Comparison of alpha-spending plans for near real-time monitoring for Guillain-Barré Syndrome after influenza vaccination during the 2010/11 influenza season.

BACKGROUND: Near real-time surveillance of the influenza vaccine, which is administered to a large proportion of the US population every year, is essential to ensure safety of the vaccine. For efficient near real-time surveillance, it is key to select appropriate parameters such as monitoring start date, number of interim tests and a scheme for spending a pre-defined total alpha across the entire influenza season. Guillain-Barré Syndrome, shown to be associated with the 1976 influenza vaccine, is used to evaluate how choices of these parameters can affect whether or not a signal is detected and the time to signal. FDA has been monitoring for the risk of GBS after influenza vaccination for every influenza season since 2008. METHODS: Using Medicare administrative data and the Updating Sequential Probability Ratio Test methodology to account for claims delay, we evaluated a number of different alpha-spending plans by varying several parameters. RESULTS: For relative risks of 5 or greater, almost all alpha-spending plans have 100% power; however, for relative risks of 1.5 or lower, the constant and O'Brien-Fleming plans have increasingly more power. For RRs of 1.5 and greater, the Pocock plan signals earliest but would not signal at a RR of 1.25, as observed in prior influenza seasons. There were no remarkable differences across the different plans in regards to monitoring start dates defined by the number of vaccinations; reducing the number of interim tests improves performance only marginally. CONCLUSIONS: A constant alpha-spending plan appears to be robust, in terms of power and time to detect a signal, across a range of these parameters, including alternate monitoring start dates based on either cumulative vaccinations or GBS claims observed, frequency of monitoring, hypothetical relative risks, and vaccine uptake patterns.

Near real-time surveillance for Guillain-Barré syndrome after influenza vaccination among the Medicare population, 2010/11 to 2013/14.

BACKGROUND: Guillain-Barré syndrome (GBS) is a serious acute demyelinating disease that causes weakness and paralysis. The Food and Drug Administration (FDA) began collaborating with the Centers for Medicare and Medicaid Services (CMS) to develop near real-time vaccine safety surveillance capabilities in 2006 and has been monitoring for the risk of GBS after influenza vaccination for every influenza season since 2008. METHODS: We present results from the 2010/11 to 2013/14 influenza seasons using the Updating Sequential Probability Ratio Test (USPRT), with an overall 1-sided α of 0.05 apportioned equally using a constant alpha-spending plan among 20 consecutive weekly tests, 5 ad hoc tests, and a 26th final end of season test. Observed signals were investigated using the self-controlled risk interval (SCRI) design. RESULTS: Over 15 million people were vaccinated in each influenza season. In the 2010/11 influenza season, we observed an elevated GBS risk during the season, with an end of season SCRI analysis finding a nonsignificant increased risk (RR=1.25, 95% CI: 0.96-1.63). A sensitivity analysis applying the positive predictive value of the ICD-9 code for GBS from the 2009/10 season estimated a RR=1.98 (95% CI: 1.42-2.76). Although the 2010/11 influenza vaccine suggested an increased GBS risk, surveillance of the identical vaccine in the 2011/12 influenza season did not find an increased GBS risk after vaccination. No signal was observed in the subsequent three influenza seasons. CONCLUSIONS: Conducting near real-time surveillance using USPRT has proven to be an excellent method for near real-time GBS surveillance after influenza vaccination, as demonstrated by our surveillance efforts during the 2010/11-2013/14 influenza seasons. In the 2010/2011 influenza season, in addition to the 2009 H1N1 influenza pandemic, using near real-time surveillance we were able to observe a signal early in the influenza season and the method has now become routine.

Chart-confirmed guillain-barre syndrome after 2009 H1N1 influenza vaccination among the Medicare population, 2009-2010.

Given the increased risk of Guillain-Barré Syndrome (GBS) found with the 1976 swine influenza vaccine, both active surveillance and end-of-season analyses on chart-confirmed cases were performed across multiple US vaccine safety monitoring systems, including the Medicare system, to evaluate the association of GBS after 2009 monovalent H1N1 influenza vaccination. Medically reviewed cases consisted of H1N1-vaccinated Medicare beneficiaries who were hospitalized for GBS. These cases were then classified by using Brighton Collaboration diagnostic criteria. Thirty-one persons had Brighton level 1, 2, or 3 GBS or Fisher Syndrome, with symptom onset 1-119 days after vaccination. Self-controlled risk interval analyses estimated GBS risk within the 6-week period immediately following H1N1 vaccination compared with a later control period, with additional adjustment for seasonality. Our results showed an elevated risk of GBS with 2009 monovalent H1N1 vaccination (incidence rate ratio = 2.41, 95% confidence interval: 1.14, 5.11; attributable risk = 2.84 per million doses administered, 95% confidence interval: 0.21, 5.48). This observed risk was slightly higher than that seen with previous seasonal influenza vaccines; however, additional results that used a stricter case definition (Brighton level 1 or 2) were not statistically significant, and our ability to account for preceding respiratory/gastrointestinal illness was limited. Furthermore, the observed risk was substantially lower than that seen with the 1976 swine influenza vaccine.