Vaccines Require Real-time Surveillance To Yield Actionable Data

In the past, monitoring the safety of vaccines – which generally are administered to large populations of healthy people – was restricted to passive postmarket surveillance through spontaneous adverse event reporting. However, in light of new vaccines being developed to avoid potential pandemics, the importance of evolving active surveillance methods has grown.

For example, government authorities and vaccine manufacturers were seeking enhanced surveillance as they rolled out a vaccine to prevent the occurrence of H1N1 influenza. The H1N1 flu vaccine was administered to a variety of populations and to a substantial healthy population, but its development was based on mock-ups and only limited clinical trial information was available. There is a need for more intense postapproval safety surveillance to identify and evaluate safety signals proactively, according to i3 Drug Safety Chief Scientist K. Arnold Chan, M.D., Sc.D.

“When vaccines are new to the marketplace, we need to determine right away whether adverse events are occurring, whether they can be scientifically linked to the vaccine, and whether any emerging risks outweigh the benefits of the product,” Chan said. “Spontaneous adverse event reporting can detect certain safety signals, but there are limitations.”

Moving toward faster safety assessment

To address these limitations, the U.S. federal government is laying the groundwork for a surveillance program that provides faster safety results for all medical products. In 2007, Congress passed The FDA Amendments Act, which mandated that a “Sentinel System” of active postmarket safety surveillance and analysis be established to monitor safety signals for approved medical products and set a goal of access to data from 25 million individuals by July 1, 2010, and 100 million individuals by July 1, 2012.

Government authorities also are taking action with regard to vaccine-specific surveillance. In July 2009, the U.S. Food and Drug Administration (FDA) published a briefing document for H1N1 flu vaccines, stating an expectation for collecting additional safety and effectiveness data post-approval.¹ The European Medicines Agency (EMEA) updated its pandemic influenza vaccine risk-management guidance to include substantial postmarket safety surveillance requirements, including monitoring of both immunocompromised subjects and pregnant women as well as surveillance of adverse events of special interest, which include Guillain-Barré syndrome, neuritis, convulsions, anaphylaxis, encephalitis, vasculitis, Bell’s Palsy, demyelinating disorders and lab-confirmed vaccine failure.²

The U.S. Centers for Disease Control and Prevention (CDC) also has established a surveillance effort that is tailored to vaccines. The Vaccine Safety Datalink (VSD) project is a collaborative effort between the CDC’s Immunization Safety Office and eight managed care organizations.³ The VSD project was established in 1990 to monitor immunization safety and address the gaps in scientific knowledge about rare and serious events following immunization; several years ago, Project staff started using an active surveillance system designed to detect adverse events (possible side effects) following vaccination in near real time.⁴

The VSD Project is using data from approximately 9 million lives, but timely identification of vaccine adverse events when an influenza pandemic is predicted “may require a substantially larger population base, particularly for rare AEs,” according to an article published in Medical Care late last year.⁵

The article’s authors – which included i3 Drug Safety’s Chan and Najat Ziyadeh – assessed the feasibility of using health care claims data to rapidly detect influenza vaccine AEs using sequential analytic methods. The study’s findings suggest that a bigger database of administrative claims data than that available in the VSD project might allow same-season vaccine safety surveillance in large, defined U.S. populations.⁶

Speeding up process will lead to timelier response

To explore this hypothesis further, i3 Drug Safety is in the process of conducting an internal study, using its own linked claims/lab/consumer information database to evaluate in real time the occurrence of 14 possible vaccine side effects of the H1N1 flu vaccine since it became available in the United States. Using individuals receiving the seasonal flu vaccine as a comparison group, i3 is following those vaccinated with the H1N1 flu vaccine and identifying claims with diagnoses codes for specific designated medical events on a daily basis.

Interim results of the observational study are expected soon, Chan said, stating that reductions in processing time for this study come in part from use of i3’s Early Access (EA) system, which facilitates early identification and assessment of targeted safety issues of concern by analyzing health insurance claims data as they are submitted. “i3 EA captures medical claims in a large insured population in near real time, which can help our clients monitor the frequency of targeted safety issues,” he explained. “Through the automated assessment of health care encounters on a daily basis, results are available with a lag time of mere days from the encounter that generated the claim.”

After collecting sufficient data about the H1N1 vaccine, i3 Drug Safety experts “will analyze the data in a statistically rigorous manner and submit it to a scientific journal for peer review,” Chan said, adding that what i3 brings to the table is not just the size of its database or its technology, but the expertise to set up appropriate queries and interpret signals correctly.

H1N1 scenario provides good example

“The H1N1 flu vaccine was one of the largest field applications of a vaccine in such a short period of time worldwide,” he noted. “i3 Drug Safety understands the enormous challenge in monitoring the safety of this vaccine, and we are conducting our own study because we want to contribute to the public health by helping to reduce delays in the surveillance system.”

Analysis of how the H1N1 flu vaccine was handled may provide some insights into how the process can be improved by more rapid safety assessment. In the United States, the largely successful management of the H1N1 flu vaccine approval and administration was based partly on good decision making and partly on luck, according to a recent article in The New York Times.⁷ In that article, the author states that although “the virus and the vaccine cooperated,” H1N1 “highlighted many national weaknesses,” including “old, slow vaccine technology.”

Chan remarked that improvements can and should be made to vaccine AE monitoring, especially in finding ways to achieve early access to the information. “Although passive adverse event reporting may provide the numerator in a risk-benefit equation, it does not provide the denominator,” he said. “Having both the numerator and the denominator will allow public health officials to better assess safety signals and make safety recommendations in real time.”

Any lessons learned from H1N1 flu surveillance will shape future approaches to vaccines and other new drugs developed to respond to potential public health crises. “There certainly is a trend at the government level to try to uncover problems with new medical products in the postmarket phase in less time than it is taking under the passive surveillance system,” Chan concluded. “Companies will have to keep up with that trend and should be seeking out ways to obtain actionable adverse event data more quickly. With comprehensive data, scientific expertise and analytics tools, i3 Safety can help them get there.”

¹http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/
BloodVaccinesandOtherBiologics/VaccinesandRelatedBiologicalProductsAdvisoryCommittee/
UCM172424.pdf

² http://www.ema.europa.eu/pdfs/human/pandemicinfluenza/
PandemicVaccines_Q&A_46147609en.pdf

³Centers for Disease Control and Prevention, “Vaccine Safety Datalink (VSD) Project,” CDC Web Site (accessed Jan. 21, 2010).

⁴ Id.

⁵ Brown, Jeffrey S, PhD; Moore, Kristen M., MPH; Braun, M. Miles, MD, MPH; Ziyadeh, Najat, MA, MPH; Chan, K. Arnold, MD, ScD; Lee, Grace M., MD, MPH; Kulldorff, Martin, PhD; Walker, Alexander M., MD, DrPH; and Platt, Richard, MD, MSc; “Active Influenza Vaccine Safety Surveillance: Potential Within a Healthcare Claims Environment,” Medical Care, Vol. 47, No.11 (November 2009).

⁶ Id.

⁷ McNeil, Donald G., Jr.; “U.S. Reaction to Swine Flu: Apt and Lucky,” The New York Times (Jan. 2, 2010).

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