Sentinel to Transform Drug Development and Oversight

FDA is modernizing adverse-event reporting as part of a revolution in drug-safety assessment.
Aug 02, 2008
Volume 32, Issue 8

Jill Wechsler
The US Food and Drug Administration has launched the Sentinel Initiative to expand and improve medical-product risk identification and evaluation. This program aims to implement a provision in the FDA Amendments Act of 2007 (FDAAA) that requires the agency to establish an "active postmarket safety surveillance and analysis" system. Instead of depending on passive, unreliable adverse-event reports sent to FDA by doctors and pharmacists, the agency should detect safety signals much more quickly through links to databases that contain health information on millions of patients.

FDAAA instructs FDA to establish a system that accesses multiple information sources, providing safety data on 25 million patients by 2010 and 100 million by 2012. This expanded drug-safety assessment program, dubbed the Sentinel System, also will collect more adverse-event (AE) reports from health professionals, provide effective analysis of health information, and enhance FDA methods for communicating new safety information to providers and patients. "We may be entering a new era for determining how drugs should be used on the market," commented Mark McClellan, former FDA commissioner and Medicare chief, now at the Brookings Institution, where he chaired a June 2008 forum on postmarket evidence.

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This shift to active postmarket surveillance promises to have a broad impact on biomedical research and drug development; an improved understanding of how drugs affect patients in real-world settings can inform drug discovery. This approach creates an opportunity to use the delivery of healthcare as a discovery platform, said FDA Commissioner Andrew von Eschenbach at the Brookings forum. Garry Neil, Johnson and Johnson's corporate vice-president, predicted that this development can "revolutionize the entire healthcare system." Bringing information about how drugs affect people back to discovery, he explained, will support new medical products that are more effective, safer, and less costly than older products.

McClellan further explained at the June 2008 annual meeting of the Drug Information Association (DIA) that an active postmarket surveillance system reflects a move away from distinct pre-and postmarket regulatory processes and toward a life-cycle approach to drug development and regulation. Rising FDA concerns about drug safety are "not just a pendulum swing," he said, but reflect higher public expectations about drug safety over the longterm.

Modernizing AERS

The development of a fully active postmarket surveillance system is still years away. FDA is "just getting started" on this major epidemiological piece of FDAAA, said Sandra Kweder, deputy director of the Center for Drug Evaluation and Research's (CDER) Office of New Drugs. Meanwhile, FDA is implementing the Sentinel System in stages, building on existing systems and public–private partnerships that can answer questions about apparent drug side effects.

An important step is to modernize and expand the agency's current spontaneous adverse-event reporting system (AERS). The system collects AE reports from health professionals and the public, who voluntarily file information on drug-related medical problems. Although passive reporting fails to capture many AEs or explain the cause of medical events or the extent of exposure, it is useful for detecting signals and for developing hypotheses about rare but serious safety issues.

FDA is working to improve methods for assessing the reports it receives through this system and to boost voluntary reporting. In March 2008, the agency issued a five-year drug-safety plan, as required by the newly revised drug user-fee program (PDUFA IV). The plan describes how the agency will improve the timeliness and accuracy of AE data. To boost voluntary reporting, FDA is collaborating with the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) on standards and 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 the aggregation and analysis of AE information.

FDA also plans to combine safety-signal detection and analysis for drugs, medical devices and other regulated products through an agency-wide FDA adverse-event reporting system (FAERS). And a user-friendly MedWatch Plus portal will allow anyone (e.g., healthcare providers, patients, and clinical researchers) to electronically report adverse events on all regulated medical products.

Although still voluntary, these initiatives will help FDA collect timely, accurate AE data, pointed out Armando Oliva, deputy director for bioinformatics in FDA's Office of Critical Path Programs, at the DIA annual meeting. More standardized data and better analytical tools will enable FDA to improve safety assessments. "Spontaneous reporting won't vanish," said Janet Woodcock, director of CDER, at the Brookings forum. But it will be conducted more efficiently than before and linked to broader analytical resources.

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