Postmarketing drug safety surveillance is a challenging and vital component of contemporary medical practice. Obtaining new information about the benefits and risks of a medication should not stop after market authorization, and it has become increasingly clear that the risk profile cannot be fully elucidated via the current approval process. Highly publicized postmarketing crises, including the increased cardiovascular risk with COX-2 inhibitors, 1 heart failure with rosiglitazone, 2 increased risk of suicide in children and adolescents taking selective serotonin reuptake inhibitors (SSRIs), 3 and most recently, increased cardiovascular death with azithromycin, 4 have raised awareness of the shortcomings of the the Food and Drug Administration’s (FDA’s) Adverse Event Reporting System (AERS), a database for storing and analyzing safety reports. 5, 6 Mining clinical databases for health outcomes provides an effective tool for mitigating these various risks, for discovering patient subpopulations that experience increased efficacy or unanticipated delayed adverse effects, and for uncovering drug interactions that typically are not examined in traditional randomized controlled trials. In this commentary, we highlight the challenges of identifying risk in the current approval process and offer steps the FDA can take to realize continuous learning and improvement as described in the Institute of Medicine’s recent report on achieving best care at lower cost. 7 We believe the FDA can foster new cross-disciplinary partnerships that leverage the growing amount of electronic clinical data to design an early-warning system that targets risks associated with the areas generating the most costs. A new active surveillance system can be used not simply to identify contraindications but to educate the medical community on real risks and to target subpopulations of patients for whom certain drugs are more beneficial or more harmful. Examination of a drug’s postapproval risk profile began in 1952 when the FDA instituted voluntary reporting of adverse events pursuant to bone marrow suppression seen with chloramphenicol. Little changed with the process until 1993, when the FDA instituted MedWatch, a program for both health care professionals and the public to report adverse effects of drugs and medical devices. AERS, a database used to compile and analyze adverse events and medication error reports, was introduced in 1998. To this point, many of the methods to evaluate postapproval drug safety surveillance were dependent on the voluntary reporting of adverse events by health care practitioners, patients, and companies. This changed in September 2007 with the Food and Drug Administration Amendments Act, which gave the FDA the authority to compel manufacturers to conduct postapproval safety studies, and formalized the Risk Evaluation and Mitigation Strategies program. The most recent initiative undertaken by the FDA, Sentinel, seeks to identify safety concerns more proactively through the use of administrative claims and pharmacy dispensing data, expanding in the future to include inpatient electronic health records and registries.

A medication that is studied in 5–10 thousand patients in a controlled environment may not identify rare adverse reactions, and is likely to underrepresent the myriad variables (age, comorbidities, other medications, clinical context) that the larger population who may be exposed to the drug will have, potentially interacting with the drug and with each other. Many times, these unaccounted variables play a considerable role in the side effect profile of a given medication, and thus may alter the risk-benefit of a given pharmaceutical …