FDA Approaches to Demonstrate Vaccine Effectiveness
J. N. Roberts
US Food and Drug Administration, Silver Spring, MD
Abstract not available
Adaptive Study Designs for Evaluation of New Vaccines
N. E. Dean
University of Florida, Gainesville, FL
Describe several novel strategies for incorporating flexibility into vaccine efficacy trials to improve study power and support regulatory decision-making
The standard paradigm for assessing the efficacy of new vaccines is to implement an individually randomized controlled trial at several preselected sites. As future disease incidence at these sites is unpredictable, in some settings this approach can have poor statistical power. Large vaccine trials may accrue few or even no cases that can be used to measure vaccine efficacy. This challenge is especially acute for emerging infectious diseases that cause limited and variable outbreaks. A potential solution is to use adaptive trial protocols that do not predefine the eligible trial population. Such an approach was successfully implemented during the West African Ebola epidemic. In Guinea, a Phase 3 trial of rVSV-ZEBOV used a cluster-randomized “ring vaccination” design where clusters were contacts and contacts of contacts of new confirmed Ebola cases. This trial provided key evidence of high vaccine efficacy used to support the product’s regulatory approval. This presentation will describe the state of the art in the design of flexible vaccine efficacy trials, with a focus on emerging infectious diseases. The first key strategy is to generalize the ring vaccination design to include other types of responsively defined populations. The second key strategy is to use high-resolution, individual-level stochastic disease models to predict areas of future transmission and inform trial planning. The third key strategy is to adopt a master protocol that accumulates data across multiple outbreaks. Finally, where randomized controlled trials are not feasible and regulatory approval is achieved through other pathways, we discuss the use of observational studies to assess vaccine effectiveness. We focus on the test negative design as an appealing low-cost approach. The combined purpose of these strategies is to enable the collection of the high quality vaccine efficacy data needed to make important public health decisions.
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Approaches to Demonstrate Influenza Vaccine Effectiveness: Real World Evidence
A. M. Fry
Centers for Disease Control and Prevention, Atlanta, GA
Describe the test negative case control design for estimating vaccine effectiveness and the advantages and disadvantages of this methodology
Annual influenza vaccination is recommended for persons 6 months and older in the United States. Ongoing genetic evolution of circulating human influenza viruses, two influenza A subtypes and two influenza B lineages, require frequent updates to vaccine viruses and the need for annual vaccination. Vaccination of almost all age groups each year and the availability of many different vaccine type choices adds complexity to influenza public health programs. Thus, annual influenza vaccine effectiveness estimates are useful to understand the impact of the vaccine on reducing influenza-associated illness burden and to inform future vaccine strain selection and policy. The Centers for Disease Control and Prevention collaborates with academic partners to monitor vaccine effectiveness each season by vaccine component and for all age groups. The US Influenza Vaccine Effectiveness Network prospectively enrolls patients from >50 ambulatory care settings and performs research influenza PCR testing on respiratory specimens. Using a test negative design, vaccine effectiveness is determined by comparing odds of testing influenza-positive among vaccinated versus unvaccinated participants. The test negative design allows subtype and lineage-specific vaccine effectiveness estimates in near real time, at the end of the season as well as interim estimates early in the season. Test negative case controls studies are also used to estimate vaccine effectiveness against laboratory-confirmed influenza-associated hospitalization. This presentation will discuss strengths and limitations of current methods and future directions.
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