FDA Seeks Active System for Monitoring Adverse Events

The US Food and Drug Administration is overhauling how it identifies and evaluates safety issues related to drugs and biologics, as required by provisions in the FDA Amendments Act (FDAAA). The legislation instructs FDA to establish a system that can access drug safety data on 25 million patients by 2010 and 100 million by 2012. Instead of relying on passive, unreliable adverse event reports sent to the FDA by doctors and pharmacists, the agency will establish an active postmarket safety surveillance and analysis system that is able to detect safety signals much more quickly.

Jill Wechsler

This expanded pharmaceutical assessment program, dubbed the Sentinel System, also aims to generate more adverse event reporting by health professionals, to analyze health information more effectively, and to 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," said Mark McClellan, former FDA commissioner and Medicare chief, now at the Brookings Institution, where he chaired a June forum on postmarket evidence.

More active postmarket surveillance further promises to have a broad impact on biomedical research and drug development, as improved understanding of how drugs affect patients in realworld settings informs drug discovery. This creates an opportunity to use the delivery of healthcare as a discovery platform, commented FDA Commissioner Andrew von Eschenbach at the Brookings forum. Johnson & Johnson Corporate Vice President Garry Neil predicted that this development can "revolutionize the entire healthcare system" by supporting new medical products that are more effective and safer and less costly.

McClellan further explained at the June 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 towards a lifecycle approach to drug development and regulation. Rising FDA concerns about drug safety are "not just a pendulum swing," he commented, but reflect higher public expectations about drug safety.

MODERNIZING AERS

One important component of the Sentinel System is a more modern and expanded FDA spontaneous adverse event reporting system (AERS). Although passive voluntary reporting fails to capture many events or to explain the cause of a medical problem, it is useful for detecting rare but serious safety signals. To boost voluntary reporting, the 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 adverse events for all FDA-regulated products. The FDA also plans to combine safety-signal detection and analysis for drugs, biologics, medical devices, and other regulated products into an agency-wide FDA adverse event reporting system (FAERS). And a user-friendly MedWatch Plus portal will allow anyone—healthcare providers, patients, clinical researchers—to electronically report adverse events on all regulated medical products.

"Spontaneous reporting won't vanish," said Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), at the Brookings forum. But it will be conducted more efficiently and linked to broader analytical resources.

DISTRIBUTED NETWORK

This expansion of AERS, though, will not lead to any giant FDA health information database for postmarket surveillance. Instead, FDA will expand its oversight capabilities by accessing data on drug use, patient outcomes, and specific safety issues held by private health plans, database operators, government agencies, and manufacturers. The aim is to build a national, integrated, electronic network for monitoring medical product safety through contracts and partnerships with these existing information sources. By using a distributed network, all the personal medical data remains behind firewalls, reducing concerns about the FDA compromising patient privacy and data security.

The FDA has been laying the foundation for the Sentinel System for years through such arrangements with healthcare "data owners" that permit it to pose specific questions for evaluation through electronic health records, claims databases, and other information sources. For example, the FDA has contracted for several years with UnitedHealth Group's Ingenix, Vanderbilt University, Kaiser Foundation Research Institute, and Harvard Pilgrim Health Care to access pharmacoepidemiologic information that can test hypotheses arising from AE reports.

The agency'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 one billion pharmacy claims a year collected by the Part D Medicare drug-benefit program, a treasure trove of pharmaceutical usage data. With additional funds to support postmarket safety surveillance, FDA plans to expand its access to CMS, VHA, and health plan databases to further expand its ability to detect and assess adverse events related to marketed therapies.

This distributed network system is expected to operate under a charter that defines which entities may join the public–private partnership, what data sources will be used, what queries can be run on the system, who will be able to run queries, how specific evaluations will be paid for, and how privacy protection will be ensured. A nonprofit network convener will channel information and queries to the partnership and determine how results will be communicated to network participants and to the general public.

Many of these administrative and policy issues will be examined by an active surveillance pilot sponsored by the Pharmaceutical Research and Manufacturers of America (PhRMA). After more than a year in development, the project is being launched as a public–private partnership involving PhRMA, the FDA, and the Foundation for NIH, with Woodcock as chair. The aim is to test approaches for organizing and operating a drug-safety query system using a distributed information network.

STREAMLINING RESEARCH

An important gain from a more efficient and proactive postmarket surveillance system will be to facilitate FDA approval of new drug applications. If the regulators have confidence that safety problems will be identified more quickly and appropriately after a drug goes to market, they may be more willing to approve a market application for a therapy that raises some risk concerns.

Biopharmaceutical manufacturers are nervous that earlier and broader assessment of postmarket data will yield false negatives that set off alarms on every new product. But FDA officials believe that enhanced drug monitoring may even reduce the need for some postmarketing studies. Instead of requiring manufacturers to sponsor a long list of postmarket clinical studies, FDA reviewers may call for six months or a year of database monitoring for certain anticipated safety concerns. Expanded 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; "The data can cut both ways."

Ultimately, it may be possible to monitor medical product safety through a national information network that connects clinicians, consumers, and providers across the healthcare system. A linked system would provide a broader picture of health problems and improve tracking of patients who shift healthcare providers, Woodcock commented at the Brookings forum. But that would raise privacy issues and require a higher level of consent and transparency, she noted "We would not do this to start," she said, "but we don't want to rule it out."

Effective communication about safety signals from interim results will be a challenge, as will efforts to provide adequate and sustained financial support for what will be a costly undertaking. But these are issues that the FDA and its Sentinel partners will address, as well as concerns related to scientific accuracy and data reliability, said von Eschenbach. FDA is not implementing the Sentinel System "solely because Congress told us to, but because it's the right thing to do," he asserted. "FDA must, will, and needs to do this."

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, jwechsler@advanstar.com