The emergence of pandemic H1N1 influenza virus in early 2009 prompted the rapid licensure and use of H1N1 monovalent inactivated (MIV) and live, attenuated (LAMV) vaccines separate from seasonal trivalent inactivated (TIV) and live, attenuated (LAIV) influenza vaccines. A robust influenza immunization program in the U.S. requires ongoing monitoring of potential adverse events associated with vaccination.
To prospectively conduct safety monitoring of H1N1 and seasonal influenza vaccines during the 2009-2010 season.
The Vaccine Safety Datalink (VSD) Project monitors ∼9.2 million members in eight U.S. medical care organizations. Electronic data on vaccines and pre-specified adverse events were updated and analyzed weekly for signal detection from November 2009 to April 2010 using either a self-controlled design or a current versus historical comparison. Statistical signals were further evaluated using alternative approaches to identify temporal clusters and to control for time-varying confounders.
As of May 1, 2010, a total of 1,345,663 MIV, 267,715 LAMV, 2,741,150 TIV, and 157,838 LAIV doses were administered in VSD. No significant associations were noted during sequential analyses for Guillain-Barré syndrome, most other neurologic outcomes, and allergic and cardiac events. For MIV, a statistical signal was observed for Bell's palsy for adults aged ≥25 years on March 31, 2010, using the self-controlled approach. Subsequent analyses revealed no significant temporal cluster. Case-centered logistic regression adjusting for seasonality demonstrated an OR for Bell's palsy of 1.26 (95% CI=0.97, 1.63).
No major safety problems following H1N1 or seasonal influenza vaccines were detected in the 2009-2010 season in weekly sequential analyses. Seasonality likely contributed to the Bell's palsy signal following MIV. Prospective safety monitoring followed by rigorous signal refinement is critical to inform decision-making by regulatory and public health agencies.
[Show abstract][Hide abstract] ABSTRACT: Many challenges arise when conducting a sequentially monitored medical product safety surveillance evaluation using observational electronic data captured during routine care. We review existing sequential approaches for potential use in this setting, including a continuous sequential testing method that has been utilized within the Vaccine Safety Datalink (VSD) and group sequential methods, which are used widely in randomized clinical trials.
Using both simulated data and preliminary data from an ongoing VSD evaluation, we discuss key sequential design considerations, including sample size and duration of surveillance, shape of the signaling threshold, and frequency of interim testing.
All designs control the overall Type 1 error rate across all tests performed, but each yields different tradeoffs between the probability and timing of true and false positive signals. Designs tailored to monitor efficacy outcomes in clinical trials have been well studied, but less consideration has been given to optimizing design choices for observational safety settings, where the hypotheses, population, prevalence and severity of the outcomes, implications of signaling, and costs of false positive and negative findings are very different. Analytic challenges include confounding, missing and partially accrued data, high misclassification rates for outcomes presumptively defined using diagnostic codes, and unpredictable changes in dynamically accessed data over time (e.g., differential product uptake). Many of these factors influence the variability of the adverse events under evaluation and, in turn, the probability of committing a Type 1 error. Thus, to ensure proper Type 1 error control, planned sequential thresholds should be adjusted over time to account for these issues.
Pharmacoepidemiology and Drug Safety 01/2012; 21 Suppl 1(S1):62-71. DOI:10.1002/pds.2324 · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bacterial and viral infections have been shown to induce relapses and accelerate the progression of multiple sclerosis (MS). Vaccination to prevent communicable disease in such patients is, therefore, of key importance. Reports of potentially detrimental effects of immunization on the course of MS, however, have prompted patients and physicians to adopt a cautious attitude towards the use of vaccines. The risks associated with a number of vaccines have been investigated in patients with MS. Vaccines against some diseases, such as tetanus and hepatitis B, are not associated with an elevated risk of MS exacerbation, whereas vaccines against other diseases, such as yellow fever, are contraindicated in patients with MS. Many patients with MS receive immunosuppressive or immunomodulatory therapy, which could make them more susceptible to infectious diseases and might also affect their ability to respond to immunization. Here, we review the indications for and possible adverse effects of vaccines in patients with MS, and address issues of vaccination in the context of immunomodulatory therapy for MS.
[Show abstract][Hide abstract] ABSTRACT: In fall 2010 in the southern hemisphere, an increased risk of febrile seizures was noted in young children in Australia in the 24 h after receipt of trivalent inactivated influenza vaccine (TIV) manufactured by CSL Biotherapies. Although the CSL TIV vaccine was not recommended for use in young children in the US, during the 2010-2011 influenza season near real-time surveillance was conducted for febrile seizures in the 0-1 days following first dose TIV in a cohort of 206,174 vaccinated children ages 6 through 59 months in the Vaccine Safety Datalink Project. On a weekly basis, surveillance was conducted with the primary approach of a self-controlled risk interval design and the secondary approach of a current vs. historical vaccinee design. Sequential statistical methods were employed to account for repeated analyses of accumulating data. Signals for seizures based on computerized data were identified in mid November 2010 using a current vs. historical design and in late December 2010 using a self-controlled risk interval design. Further signal evaluation was conducted with chart-confirmed febrile seizure cases using only data from the primary approach (i.e. self-controlled risk interval design). The magnitude of the incidence rate ratio and risk difference comparing risk of seizures in the 0-1 days vs. 14-20 days following TIV differed by receipt of concomitant 13-valent pneumococcal conjugate vaccine (PCV13). Among children 6-59 months of age, the incidence rate ratio (IRR) for TIV adjusted for concomitant PCV13 was 2.4 (95% CI 1.2, 4.7) while the IRR for PCV13 adjusted for concomitant TIV was 2.5 (95% CI 1.3, 4.7). The IRR for concomitant TIV and PCV13 was 5.9 (95% CI 3.1, 11.3). Risk difference estimates varied by age due to the varying baseline risk for seizures in young children, with the highest estimates occurring at 16 months (12.5 per 100,000 doses for TIV without concomitant PCV13, 13.7 per 100,000 doses for PCV13 without concomitant TIV, and 44.9 per 100,000 doses for concomitant TIV and PCV13) and the lowest estimates occurring at 59 months (1.1 per 100,000 doses for TIV without concomitant PCV13, 1.2 per 100,000 doses for PCV13 without concomitant TIV, and 4.0 per 100,000 doses for concomitant TIV and PCV13). Incidence rate ratio and risk difference estimates were lower for children receiving TIV without concomitant PCV13 or PCV13 without concomitant TIV. Because of the importance of preventing influenza and pneumococcal infections and associated complications, our findings should be placed in a benefit-risk framework to ensure that population health benefits are maximized.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.