Assessment of Quadrivalent Human Papillomavirus Vaccine Safety Using the Self-Controlled Tree-Temporal Scan Statistic Signal-Detection Method in the Sentinel System

Abstract

The self-controlled tree-temporal scan statistic—a new signal-detection method—can evaluate whether any of a wide variety of health outcomes are temporally associated with receipt of a specific vaccine, while adjusting for multiple testing. Neither health outcomes nor postvaccination potential periods of increased risk need be prespecified. Using US medical claims data in the Food and Drug Administration’s Sentinel system, we employed the method to evaluate adverse events occurring after receipt of quadrivalent human papillomavirus vaccine (4vHPV). Incident outcomes recorded in emergency department or inpatient settings within 56 days after first doses of 4vHPV received by 9- through 26.9-year-olds in 2006–2014 were identified using International Classification of Diseases, Ninth Revision, diagnosis codes and analyzed by pairing the new method with a standard hierarchical classification of diagnoses. On scanning diagnoses of 1.9 million 4vHPV recipients, 2 statistically significant categories of adverse events were found: cellulitis on days 2–3 after vaccination and “other complications of surgical and medical procedures” on days 1–3 after vaccination. Cellulitis is a known adverse event. Clinically informed investigation of electronic claims records of the patients with “other complications” did not suggest any previously unknown vaccine safety problem. Considering that thousands of potential short-term adverse events and hundreds of potential risk intervals were evaluated, these findings add significantly to the growing safety record of 4vHPV.

Defining the interval for monitoring potential adverse events following immunization (AEFIs) after receipt of live viral vectored vaccines

“…Given the large number of statistical tests done, adjustments for multiple testing are needed to minimize the number of false positive signals that would otherwise waste valuable time and resources needed for assessment of true signals. This hope is coming closer to fruition with the development of the just described RCA for pre-specified AESI 58,59 and TreeScan 60 (https://www.treescan.org/) for previously unspecified outcomes.…”

An Overview Of Vaccine Development, Approval, And Regulation, With Implications For COVID-19

“…32 W. Katherine Yih and colleagues used this approach to evaluate the quadrivalent human papillomavirus vaccine, and found only mild adverse reactions such as injection site rashes. 33 To complement the CDC post-market safety surveillance, the FDA uses data from the Centers for Medicare and Medicaid Services (CMS) and the FDA's Sentinel Post-Licensure Rapid Immunization Safety Monitoring (PRISM) system that was inaugurated during the 2009 H1N1 pandemic. 34 FDA is also setting up a new system based on commercial insurance claims data to replace or complement the FDA Sentinel PRISM system.…”

Vaccines After an Emergency Use Authorization (EUA): Modern Evidence Generation Approaches

“…Nature of statistical inference For AEs that occurs in near proximity to administration of the COVID19 vaccine, self-control methods may be used. For longer-term AEs, the choice of comparator, establishing the risk set will be required [ 23 ] 8.a Multiple statistical approaches are used, each with strengths and limitations 8.b There is no one approach that is a gold standard Process Considerations Implementation Considerations 9. Frequent meetings of experts in each region of the globe reviewing data, adjudicating signals and reporting their findings to other such expert groups globally 9.a Regulators have compared safety concerns for influenza vaccines so a precedent exists 9.b Regular communications and postings after each meeting for the public will be critical given the ambition to vaccinate most of the world’s population 10.…”