Regulatory Response To Pandemic Relies On Real-World Data Analysis

By Deborah Borfitz 

July 13, 2021 | A team of regulatory experts presented at the recent DIA 2021 Global Annual Meeting on COVID-19 real-world data (RWD) analysis and vaccine surveillance. Representatives from the U.S. Food and Drug Administration (FDA) covered the COVID-19 Evidence Accelerator, National COVID Cohort Collaborative (N3C) Data Enclave, and a study describing ethnic and racial disparities in COVID-related hospitalizations, while those from the Danish Medicines Agency focused on COVID-19 cohort data analysis related to post-infection complications and vaccine safety. 

First up was Stine Hasling Mogensen, senior scientific advisor for the Danish Medicines Agency, talking about a study launched in collaboration with academia that found the risk of severe post-acute complications after SARS-CoV-2 infection not requiring hospital admission is low. The caveat was that visits to general practitioners and outpatient clinics increased along with initiation of prescription drugs, suggesting possible late or delayed complications or persistent COVID-related symptoms (“long COVID”). 

As recently reported in The Lancet Infectious Diseases (DOI: 10.1016/S1473-3099(21)00211-5), the population-based cohort study included all Danish residents who, during the first wave of the pandemic, tested positive for SARS-CoV-2 but were not hospitalized—a total of nearly 9,000 individuals. Data sources included the Danish Prescription Registry, Danish National Patient Registry (inpatient and outpatient hospital diagnoses), Danish National Laboratory database (creatinine measurements), and Danish National Health Insurance Register (general practitioner visits). 

Results from data analysis took a few weeks, says Mogensen. The study examined incident drug use, hospital diagnoses, and overall healthcare use from two weeks to six months after a positive SARS-CoV-2 test in the 9,000 selected individuals. Statistical analysis adjusted for differences in baseline healthcare use. The comparator group included more than 80,000 SARS-CoV-2-negative individuals. 

The focus was on risk and risk ratios for initiation of new medications, Mogensen says. Overall, a positive COVID-19 test did not increase the risk of being prescribed a new drug although bronchodilating agents (specifically, short-acting β2-agonists) were an exception.

“After six months, COVID patients had a slightly increased need for treatment, especially [for abnormalities of] breathing,” she says. They also more often needed outpatient care than individuals who tested negative for SARS-CoV-2.

It is likely that the risk of persistent symptoms such as fatigue, for which individuals might not seek care, were vastly underestimated, adds Mogensen. The agency may do a follow-up study to better assess the duration and spectrum of systems after SARS-CoV-2 infection. 

AstraZeneca Vaccine

A regulator-commissioned population study conducted by several Danish institutions looked at rates of cardiovascular and hemostatic events in the first 28 days after vaccination with the Oxford-AstraZeneca vaccine in Denmark and Norway compared with that observed in the general populations, reports Anton Pottegard, professor at the University of Southern Denmark. Results are newly published in The BMJ (DOI: 10.1136/bmj.n1114). 

Participants were everyone ages 18 to 65 years old who had received their first vaccination, before vaccination program were halted due to safety concerns, with the general populations of Denmark and Norway serving as comparator cohorts. The vaccinated cohorts in the two countries had roughly the same median age and gender balance, Pottegard says, and were “almost exclusively healthcare professionals and social service workers,” per Danish and Norwegian COVID-19 vaccination strategies. 

The study looked at standardized morbidity differences and ratios and found no rise in the rate of critical events, he says. Although it uncovered a marked increase in venous thromboembolic events (59 observed versus 30 expected) as well as a clearly increased rate of cerebral venous thrombosis (seven observed versus 0.3 expected), the absolute risk was small considering the proven beneficial effects of the vaccine. 

Conversely, there was no observed increase in the rate of overall arterial events, Pottegard continues. A moderate level of bleeding and coagulation disorders were observed but may have been a consequence of “heightened surveillance.” 

Bleeding events were driven primarily by bleeding from the respiratory tract. When hospital contacts shorter than five hours were excluded from the analysis, no excess bleeding events were observed, he notes.

Supplementary analysis found a slightly higher absolute excess rate of thromboembolic events among younger individuals (18-44 years), Pottegard reports. No excess rate of venous thromboembolism was observed among men and their relatively small number (less than one-quarter of the vaccinated cohort) is not believed to have biased the analysis given their absolute number was in the tens of thousands. 

The study’s main limitations were that it excluded people over age 65 and did not provide information on the safety of the second dose, says Pottegard. The increased rates of observed thromboembolic events need to be investigated further, including in country-specific settings where people are predominantly of non-white ethnicities. 


Cross-vaccination with the AstraZeneca and Pfizer (mRNA) vaccines was the subject of a presentation by Mona Vestergaard Laursen, senior advisor in the data analytics center at the Danish Medicines Agency. This “off-label” combined use of the two vaccines was explored after the AstraZeneca vaccine was put on pause nationwide in mid-April. 

The study, set up by the Statens Serum Institut in Copenhagen, kicked off in mid-May and is expected to conclude at the end of July, she says. It has been enrolling people who have received one shot of each vaccine as well as people who have had both of their Pfizer shots and are serving as the control group, and both cohorts will be followed for 28 days post-vaccination.

Researchers will be looking for hospital contacts for conditions such as thromboembolic events, acute myocarditis, and anaphylaxis-related complications. Four interim analyses are being conducted, when study vaccination completion rates hit 10%, 25% 50%, and 75%, Laursen says.   

The study taps Denmark’s unique Central Person Registry that includes a personal identifier for every citizen residing in the country (as of 1968), in addition to their age, gender, vital status, migration, and death, explains Laursen. This is in addition to multiple other national databases, including the Danish Microbiology Database, which provides current microbiological test results from patients across Denmark. 

“Real-world data is an important tool in pandemic control and monitoring of COVID-19 vaccine rollout and surveillance,” Laursen says. Results of the first interim analysis from the cross-vaccination study are expected soon, she adds.

Wrangling Real-World Data 

A project harmonizing COVID-19 RWD elements was covered by Mitra Rocca, associate director of medical informatics, Office of Translational Medicine, in the FDA’s Center for Drug Evaluation and Research (CDER). As set forth by the 21st Century Cures Act, the agency is expected to establish policies around the potential use of real-world evidence and post-approval study requirements. It has already published a framework for evaluating the potential use of real-world evidence to help support regulatory approvals as well as a suite of related guidances. 

The value of RWD, from which real-world evidence is derived, is near-real-time insights on patients that can inform the evaluation of medicines, the natural history of diseases, and the analysis of clinical outcomes, says Rocca. The FDA will be developing technical tools and identifying gaps in existing methods and data.

On the pandemic front, the FDA is leading the COVID-19 Evidence Accelerator in collaboration with the Reagan-Udall Foundation and Friends of Cancer Research to enable the gathering and designing of quick turnaround queries and sharing the results, she says. The initiative currently has two workstreams—Accelerator Parallel Analyses (for developing key research questions that multiple organizations and teams can address simultaneously) and Accelerator Lab Meetings (for sharing findings on critical questions). 

The COVID-19 Evidence Accelerator identified the data elements being harmonized with several common data models (e.g., Patient-Centered Clinical Research Network, FDA’s Sentinel program, OMOP) and open standards (i.e., FHIR). COVID-19 data elements are being mapped to USCDI and CDISC and validated with standards developing organizations, Rocca says. 

The National Institutes of Health, meanwhile, is taking the lead on N3C. Rocca serves on N3C’s data ingestion and harmonization workstream, which now has 55 academic centers submitting data on two million COVID-positive patients for harmonization into a common data model (based on OMOP standards) to maximize analytics. 

The research community can obtain datasets from a centralized resource known as the N3C Data Enclave, to study COVID-19 and identify potential treatments, Rocca says. Data can be accessed at one of three levels—limited (for researchers at U.S.-based institutions only), deidentified (open to domestic and foreign researchers) and synthetic (eligibility extends to citizen scientists). 

For a OneSource COVID Trial, the FDA is collaborating with the University of California, San Francisco, where the study began five years ago for breast cancer and is now being reused for COVID-19, Rocca continues. Source data on COVID-19 patients in the critical care environment is being captured from electronic health records (EHRs) using standardized clinical research data.

The trial is using SMART on FHIR, a technology platform that allows healthcare organizations to plug third-party medical apps into their clinical data systems. The I-SPY COVID platform is also being used, she says. 

Study management is being streamlined through EHR integration, pulling in demographic, medication and lab data, says Rocca. The OneSource platform is also pulling patient-reported outcomes into EHRs. Lab data can be extracted directly. For concomitant medications, the goal is to integrate EHR and electronic data capture systems.

Vaccination Targets 

Richard Foreshee, associate director for analytics and benefit-risk assessment in the FDA’s Center for Biologics Evaluation and Research (CBER), reports on the natural history of risk factors for COVID-19 hospitalizations among adults ages 65 and up. The findings emerged from a retrospective cohort study conducted jointly by CBER, CDER, the Center for Medicare & Medicaid Services (CMS), and a third-party contractor before any vaccines were available in the U.S.

The study enrolled Medicare fee-for-service beneficiaries who were neither living in a nursing home nor had end-stage renal disease and looked at standard demographic and socioeconomic variables— including dual eligibility (low income), neighborhood (Area Deprivation Index), and health status, he says. Key results were that being older corresponded with a slightly higher risk of being hospitalized and being dual eligible more than doubled the risk.  

Likewise, the risk of COVID-related hospitalization doubled among both blacks and Hispanics, continues Foreshee. Relative to whites, North American Natives were more than three times more likely to be admitted to the hospital.

When looking at hospitalizations of those who were dual eligible versus those who were not, notable differences were seen among whites (three times more at risk) and North American Natives (two and a half times more at risk), he says. Dual-eligibility status also impacted differences in risk between nonwhites and whites, narrowing the gap for Blacks and Hispanics but not for North American Natives. 

The key health conditions increasing the risk of hospitalization were hypertension, diabetes, and obesity, Foreshee says. Immunocompromised status and frailty also increased the risk. Age alone did not have a particularly large impact, he notes. 

Data from the study is being used in the emPOWER In Action program of CMS to help target high-need individuals for vaccination, says Foreshee. The study confirmed findings from earlier studies, in addition to providing important insights on racial and ethnic differences in the risk of being hospitalized due to COVID-19 infection.

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