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Safety surveillance to transform drug development and oversight


FDA has launched the Sentinel Initiative to expand and improve medical product risk detection and evaluation. Instead of relying on passive, voluntary adverse event (AE) reports sent to FDA by physicians and pharmacists, the agency would be able to detect safety signals much more quickly through links to health information databases containing information about millions of patients.

Key Points

FDA has launched the Sentinel Initiative to expand and improve medical product risk detection and evaluation. Instead of relying on passive, voluntary adverse event (AE) reports sent to FDA by physicians and pharmacists, the agency would be able to detect safety signals much more quickly through links to health information databases containing information about millions of patients.

The FDA Amendments Act (FDAAA) instructs FDA to establish a system that can access pharmacy data on 25 million patients by 2010 and 100 million patients by 2012. This expanded drug safety assessment program, dubbed the Sentinel System, is expected to generate more AE reporting by health professionals and more effective analysis of health information. A related goal is to enhance FDA methods for communicating new safety information to providers and patients.

"The pieces are in place to do this now," observed Mark B. McClellan, MD, PhD, former FDA commissioner and Medicare chief, now at the Brookings Institute, at the June annual meeting of the Drug Information Association (DIA). He described the push for active postmarket surveillance as part of broader public interest in knowing more about how prescription drugs are developed and used. Increasing FDA concerns about drug safety are "not just a pendulum swing," he said, but reflect higher public expectations about drug safety over the long run.

Although a fully active, real-time postmarket surveillance system will take years to develop, FDA has launched several initiatives to modernize and expand the agency's current spontaneous AE reporting system (AERS), which collects AE reports from health professionals when and if they detect drug-related medical problems. To make AE data more timely and accurate, FDA is supporting several initiatives to encourage more public reporting of safety issues related to medical products. Together with the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH), FDA has developed standards for a common format for reporting AEs for all FDA-regulated products. This approach will make it possible to link AE information from clinical studies with that from postmarket surveillance and will facilitate aggregation and analysis of this information.

FDA also is establishing an agency-wide AERS that will combine safety signal detection and analysis for drugs, medical devices and other regulated products. A user-friendly MedWatch Plus portal will allow anyone-healthcare providers, patients, or clinical researchers-to electronically report AEs on all regulated medical products. FDA also is exploring new mechanisms for detecting AE signals and for analyzing the AE data the agency collects.

"Spontaneous reporting won't vanish," commented Janet Woodcock, MD, director of the Center for Drug Evaluation and Research (CDER), at a June 2008 forum on postmarket evidence at the Brookings Institution. It will, however, be conducted more efficiently and will be linked to much broader resources.


While FDA improves its spontaneous AERS, it is expanding its ability to build a national, integrated, electronic system for monitoring medical product safety that is maintained and controlled by private health plans, insurance plans, government agencies, and medical product manufacturers. The Sentinel System will access these existing electronic databases through a distributed information network.

FDA has been laying the foundation for such a system that can evaluate different aspects of medical product safety and performance through partnerships and collaborations with these healthcare "data owners." FDA uses this approach to formulate safety questions for health systems to evaluate and pick up early warnings of AEs through electronic health records, claims databases, and other information sources. This system allows all of the personal medical data to remain behind firewalls, reducing concerns about patient privacy and data security.

FDA has contracted for several years with UnitedHealth Group's Ingenix, Vanderbilt University, Kaiser Foundation Research Institute, Harvard Pilgrim Health Care, and others to access pharmacoepidemiologic information so the agency can test hypotheses arising from AE reports. FDA's Center for Biologics Evaluation and Research (CBER) works with the CDC, the Veterans Health Administration (VHA), the Centers for Medicare and Medicaid Services (CMS), and large health plans to monitor influenza vaccine use and related outcomes. A new CMS policy now gives FDA access to 1 billion pharmacy claims per year that are generated from the Part D Medicare drug benefit program. The ability to tap into this information source promises to greatly expand FDA postmarket surveillance and enhance appropriate drug use.


To move forward, FDA is working with health plans and database operators to establish a charter that defines:

The partnership also may conduct research into best practices and methods and to establish standards for postmarket assessment. There is a need for new models for data aggregation that protect patient privacy while allowing FDA to be able to trace back to individual cases when necessary. FDA also seeks improved statistical methods to sort out causality from large information databases in order to distinguish meaningful signals.


This shift to more active postmarket surveillance promises, moreover, to have a broad effect on biomedical research and drug development based on improved understanding of how drugs affect patients in real-world settings. Postmarket information will enable researchers to use the delivery of healthcare as a discovery platform, commented FDA commissioner Andrew von Eschenbach, MD, at the Brookings forum. FDA is not implementing the Sentinel System "solely because Congress told us to," Dr von Eschenbach asserted. "FDA must, will, and needs to do this."

An active postmarket surveillance system can support FDA approval of NDAs. If the regulators have confidence that safety problems will be identified quickly and efficiently after a drug goes to market, they may be more willing to approve a market application for a product that raises some risk concerns. Postmarket assessment may put to rest concerns about the safety of a new drug or vaccine that are raised in prelicensure studies, observed CBER director Jesse Goodman, MD, MPH, at a press briefing. "The data can cut both ways," he commented.

More efficient postmarket surveillance also may reduce FDA demands for extensive phase 4 studies and rely more on active surveillance to uncover safety problems. Pharmaceutical marketers are nervous that more analysis of postmarket data will yield false negatives that set off alarms for every new drug. But FDA officials believe the Sentinel System will enhance drug monitoring and may even reduce the need for some postmarketing studies. "We're moving from an era where drug companies controlled phase 4," said Dr McClellan, observing that other information sources are becoming more important in identifying safety issues than clinical studies sponsored by manufacturers.


Although the ultimate goal is to create a system that can generate safety signals in real-time, FDA will start with queries on known drug side effects. In the future, there may be links among various databases and registries; however, transferring data from healthcare organizations to FDA would raise additional privacy issues and would require a higher level of patient consent and transparency up front. "This could be something for the future," Dr Woodcock said. "We would not do this from the start, but don't want to rule it out."

Effective communication about safety signals from interim results will be a challenge, as will efforts to sufficiently support and sustain what will be a costly undertaking.

More active surveillance based on electronic medical records (EMRs) will require more attention to ensuring patient privacy and data security. It also will require attention to liability concerns of health plans providing access to patient data. Current privacy laws permit FDA to access health information data for public health purposes, and it may be possible for the agency to delegate that authority to partners in a drug safety surveillance program. The Government Accountability Office (GAO) will be reporting to Congress next year on FDA's ability to ensure the privacy, confidentiality, and security of patient information in establishing an active postmarket risk identification and analysis system.

Ms Wechsler is a Washington-based reporter specializing in federal and state healthcare issues.

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