FDA Looks To Mini-Sentinel Again For Answers On Seasonal Flu Vaccine Safety

New study will assess risk of febrile seizures following administration with inactivated influenza vaccine, with or without Pfizer's pneumococcal vaccine Prevnar 13, in young children.

FDA's Center for Biologics Evaluation and Research is once again turning to the Mini-Sentinel post-marketing surveillance system to assess the risks of febrile seizures in children following immunization with seasonal influenza vaccine.

The study will be a protocol-based assessment of the risk of febrile seizures following inactivated influenza vaccination with or without concomitant administration of Pfizer Inc.'s Prevnar 13 (pneumococcal 13-valent conjugate vaccine, PCV13) during the 2013-2014 and 2014-2015 flu seasons among children ages 6 months through 23 months.

The study will evaluate a statistical signal for seizures seen in an earlier Mini-Sentinel sequential analysis.

The study's objective will be to evaluate the statistical signal for seizures after concomitant influenza and Prevnar 13 vaccination that was identified in an earlier Mini-Sentinel sequential analysis, according to the draft protocol, which is open for comment until Sept. 25.

Mini-Sentinel is a pilot project of FDA's Sentinel Initiative, an active surveillance system that allows for monitoring of drug and biologic safety issues through electronic health care data from multiple sources, including payers.

The proposed study marks the third time in the last few years that the Mini-Sentinel program has been called upon to investigate concerns about a possible link between seasonal influenza vaccination and febrile seizures.

Previous Studies …

In 2010, an increased risk of febrile seizures was seen in Australian children ages six months to four years old following vaccination with CSL Ltd.'s trivalent, inactivated influenza vaccine. Those findings led FDA to update the warning and precautions section of labeling for CSL's Afluria, the antigenically equivalent vaccine manufactured for the US market, and to change the approved use from individuals six months and older to those five years and older.

In January 2011, FDA reported its Vaccines Adverse Event Reporting System (VAERS) had received an increased number of reports of febrile seizures following vaccination with Sanofi's trivalent inactivated influenza vaccine Fluzone. The Centers for Disease Control and Prevention's Vaccine Safety Datalink also identified an increased risk of seizures following trivalent inactivated influenza vaccination after adjusting for concomitant use of Prevnar 13.

Prevnar 13 is approved for use in children ages 6 months to 17 years old and in adults 50 years and older.

FDA initiated a study through the Mini-Sentinel Postlicensure Rapid Immunization Safety Monitoring (PRISM) program to further investigate febrile seizures after vaccination with Fluzone and other inactivated influenza vaccines in children younger than five years of age during the 2010-2011 influenza season.

That study, results of which were announced in May 2014, found no evidence of a statistically significant elevated risk of febrile seizures following vaccination with trivalent inactivated influenza vaccine, Prevnar 13 or diphtheria/tetanus/acellular pertussis vaccine (Also see "In Brief: Bristol’s Nivolumab Shows Survival, Boehringer Gains A Breakthrough & Sentinel Takes On Flu Vaccines, Plus CHMP Opinions" - Pink Sheet, 30 Jun, 2014.).

There also was no evidence to suggest that same-day vaccination with seasonal influenza vaccine and Prevnar 13 increased the risk of seizures compared to separate-day vaccination.

However, a subsequent Mini-Sentinel study that used a prospective sequential analysis found a statistical signal for increased seizure risk in children ages 6-23 months who received trivalent or quadrivalent inactivated influenza vaccine with concomitant Prevnar 13 in the 2013-2014 season, as compared to influenza vaccine recipients from historical seasons prior to widespread use of the pneumococcal vaccine (Also see "FDA’s Influenza Watchword For 2015 Is Speed" - Pink Sheet, 11 May, 2015.).

Given the lack of data on the risk of seizures in Prevnar 13 recipients who did not receive inactivated influenza vaccine, the PRISM prospective surveillance study was unable to determine whether the signal, if real, was due entirely to Prevnar 13 or some interaction with the seasonal influenza vaccine.

… Raise Questions For New Analysis

The current study seeks to evaluate the statistical signal seen in the current-versus-historical sequential analysis of the 2013-2014 flu season.

The analysis will use Mini-Sentinel electronic data from two surveillance seasons that had the same inactivated influenza vaccine formulation. The study will use a self-controlled risk interval design to minimize confounding, the protocol states.

"Our comparison will be of the risk in exposed vs. unexposed time from the same vaccinees rather than of the risk in exposed time of vaccinees in the seasons of interest vs. of different vaccinees in historical seasons," the protocol states. "By using data from two seasons combined, we will increase power. This study will also provide insight into the role of PCV13 vaccination in generating the 2013-14 statistical signal by collecting information on the risk of febrile seizures among those who received only the PCV13 vaccine."

The proposed data partners for the study are HealthCore, Aetna Inc., Optum and Humana Inc. The population will consist of children ages 6-23 months who were: members of any of the participating data partners between July 1, 2013 and June 30, 2015; received a dose of inactivated influenza vaccine or Prevnar 13; and were enrolled in medical coverage from 180 days prior to vaccination through 20 days after vaccination.

During the period of interest, Sanofi's Fluzone and Fluzone Quadrivalent were the only inactivated influenza vaccines approved for children ages 6-23 months in the US. Consequently, any dose of age-appropriate Fluzone or a generic code for influenza vaccination will be counted as an exposure.

Two other Mini-Sentinel studies involving seasonal influenza vaccine safety are ongoing.

A final report from a study on influenza vaccines and pregnancy outcomes is targeted for Spring 2016, while a report related to birth outcomes is expected in Fall 2016.

Prevnar 13 And Kawasaki Disease

Mini-Sentinel also is planning to examine the association between Prevnar 13 vaccination and Kawasaki disease.

The study objectives include determining the existence and magnitude of any increased risk of Kawasaki disease in the 28 days following Prevnar 13 vaccination and, if an excess risk is found, exploring the role of concomitant vaccines.

Kawasaki disease is an acute, self-limited vasculitis and is the leading cause of acquired heart disease in children in the US.

Post-licensure surveillance of Prevnar 13 through the Vaccine Safety Datalink revealed an increased risk of Kawasaki disease with Prevnar 13 compared to Prevnar 7, although this finding did not reach the level of statistical significance.

An FDA 18-month, post-marketing safety evaluation required under the FDA Amendments Act identified reports of Kawasaki disease with Prevnar 13 in VAERS, although the proportion of reports was similar to that for other vaccines, according to FDA slides presented at a Sept. 16 meeting of the agency's Pediatric Advisory Committee.

The study will include infants and children, exposed or unexposed to Prevnar 13, from birth until 23.99 months of age who were members of participating data partners during 2008-2015, according to the draft protocol, which is open for public comment until Sept. 29.