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Real-Time Surveillance

Marco Hoekendijk and Arnold Chan at i3 Drug Safety highlight the importance of active post-market surveillance to identify potential adverse side effects of new medicines and vaccines

In the past, monitoring the safety of vaccines – which are generally administered to large populations of healthy people – was restricted to passive post-market surveillance through spontaneous reporting of advense events (AEs) or side effects. However, in light of new vaccines being developed to avoid potential pandemics, the importance of evolving more active surveillance methods has grown.

When vaccines are new to the marketplace, there is a need to determine quickly if any AEs are occurring (whether or not they can be linked scientifically to the vaccine) and if any emerging risks outweigh the benefits of the product. Spontaneous AE reporting can detect certain safety signals, but there are limitations to this approach.

For example, government authorities and vaccine manufacturers were seeking enhanced surveillance as they rolled out a vaccine to prevent the occurrence of the H1N1 influenza virus. The H1N1 flu vaccine was administered to a variety of populations, and to a substantially healthy population. But its development was based on mock-ups, and only limited clinical trial information was available. This highlights the need for more intense post-approval safety surveillance methods to identify and evaluate safety signals proactively.


To address these limitations, the US federal government is laying the groundwork for a surveillance programme that provides faster safety results for all medical products. In 2007, the US Congress passed the FDA Amendments Act, which mandated that a ‘Sentinel System’ of active post-market 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 1st July 2010, and 100 million individuals by 1st July 2012.

Government authorities are also taking action with regards to vaccine-specific surveillance. In July 2009, the 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 post-market safety surveillance requirements. This included monitoring of both immunocompromised subjects and pregnant women, as well as surveillance of AEs of special interest, which include Guillain- Barré syndrome, neuritis, convulsions, anaphylaxis, encephalitis, vasculitis, Bell’s Palsy, demyelinating disorders and lab-confirmed vaccine failure (2).

Safety Decisions

The EMEA recognised that only limited data on safety of H1N1 vaccines would be available when they were administered to the public. Clinical trials are relatively small in size and very rare side effects might not be identified until the vaccines have been used on a wide scale in large numbers of people. Clinical trials typically exclude high risk groups, such as pregnant women, children and patients with co-morbidity. In addition, longer-term safety data would not be available and associations with very rare conditions could only be ruled out by careful postmarketing surveillance. This is always the case with new vaccines and medicines in general at the time of their introduction. H1N1 vaccine post-marketing surveillance was therefore crucial and the EMEA looked for several ways to speed up the risk-benefit evaluation of the vaccines and risk management. The routine spontaneous pharmacovigilance system within EU member states would continue, and reports would be sent as usual to the EMEA Eudravigilance database. In addition, manufacturers were required to send simplified periodic safety update reports (PSURs) to the EMEA and a vaccine safety monitoring programme was set up.

European countries united in the Vaccine Adverse Event Surveillance and Communication (VAESCO) consortium and coordinated by the Brighton Collaboration set up a common vaccine safety monitoring programme through linkage of large computerised clinical databases and immunisation registries. An important aspect of the analysis of spontaneous AE reporting and data from clinical studies is the collection of background information on the incidence of AEs of special interest (AESIs) and important expected AEs (6). The vaccine safety data linkage system is being used to develop age- and sex-specific background incidence data on rare and more common AEs that could possibly be related to the administration of vaccines. This, together with the submission of simplified PSURs, allows for an appropriate risk-benefit evaluation of H1N1 vaccines and risk management. These are usually required on a sixmonth basis, but simplified PSURs have been reduced to monthly reporting, which allows for a much faster identification of potential safety issues.

The US Centers for Disease Control and Prevention (CDC) has also 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 organisations (3). The VSD project was established in 1990 to monitor immunisation safety and address the gaps in scientific knowledge about rare and serious events following immunisation. Several years ago, project staff started using an active surveillance system designed to detect AEs following vaccination in near real-time (3). The VSD project collects data from approximately 9 million patients, but timely identification of vaccine AEs when an influenza pandemic is predicted “may require a substantially larger population base, particularly for rare AEs,” according to Brown et al (4).

One particular study has assessed the feasibility of using healthcare 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 US populations (4).


To explore this hypothesis further, internal studies are currently being conducted, using a combination of linked claims, lab and consumer information databases to evaluate in real-time the occurrence of 14 possible vaccine side effects of the H1N1 vaccine since it became available in the US. Using individuals receiving the seasonal flu vaccine as a comparison group, the study 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. Reductions in processing time for this study come in part from use of a ‘fast-track access’ system (FTA) which facilitates early identification and assessment of targeted safety issues of concern by analysing health insurance claims data as they are submitted. The FTA system captures medical claims in a large insured population in near real-time, which can help clients monitor the frequency of targeted safety issues. Through the automated assessment of healthcare encounters on a daily basis, results are available with a lag time of mere days from the encounter that generated the claim.


The H1N1 flu vaccine was perhaps the largest field application of a vaccine in such a short period of time worldwide. Monitoring the safety of the vaccine provides an enormous challenge and an opportunity 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 insights into how the process can be improved by more rapid safety assessment. The largely successful management of the H1N1 flu vaccine approval and administration in the US was partly based on good decisionmaking, and partly on luck, according to a recent article (5). The author states that although “the virus and the vaccine cooperated,” H1N1 “highlighted many national weaknesses,” including “old, slow vaccine technology”.

Improvements can and should be made to vaccine AE monitoring, especially in finding ways to achieve early access to the information. Although passive AE reporting may provide the numerator in a risk-benefit equation, it does not provide the denominator. 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. The trend at the government level is to uncover problems with new medical products in the post-market phase in less time than it is taking under the passive surveillance system. Companies will have to keep up with that trend and should be seeking out ways to get actionable AE data more quickly.


  1. FDA Center for Biologics Evaluation and Research Office of Vaccine Research and Review: Regulatory Considerations Regarding the Use of Novel Influenza A (H1N1) Vaccine, 23rd July 2009, soryCommittees/CommitteesMeeti ngMaterials/BloodVaccinesandOth erBiologics/VaccinesandRelatedBi ologicalProductsAdvisoryCommitte e/UCM172424.pdf
  2. The European Medicines Agency, Questions and Answers on Vaccines for the H1N1 Pandemic, 24 July 2009, man/pandemicinfluenza/Pandemi cVaccines_Q&A_46147609en.pdf
  3. Centers for Disease Control and Prevention, ‘Vaccine Safety Datalink (VSD) Project’, accessed 21 Jan, 2010
  4. Brown JS, Moore KM, Braun MM, Ziyadeh N, Chan KA MD, Lee GM Kulldorff M, Walker AM and Platt R, Active Influenza Vaccine Safety Surveillance: Potential Within a Healthcare Claims Environment, Medical Care 47(11), November 2009
  5. McNeil DG, US Reaction to Swine Flu: Apt and Lucky, The New York Times, accessed 2 Jan, 2010
  6. European Medicines Agency, European Strategy for Influenza A/H1N1 Vaccine Benefit-Risk Monitoring

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Marco Hoekendijk is a Senior Medical Director at i3 Drug Safety. Prior to joining i3, he was Associate Director, Global Drug Safety, for Schering Plough in the Netherlands. There he had various responsibilities related to both post-marketing and clinical research safety surveillance. He has also worked as a clinical research physician on numerous clinical trials.

Arnold Chan is a pharmacoepidemiologist whose research has focused on drug, device and vaccine safety, utilisation and efficacy. He directs i3 Aperio, which tracks newly approved prescription drugs use in the real-world to provide stakeholders with information on potential safety issues. Prior to joining i3, he was director of the pharmacoepidemiology programme at the Harvard School of Public Health and published more than 100 articles and book chapters. He is also co-editor of Pharmacoepidemiology and Therapeutic Risk Management.

Marco Hoekendijk
Arnold Chan
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