Real-World Evidence: CDC Prioritizing Populations, Outcomes For COVID-19 Vaccine Effectiveness Studies
Executive Summary
Strategy for assessing how the earliest vaccines to reach market perform beyond clinical trials includes leveraging existing surveillance and data platforms, and employing a diversity of study approaches, CDC epidemiologist says; high-priority areas for study include protection against symptomatic illness among health care workers and prevention of severe disease in the elderly.
As the most advanced COVID-19 vaccine candidates in the US approach their Phase III enrollment targets, the Centers for Disease Control and Prevention and other government health agencies are prioritizing populations and outcomes for real-world effectiveness studies that will begin once the vaccines reach market.
The strategy for assessing how the earliest vaccines perform beyond the confines of a clinical trial setting includes leveraging existing surveillance and data platforms, harmonizing methods and combining similar platforms, and employing a diversity of study approaches given the inherent limitations with observational studies, said CDC medical epidemiologist Jennifer Verani.
In an 18 September presentation at a two-day FDA virtual workshop on use of real-world evidence for assessing vaccine effectiveness, Verani discussed the prospects for using real-world data to fill in evidentiary gaps in the effectiveness of COVID-19 vaccines and to inform policy development as more vaccine candidates reach market and more doses become available.
'Urgent Need' For Effectiveness Data
Vaccine candidates from Moderna, Inc., Pfizer Inc., AstraZeneca PLC and Johnson & Johnson are all in Phase III trials in the US. Pfizer appears to be the furthest ahead and could have safety and effectiveness data to support an emergency use authorization request in October. (Also see "Pfizer Appears Slightly Ahead Of Moderna In COVID-19 Vaccine Race" - Pink Sheet, 17 Sep, 2020.)
As soon as a vaccine becomes available under either EUA or a biologics license application approval, there will be an “urgent need” for data on vaccine effectiveness, said Verani, who is part of the vaccine effectiveness team in the CDC’s COVID-19 vaccine planning unit.
A vaccine’s real-world performance can vary from that in the clinical trial setting for a host of reasons, including delayed administration of the second dose for multi-dose vaccines, burdensome cold chain requirements expected for some products, and underlying medical conditions of vaccinated individuals, she said.
In addition, there will be gaps in the clinical trial data available at the time of EUA or licensure that RWE can help supplement, particularly as regards outcomes and subpopulations.
While data from vaccine effectiveness studies must be timely and accurate to guide vaccine policy, there is a need to prioritize and focus on the information that will be most useful for guiding policy, she said.
Verani showed a schematic matrix in which the highest priority areas are represented by a star, with the empty boxes representing areas where data are desired but not with the same level of urgency. The “not prioritized” boxes reflect areas in which data would be nice to have but will not be essential for guiding policy.
Among the highest priority areas for initial real-world effectiveness studies will be how well a vaccine protects against symptomatic illness among the initial groups that receive the vaccine, such as health care workers and other essential workers, in addition to how well it prevents severe illness in the elderly and long-term care facility residents.
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This schematic continues to evolve because discussions about prioritization during the earliest phase of vaccine rollout are still ongoing and the CDC continues to get expert input on the most relevant data to inform policy, Verani said. (Also see "COVID Vaccine Distribution Plan From National Academies Leaves Room For Adjustments Based On Trial Results" - Pink Sheet, 1 Sep, 2020.)
Leveraging Existing Platforms
The CDC and other government agencies plan to leverage existing surveillance data and platforms whenever possible to facilitate rapid launch of COVID-19 vaccine effectiveness studies, Verani said, adding: “We do not want to be recreating the wheel in the era of warp speed.”
The most obvious platforms that could be leveraged for such studies are the existing networks for evaluating seasonal influenza vaccine effectiveness, because they were designed with similar objectives in mind and would require the least modification, Verani said.
Testing for the novel coronavirus began in the flu surveillance network just as the seasonal flu season reached its annual peak in the US earlier this year. (Also see "Coronavirus Surveillance Expected To Rely On Existing Flu Network Without Much Strain" - Pink Sheet, 4 Mar, 2020.)
Other platforms that potentially could be leveraged include:
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COVID-19 disease surveillance;
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SARS-CoV-2 epidemiology cohorts;
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Electronic health record databases;
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Claims databases; and
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Serial serosurveys.
Potential Studies Designs For COVID-19 VE Studies
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Cohort – Follow a cohort including vaccinated and unvaccinated individuals and compare rates of outcomes; can be prospectively designed or retrospectively use electronic databases.
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Conventional Case-Control – Enroll COVID-19 cases and controls from the same source population and compare vaccination status.
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Test-Negative Design (TND) Case-Control – Enroll and test patients with acute respiratory infection; compare vaccination of SARS-CoV-2-positive cases with “test negative” controls
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Screening Method – Compares vaccine coverage in cases with that of source population
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Ecologic Analyses – Assess associations between vaccination and disease at group, rather than individual, level.
Researchers in various government agencies – including the CDC, FDA, Department of Defense and Indian Health Service – also are striving to harmonize methods across platforms because having consistent case definitions, variables and analytic methods will improve the comparability of results from different studies, Verani said.
“Whenever feasible and scientifically sound, we are also trying to combine similar platforms. Doing so will improve the geographic representation of the studies, increase the statistical power and help us generate a more timely and robust VE estimate.”
The CDC and other government agencies are planning to use a diversity of epidemiological approaches because all observational studies have their limitations, Verani said. (See box.)
The list of currently planned COVID-19 VE research projects includes a combination of studies that involve prospective data collection as well as electronic cohort analyses to address what are considered to be the priority data needs, Verani said.
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Priority Focus |
Prospective Data Collection |
Electronic Cohort Analyses |
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Immediate Priority |
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Does vaccine work as expected? |
Test-negative design (TND) among health care workers
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Subsequent Priorities |
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Severe disease |
TND plus facility controls among adults
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Electronic health record (EHR) cohorts for adults (CDC, VA, FDA)
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Non-severe disease |
TND plus facility controls among adults
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EHR cohorts for adults |
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Infection (transmission) |
Composite cohort for adults
New community COVID-19 VE cohort adults (pending funding)
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Elderly (including long-term care facility residents) |
Conventional case-control among 65+ years
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CMS cohort for 65+ years and for LTCF residents; EHR cohorts for adults |
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Individuals with key underlying medical conditions |
*Severe disease and elderly prospective studies designed to have sufficient power |
CMS; EHR cohorts for adults |
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Key race/ethnicity groups |
*Severe disease and elderly prospective studies designed to have sufficient power |
CMS; EHR cohorts for adults |
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Source: CDC medical epidemiologist Jennifer Verani’s slides at the FDA’s 18 September workshop on Considerations for the Use of Real-World Evidence to Assess the Effectiveness of Preventive Vaccines |
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Additional COVID-19 VE Studies In Planning Phase
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Screening method using disease surveillance platforms and COVID-19 Vaccine Administration and Management System (VAMS) |
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Analysis of National Healthcare Safety Network data on long-term care facility residents |
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Ecologic analyses of disease surveillance data and/or serial serosurvey data in conjunction with vaccination coverage |
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Studies in Native American/Alaska Native populations
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Studies in pregnant women |
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Studies in children |
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Source: CDC medical epidemiologist Jennifer Verani’s slides at the FDA’s 18 September workshop |
Vaccination And Behavior
Speakers at the FDA meeting discussed a host of challenges and potentially confounding factors inherent in conducting COVID VE studies, some of which will be universal to all studies regardless of the methodological design.
“The biggest threat in my mind … is that vaccination may correlate with risk of disease independently of vaccination,” Verani said. “People who choose to get vaccinated may also adopt other preventive behaviors, such as mask use or social distancing, that would decrease their risk of disease independent of vaccination and lead to an inflated VE estimate.”
"Alternatively, people who get vaccinated may engage in more risky behavior because they feel protected, which could potentially bias the VE estimate toward the null,” she said.
Link Reimbursement To Product Identification
Given the potential for simultaneous availability of multiple vaccines, there needs to be a way to reliably identify the specific vaccine given to a specific individual in the datasets used for VE studies, several speakers said.
“We will not be able to do these studies well if there is not appropriate product-specific coding,” Verani said.
“A technical challenge could be identifying the product-specific vaccine in real-world data,” said Kourtney Davis, senior director and head, therapy area matrix, global epidemiology at Janssen R&D LLC.
Davis said there should be product-specific Current Procedural Terminology (CPT) codes available at the time of vaccine authorization, “and also some kind of a mandate for those to be used in the claims for reimbursement so we make sure we’re always capturing those exposures.”
“A technical challenge could be identifying the product-specific vaccine in real-world data” - Janssen's Kourtney Davis
The Trump Administration has said it is working to ensure that no American has to pay any money out of pocket to receive the vaccine, but that costs for administering the vaccine would be reimbursed by government programs and private insurers. (Also see "Reimbursement Challenges Await COVID-19 Vaccines Given Emergency Use Authorization" - Pink Sheet, 21 Sep, 2020.)
The FDA and Centers for Medicare and Medicaid Services are trying to ensure that reimbursement to a provider or pharmacy for administering the vaccine is linked to identification of the specific product used, said Hector Izurieta, associate director for novel clinical investigations at the FDA Center for Biologics Evaluation and Research’s Office of Vaccine Review and Research.
If such a system were to be in place, the process of administering the vaccine would be reimbursed only if the pharmacy or provider used National Drug Codes to identify the vaccine administered, Izurieta said. “That’s absolutely essential under the assumption that more than one vaccine would be available at the same time.”
The CDC’s interim playbook for local and state implementation of COVID-19 vaccination programs emphasizes the need to leverage technology, including through common IT infrastructure known as a “data lake,” to ensure accurate identification of the first vaccine dose and timely administration of the second for multi-dose vaccines. (Also see "COVID-19 Vaccines: US Distribution Plans Include ‘Data Lake’ For Centralized Tracking" - Pink Sheet, 16 Sep, 2020.)
Vaccine product, lot number and manufacturer identity are among the data elements that immunization information systems must report to the CDC, the interim playbook states.
In addition, for vaccines authorized under an EUA, a two-dimensional bar code that will be available on the vaccine carton, and also on the vials for some vaccines, will include the NDC and lot number. Each vaccine manufacturer also will include a Quick Response code on the vaccine carton for accessing FDA-authorized, product-specific EUA fact sheets.