Drug Safety and Shortages Challenge Manufacturers

As drug shortages make headlines, FDA tets the Sentinel safety system and its effect on healthcare
Mar 01, 2011
Volume 24, Issue 3

Jill Wechsler
A prime objective of FDA policies is to ensure the safety of the nation's drug supply, a task that entails calculating risks and preventing harm. The recent emergence of serious side effects associated with Roche/Genentech's Avastin (bevacizumab) prompted FDA to re-evaluate the risks and benefits associated with this cancer therapy and ultimately to recommend rescinding the drug's indication to treat breast cancer. That decision generated an outcry from patients who believe the therapy is saving lives.

Similar situations for patients and physicians arise from inadequate supplies of crucial drugs due to manufacturing difficulties, supply-chain problems, and regulatory actions. More effective adverse-event reports and databases may help patients avoid unsafe therapies in the future. Methods for accessing and evaluating this type of information are advancing rapidly, but require considerable research on appropriate assessment techniques and communications strategies. In the future, such data analysis may help healthcare providers and payers assess comparative treatments and quality of care, and also support clinical trials for new medical therapies.


Faster information about drug-safety problems is the goal of FDA's Sentinel surveillance system for detecting adverse-drug events. As required by the FDA Amendments Act of 2007 (FDAAA), Sentinel augments FDA's passive adverse-event reporting system by accessing electronic drug-use information held independently by private health plans and government health programs [see the March 2010 Washington Report in BioPharm International]. While this idea sounds fairly straightforward, it's a complex undertaking that involves linking diverse databases and establishing standard analytical methods that can detect and assess resulting safety signals.

As a prelude to a fully operational real-time safety monitoring system, FDA has established a Mini-Sentinel pilot program to meet the FDAAA requirement to access data on at least 100 million individuals by July 1, 2012. The agency exceeded its first mandated goal for Sentinel in July 2010 by tapping into drug-use information on more than 25 million patients. These accomplishments and how leaders of the Sentinel Initiative have laid the groundwork for the system during the past two years were discussed at a January workshop organized by the Brookings Institute and at the Drug Information Association's January 2011 pharmacovigilance conference.

Now the program is moving forward with plans to test scientific methods for further investigating specific drug use issues, explained Judy Racoosin, scientific lead for Sentinel in FDA's Center for Drug Evaluation and Research (CDER). A Coordinating Center operated by Richard Platt of the Harvard Pilgrim Health Care Institute has been established to send queries to databases operated by Kaiser Permanente, Aetna, Partners Healthcare, and Humana, among others, and then evaluate resulting responses. FDA also has formed a drug surveillance collaboration with other federal agencies, including the Centers for Medicare and Medicaid Services, the Veterans Administration, and the Department of Defense, to query these health databanks on safety issues of mutual interest.

The project has established basic principles and policies, including a Common Data Model and core safety surveillance methods. Researchers have examined which regression methods are applicable for sequential surveillance programs and have identified Health Outcomes of Interest that deserve evaluation. Because the Sentinel Initiative involves public health activities, as opposed to research, the query and analysis process does not require institutional review board approval to proceed.

A key feature of this distributed data system is that patient health information remains with the data holders, an approach designed to ensure the privacy and security of personal health information. While the system currently taps into administrative and claims data, a goal is to add clinical data in the future, at least for some patient cohorts. For now, data holders may be asked to provide certain patient-level information if needed to followup on unclear findings, but that data would be stripped of direct patient identifiers before transmission.

This year, the Mini-Sentinel pilot is testing several protocols to see how well the system can evaluate emerging safety concerns. One initiative will assess whether certain postmarketing regulatory initiatives, such as risk evaluation and mitigation strategies (REMS) can enhance the safe use of medicines. Another project is monitoring adverse events associated with four relatively new, but routinely administered vaccines. An extensive study examining adverse cardiological events in users of diabetes drugs will compare the incidence of myocardial infarction in patients prescribed saxagliptin (Bristol-Myers Squibb's Onglyza) to those taking other diabetes treatments to demonstrate how well Sentinel can monitor drug safety in large populations.

These studies can use some of the findings of the Observational Medical Outcomes Partnership (OMOP), a collaboration between industry, FDA, and the Foundation for the NIH. OMOP is conducting research on how well different methods and data sources can identify valid safety signals and whether meaningful information can be gleaned from disparate observational data sources that use a wide variety of terms.

The program has identified important technical, organizational, and resource capabilities of a successful active surveillance site and ways to assess the strength of associations between drug exposure and specific adverse events, such as liver failure or bleeding. OMOP's success in identifying methods and tools through an open, collaborative process has prompted the participants to extend the partnership beyond its initial two-year timeframe and to expand from drug safety issues to methods that could apply to medical devices and biologics, plus approaches for comparative effectiveness resarch (CER) and healthcare quality measures.

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