INCREASING UNDERSTANDING OF ENHANCED INFLUENZA VACCINE PRODUCTS IN LONG-TERM CARE SETTINGS
Real-World Evidence: What It Says About Enhanced In uenza Vaccine Products
Real-world evidence is derived from the analysis of data from electronic medical records, medical claims and billing data, information from product and disease registries, patient-generated data, and data gathered by personal devices and health applications.
Data collected for real-world evidence, which often come from clinical practice and medical records, are useful for verifying the safety and e cacy of enhanced in uenza vaccine products. Real-world evidence also provides insights and expands understanding of how these products a ect health at the population level.
When medications and biological agents such as vaccines reach the market, the U.S. Food and Drug Administration has already reviewed e cacy and safety data and approved the products for general use. Yet many of the studies used to obtain this approval exclude older adults and, more speci cally, residents of long-term care facilities.
To compensate for this exclusion, researchers use data-mining techniques to study the real-world use of vaccines and other agents. Large databases contain electronic medical records, medical claims and billing data, information from product and disease registries, patient-generated data (sometimes from home settings), and data gathered by personal devices and health applications. Studies can be randomized trials (e.g., large simple trials, pragmatic clinical trials) or observational studies, conducted either retrospectively or prospectively.1-3
Identifying Real-World Data on Enhanced In uenza Vaccines
Bias is a primary threat to the validity of real-world studies. In vaccine studies, it is di cult to identify groups of patients and compare them because people who have chosen not to be vaccinated may also be less likely to present for medical care when they are ill. This creates selection bias. If comparisons are made with patients who have other conditions requiring routine medical care, they cannot be assumed to be “similar” to those with in uenza. Patients presenting with in uenza-like illness (ILI) who have pathogens other than the in uenza virus often recover on their own and can be lost to follow-up thereby increasing the bias in results.
The test-negative case–control study was adopted for vaccine e ectiveness research in recent years to overcome many of these concerns. As depicted in Figure 1 on the next page, eligibility for study inclusion is simply presentation with ILI. This assures similarity among those included in the analysis. All patients presenting with ILI and agreeing to be in the study are tested for in uenza. Those testing positive become the “cases,” while those with negative test results become the “controls.”
Through patient interviews, reviews of medical records, or searches in immunization information systems, researchers determine who received the seasonal in uenza vaccine for that year, when those patients were vaccinated, and which vaccine they received. No one is lost to follow-up because all data are collected at the incident visit. Percentages are calculated to determine vaccine e ectiveness and statistical tests are used to assess signi cance and determine con dence intervals.4
The Centers for Disease Control and Prevention (CDC) uses a test-negative design in several networks to estimate vaccine e ectiveness, including the U.S. Flu Vaccine E ectiveness Network and the Hospitalized Adult In uenza Vaccine E ectiveness Network (HAIVEN). Sites across the country participate in these networks through contracts with CDC, and many of these sites also participate in industry-sponsored research.
Real-World Evidence: Evaluating Enhanced In uenza Vaccines
Several studies illustrate other ways in which real-world evidence is used to compare e ectiveness of enhanced in uenza vaccines with standard formulations. When research on in uenza is conducted in long-term care facilities, a cluster-randomized design is often used to clearly identify the e ects of di erent vaccines on the individual as well as “herd” e ects, such as reduced person-to-person spread.
Real-world studies of enhanced in uenza vaccines include the following:
The trivalent version of the high-dose enhanced in uenza vaccine produced signi cantly higher antibody levels and better protection against laborator y-con rmed in uenza illness, compared with the standard-dose trivalent vaccine, in a randomized, double-blind, active-controlled trial of 31,989 adults aged 65 years or older.5
The high-dose enhanced in uenza vaccine reduced respiratory-related hospital admissions compared with the standard-dose product during the 2013–14 in uenza season. The study included residents aged 65 years or older in 823 nursing homes cluster-randomized to either the high-dose or standard-dose vaccine.6
During the 2016–17 in uenza season, an enhanced vaccine lowered all-cause hospitalizations by 6% and hospitalizations for in uenza and pneumonia by 20% among 50,012 nursing home residents aged 65 years or older, compared with a standard trivalent in uenza vaccine, in a cluster-randomized study.7
Resources
Figure 1. Test-Negative Design for Evaluating In uenza Vaccine E ectiveness
Patients present with in uenza-like illness during in uenza season
Cases test positive for in uenza
Controls test negative for in uenza
1. Sherman RE, Anderson SA, Dal Pan GJ, et al. Real-world evidence—what is it and what can it tell us? N Engl J Med. 2016;375(23):2293–2297.
2. U.S. Food and Drug Administration. Framework for FDA’s Real-World Evidence Program. December 2018. Available at: https://www.fda.gov/media/120060/download. Accessed May 18, 2020.
3. U.S. Food and Drug Administration. Submitting documents using real-world data and real-world evidence to the Food and Drug Administration for drugs and biologics; draft guidance for industry; availability. May 9, 2019. Available at: https://www.federalregister.gov/documents/2019/05/09/2019-09529/submitting-documents-using-real-world-data-and-real-world-evidence-to-the-food-an d-drug. Accessed May 18, 2020.
4. Fukushima W, Hirota Y. Basic principles of test-negative design in evaluating influenza vaccine effectiveness. Vaccine. 2017;35(36):4796–4800.
5. DiazGranados CA, Dunning AJ, Kimmel M, et al. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med. 2014;371(7):635–645.
6. Gravenstein S, Davidson HE, Taljaard M, et al. Comparative effectiveness of high-dose versus standard-dose influenza vaccination on numbers of US nursing home residents admitted to hospital: a cluster-randomised trial. Lancet Respir Med. 2017;5(9):738–746.
7. Gravenstein S, Davidson HE, McConeghy K, et al. Effectiveness of adjuvanted vs. non-adjuvanted influenza vaccine in U.S. nursing homes. Presented at: National Foundation for Infectious Diseases 2019 Clinical Vaccinology Course; November 2019; Washington, DC.