Black Box Warnings and Drug Safety: Examining the Determinants and Timing of FDA Warning Labels

Abstract

ABSTRACT Comparing the safety of prescription drugs over time is difficult due to the paucity of reliablequantitative measures of drug safety. Both the acad emic literature and popular press have focusedon drug withdrawals as a proxy for breakdowns in th e drug safety system. This metric, however, isproblematic because withdrawals are rare events , and they may be influenced by factors beyond adrug's safety profile. In the current paper, we propose a new measure: the incidence and timing ofBlack Box Warnings (BBWs). BBWs are warnings placed on prescription drug labels when a drugis determined to carry a significant risk of a serious or life-threatening adverse event. Using a uniquedata set, one that includes all new molecular entities (NMEs) submitted to the FDA between May1981 and February 2006, and subsequently approved and marketed, we analyze the timing andincidence of BBWs. Our analyses also use data on several drug characteristics likely to affect theprobability a new drug will receive a BBW. We draw several conclusions from our analyses. Forexample, drugs receiving priority FDA review are more likely to have BBWs at the time of approvalthan NMEs receiving standard review. We also find that early prescription volume and orphan drugstatus are associated with an increased like lihood of receiving a BBW. We do not, however, find asignificant difference in the rate of BBWs across time cohorts. A comparison of NMEs approvedbefore and after the 1992 Prescription Drug User Fee Act (PDUFA), which authorized the paymentof user fees from drug manufacturers to the FDA in an effort to expedite new drug application(NDAs) review times, did not reveal a statistically significant difference in the rate of BBWs. Criticsof PDUFA maintain that reduced FDA-approval times under PDUFA have compromised drugsafety. We do not find empirical support for this contention. Allan BegoshSuite 15-36Office of the CommissionerFood and Drug Administration5600 Fishers LaneRockville, MD 20857allan.begosh@FDA.govJohn GoldsmithSuite 15-36Office of the CommissionerFood and Drug Administration5600 Fishers LaneRockville, MD 20857jcgoldsm@erols.comEd HassSuite 15-36Office of the CommissionerU.S. Food and Drug Administration5600 Fishers LaneEd.Hass@FDA.HHS.GOVRandall W. LutterSuite 15-36Office of the CommissionerFood and Drug Administration5600 Fishers LaneRockville, MD 20857Rlutter@oc.fda.govClark NardinelliSuite 15-36Office of the CommissionerFood and Drug Administration5600 Fishers LaneRockville, Maryland 20857Clark.Nardinelli@FDA.HHS.GOVJohn A. VernonUniversity of ConnecticutDepartment of Finance2100 Hillside RoadStorrs, CT 06269Office of the Commissioner, US FDAand NBERjvernon@business.uc