: (1) variation in data capture of self-reported data, (2) data augmentation from external sources of self-reported data, and (3) imputation methods, including Bayesian analysis and multiple regression. RESULTS: Researchers reduced data missingness with high validity for Asian, Black, White, and Pacific Islander racial groups and Hispanic ethnicity. Native American and multiracial groups were difficult to validate due to relatively small sample sizes. CONCLUSIONS: Limitations on accessible self-reported data for validation will dictate methods to improve race and ethnicity data capture. We recommend methods leveraging multiple sources that account for variations in geography, age, and sex.

Real-world utilization of SARS-CoV-2 serological testing in RNA positive patients across the United States.

BACKGROUND: As diagnostic tests for COVID-19 were broadly deployed under Emergency Use Authorization, there emerged a need to understand the real-world utilization and performance of serological testing across the United States. METHODS: Six health systems contributed electronic health records and/or claims data, jointly developed a master protocol, and used it to execute the analysis in parallel. We used descriptive statistics to examine demographic, clinical, and geographic characteristics of serology testing among patients with RNA positive for SARS-CoV-2. RESULTS: Across datasets, we observed 930,669 individuals with positive RNA for SARS-CoV-2. Of these, 35,806 (4%) were serotested within 90 days; 15% of which occurred <14 days from the RNA positive test. The proportion of people with a history of cardiovascular disease, obesity, chronic lung, or kidney disease; or presenting with shortness of breath or pneumonia appeared higher among those serotested compared to those who were not. Even in a population of people with active infection, race/ethnicity data were largely missing (>30%) in some datasets-limiting our ability to examine differences in serological testing by race. In datasets where race/ethnicity information was available, we observed a greater distribution of White individuals among those serotested; however, the time between RNA and serology tests appeared shorter in Black compared to White individuals. Test manufacturer data was available in half of the datasets contributing to the analysis. CONCLUSION: Our results inform the underlying context of serotesting during the first year of the COVID-19 pandemic and differences observed between claims and EHR data sources-a critical first step to understanding the real-world accuracy of serological tests. Incomplete reporting of race/ethnicity data and a limited ability to link test manufacturer data, lab results, and clinical data challenge the ability to assess the real-world performance of SARS-CoV-2 tests in different contexts and the overall U.S. response to current and future disease pandemics.

Real world data (RWD) in pediatrics.

Unique challenges pertain when studying children, although many research principles are the same as those when studying adult populations. This truism extends to the use of real-world data (RWD). RWD are particularly relevant to pediatrics because they may potentially provide an additional source of data to inform pediatric labeling and practice patterns when clinical trials have not been or cannot be conducted. The purpose of this commentary is to provide a brief overview of the unique issues in using RWD to study the effectiveness or safety of medical therapies in children.

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. OR [95% CI]: 0.83 [0.71, 0.96]) and more likely to receive other steroids corticosteroids (adj. OR [95% CI]: 2.13 [1.90, 2.39]), relative to White patients. Hispanic/Latino patients were less likely to receive dexamethasone than Not Hispanic/Latino patients (adj. OR [95% CI]: 0.69 [0.58, 0.82]). CONCLUSIONS: Our findings suggest that COVID-19 treatments patients received in Optum varied by race and ethnicity after adjustment for other possible explanatory factors. In the face of rapidly evolving treatment landscapes, policies are needed to ensure equitable access to novel and repurposed therapeutics to avoid disparities in care by race and ethnicity.

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. Trends for heterogeneity in mortality risk and rate across severity classifications were evaluated using Cochran-Armitage and Logrank trend tests, respectively. RESULTS: Among 118 117 patients, the algorithm categorized patients in increasing severity as NEITHER (36.7%), O2/NIV (54.3%), and IMV (9.0%). Associated mortality risk (and 95% CI) was 11.8% (11.6-12.0%) overall and increased with severity [3.4% (3.2-3.5%), 11.5% (11.3-11.8%), 47.3% (46.3-48.2%); p < 0.001]. Mortality rate per 1000 person-days (and 95% CI) was 15.1 (14.9-15.4) overall and increased with severity [5.7 (5.4-6.0), 14.5 (14.2-14.9), 32.7 (31.8-33.6); p < 0.001]. CONCLUSION: As expected, we observed a positive association between the algorithm-defined severity on admission and 28-day mortality risk and rate. Although performance remains to be validated, this provides some assurance that this algorithm may be used for confounding control or stratification in treatment effect studies.

Perspectives on statistical strategies for the regulatory biomarker qualification process.

Qualification of a biomarker for use in a medical product development program requires a statistical strategy that aligns available evidence with the proposed context of use (COU), identifies any data gaps to be filled and plans any additional research required to support the qualification. Accumulating, interpreting and analyzing available data is outlined, step-by-step, illustrated by a qualified enrichment biomarker example and a safety biomarker in the process of qualification. The detailed steps aid requestors seeking qualification of biomarkers, allowing them to organize the available evidence and identify potential gaps. This provides a statistical perspective for assessing evidence that parallels clinical considerations and is intended to guide the overall evaluation of evidentiary criteria to support a specific biomarker COU.

Design and analysis choices for safety surveillance evaluations need to be tuned to the specifics of the hypothesized drug-outcome association.

BACKGROUND: We reviewed the results of the Observational Medical Outcomes Research Partnership (OMOP) 2010 Experiment in hopes of finding examples where apparently well-designed drug studies repeatedly produce anomalous findings. OMOP had applied thousands of designs and design parameters to 53 drug-outcome pairs across 10 electronic data resources. Our intent was to use this repository to elucidate some sources of error in observational studies. METHOD: From the 2010 OMOP Experiment, we sought drug-outcome-method combinations (DOMCs) that met consensus design criteria, yet repeatedly produced results contrary to expectation. We set aside DOMCs for which we could not agree on the suitability of the designs, then selected for an in-depth scrutiny one drug-outcome pair analyzed by a seemingly plausible methodological approach, whose results consistently disagreed with the a priori expectation. RESULTS: The OMOP "all-by-all" assessment of possible DOMCs yielded many combinations that would not be chosen by researchers as actual study options. Among those that passed a first level of scrutiny, two of seven drug-outcome pairs for which there were plausible research designs had anomalous results. The use of benzodiazepines was unexpectedly associated with acute renal failure and upper gastrointestinal bleeding. We chose the latter as an example for in-depth study. The factitious appearance of a bleeding risk may have been partly driven by an excess of procedures on the first day of treatment. A risk window definition that excluded the first day largely removed the spurious association. CONCLUSION: One cause of reproducible "error" may be repeated failure to tie design choices closely enough to the research question at hand. Copyright © 2016 John Wiley & Sons, Ltd.

The role of quantitative safety evaluation in regulatory decision making of drugs.

Evaluation of safety is a critical component of drug review at the US Food and Drug Administration (FDA). Statisticians are playing an increasingly visible role in quantitative safety evaluation and regulatory decision-making. This article reviews the history and the recent events relating to quantitative drug safety evaluation at the FDA. The article then focuses on five active areas of quantitative drug safety evaluation and the role Division of Biometrics VII (DBVII) plays in these areas, namely meta-analysis for safety evaluation, large safety outcome trials, post-marketing requirements (PMRs), the Sentinel Initiative, and the evaluation of risk from extended/long-acting opioids. This article will focus chiefly on developments related to quantitative drug safety evaluation and not on the many additional developments in drug safety in general.

Building a roadmap to biomarker qualification: challenges and opportunities.

The traditional route for regulatory acceptance of biomarkers in drug development is through submission of biomarker data in drug approval submissions in the context of a single drug development program. The US FDA's Critical Path Initiative called for establishment of a biomarker qualification process to enable progress in the drug development paradigm. In response to this, the Center for Drug Evaluation and Research (CDER) established a Biomarker Qualification Program (BQP) to qualify a biomarker for a specific context of use (COU). The qualified biomarker can then be used in multiple drug development programs for this COU without re-review. Here, we describe some of the features of the BQP and two new initiatives that have the potential to aid biomarker development through early interactions with the FDA. Finally, we discuss some of the feedback the FDA has received from submitters and the BQP's actions to strengthen the program.

Review of oncology and hematology drug product approvals at the US Food and Drug Administration between July 2005 and December 2007.

BACKGROUND: The Office of Oncology Drug Products (OODP) in the Center for Drug Evaluation and Research at the US Food and Drug Administration began reviewing marketing applications for oncological and hematologic indications in July 2005. We conducted an overview of products that were reviewed by the OODP for marketing approval and the regulatory actions taken during July 2005 to December 2007. METHODS: We identified all applications that were reviewed by the OODP from July 1, 2005, through December 31, 2007, and reviewed the actions that OODP took. We also sought the basis for the actions taken, including the clinical trial design, endpoints used, patient accrual in the trial(s) supporting approval, and the type of regulatory approval. RESULTS: During the study period, the OODP reviewed marketing applications for 60 new indications and took regulatory action on 58 indications. Regulatory action was based on a risk-benefit evaluation of the data submitted with each application. Products that demonstrated efficacy and had an acceptable risk-benefit ratio were granted either regular or accelerated marketing approval for use in the specific indication that was studied. Regular approval was based on endpoints that demonstrated that the drug provided clinical benefit as evidenced by a longer or better life or a favorable effect on an established surrogate for a longer or better life. Accelerated approval was based on a less well-established surrogate endpoint that was reasonably likely to predict a longer or better life. Of the 53 new indications that were approved during the study period, 39 received regular approval, nine received accelerated approval, and five were converted from accelerated to regular approval. Five applications were not approved, and two applications were withdrawn before any regulatory action was taken. Eighteen of the 53 indications that were approved were for new molecular entities. CONCLUSION: During the study period, regulatory action was taken on 58 of the 60 marketing applications. Fifty-three applications were approved. A variety of clinical trial endpoints were used in the approval trials.

Use of progression-free survival as a surrogate marker in oncology trials: some regulatory issues.

There has been interest in using progression-free survival as a surrogate endpoint for overall survival in oncology clinical trials. In order to objectively define this endpoint, clear understanding of what progression means, how it is measured and what its implications are need to be discussed. This article discusses some regulatory aspects of using progression-free survival as an endpoint.

Cefotetan-induced haemolytic anaemia. A review of 85 cases.

OBJECTIVE: Reports of cefotetan-associated haemolytic anaemia have prompted a US Food and Drug Administration (FDA) review of the overall number, severity, and causality of such cases. METHODS/RESULTS: A search of the FDA's Spontaneous Reporting System and the World Health Organization's database revealed 85 cases of haemolytic anaemia since the approval of cefotetan in 1985, 15 of them fatal. Moderate to severe haemolysis was reflected in a mean fall in haemoglobin levels by 6.65 mg/dl (n = 20) and a mean final haemoglobin concentration of 5.2 mg/dl (n = 52). Transfusion of packed red blood cells was required in 47 patients (55.3%). New onset renal dysfunction was noted in 7 patients (8.2%). The direct antiglobulin test was positive in 50 patients (59%), and serological studies revealed antibodies to cefotetan in 30 patients (35%). CONCLUSION: These data suggest that treatment with cefotetan may induce severe autoimmune haemolytic anaemia.