Safety of Newly Approved Drugs
Authors: Robert J. Temple, Martin H. Himmel
Journal: JAMA (2002)

IN THIS ISSUE OF THE JOURNAL, LASSER AND COLLEAGUES 1 examine the timing and nature of the black box warnings added to labeling, as reflected in the Physicians’ Desk Reference, and of removal of drugs from the market to address the question of whether clinicians should hesitate to prescribe new drugs that may have unrecognized adverse drug reactions (ADRs). Premarketing trials in a few thousand (usually relatively uncomplicated) patients do not detect all of a drug’s adverse effects, especially relatively rare ones. Frequent postmarketing labeling changes are therefore inevitable and should be anticipated. Sometimes the new information is so important it fundamentally changes the place of the drug in therapy (eg, leads to second-line status) and sometimes the postmarketing discoveries cause the drug to be withdrawn. Examining the appearance of black box warnings and withdrawals is a reasonable way to seek out the most important new ADRs, so that their implications can be considered. Use of the Physicians’ Desk Reference to determine the timing of the labeling change is convenient, but does not give an accurate measure; this approach inevitably overestimates the delay between marketing and the labeling event because the Physicians’ Desk Reference cannot change between editions, while labeling does change. Although the Physicians’ Desk Reference is a widely used reference, important labeling changes are often communicated to physicians by “Dear Health Care Professional” letters, and, once in labeling, the black box warning appears prominently in drug promotion materials. The use of the Physicians’ Desk Reference to estimate time of black box warning appearance will make the warnings added early in the life of the drug seem more delayed than they were but will not greatly affect the warnings added late (TABLE). Lasser et al found a total of 56 drugs approved between 1975 and 1999 that acquired a black box warning or were removed from the market. That represents 10% of the 548 new chemical entities approved during that period. Their Kaplan-Meier analysis suggests a 20% ultimate risk of withdrawal or black box warning, but this rate is at least debatable, as the earlier detection of ADRs in recent years may mean fewer late discoveries. Clearly, physicians and patients should be aware that recently marketed drugs are at risk of being found to cause unsuspected serious adverse effects. But how often do such findings affect prescribing as opposed to inducing more careful or more fully aware use? To answer this question, it is worth looking more closely at the ADRs that resulted in black box warnings or withdrawals. In the study by Lasser et al, of the 45 drugs in their Table 1 and 16 drugs in their Table 2 (total 56 because 5 had a box warning and were also withdrawn) that received a black box warning or were withdrawn, several points should be noted. First, 7 labeling changes were related solely to the results of the Cardiac Arrhythmia Suppression Trial (CAST), including the 3 type 1C antiarrhythmic agents (flecainide acetate, encainide hydrochloride, moricizine) studied in the trial as well as 4 drugs not evaluated in the trial (disopyramide phosphate, mexiletine hydrochloride, bepridil hydrochloride, propafenone hydrochloride) with type 1 antiarrhythmic properties (tocainide hydrochloride also acquired this warning) that were relabeled because of a general reconsideration of the use of antiarrhythmics for non–lifethreatening ventricular arrhythmias. None of these drugs (including encainide) was withdrawn because of this finding, and flecainide acetate and moricizine continue to be marketed for certain uses. Moreover, none of the drugs had ever had the claim of postinfarction suppression of largely asymptomatic ventricular premature beats that was studied in CAST. While CAST was a seminal event in the use of antiarrhythmics, the study was not the usual means used for postmarketing discovery of ADRs. Indeed, most of the drugs relabeled were not even in CAST, and the new warning applied to all antiarrhythmics, such as quinidine gluconate and quinidine sulfate and procainamide hydrochloride, not just the newer ones. Second, 2 labeling changes (atenolol and metoprolol) reflected appropriate concern with abrupt withdrawal of