Evaluation of Pre-marketing Factors to Predict Post-marketing Boxed Warnings and Safety Withdrawals

Abstract

Although drugs approved with a boxed warning or priority review are more likely to experience serious post-marketing safety events, other information provided during the FDA drug review that is easy to quantify is generally not associated with post-marketing safety events. It appears that these post-marketing events are not discernible during a pre-marketing review and therefore might not be avoidable using current review data.

New and incremental FDA black box warnings from 2008 to 2015

“…simultaneous addition of a fatal toxicity and a drug-drug interaction), we classified the update as major. This approach was consistent with a recent study by FDA authors investigating pre-marketing factors associated with postmarketing BBWs and safety withdrawals [10]. All BBWs were reviewed and classified by one author (MTS), and all cases of uncertainty were reviewed by at least one additional author (JSR and/or SSD).…”

“…Drugs approved with a BBW are more likely to receive an incremental BBW after FDA approval, and post-marketing BBWs may be issued many years after initial regulatory approval [2,10]. Indeed, initial FDA regulatory approval was granted before 1992 for a substantial number of the drugs receiving new BBWs and major updates in our sample.…”

Old Drugs, New Concerns

“…8 In a similar study, about 20% of serious safety actions were related to rare events. 9 Surprisingly, the number of patients in clinical trials was not associated with the frequency of serious post-marketing safety actions. However, drugs that were approved with initial boxed warnings or those with priority review status were strongly associated with a subsequent boxed warning.…”

“…that occur following FDA-approval for novel drugs. 8,9 Downing et al analyzed over 200 drugs that had been on the market for a median of 12 years and found that post-marketing safety actions were associated with about one-third of the drugs, occurring at a median of 4 years following drug approval. 8 The types of drugs more likely to be associated with safety events included biologicals and psychiatric drugs.…”

“…However, drugs that were approved with initial boxed warnings or those with priority review status were strongly associated with a subsequent boxed warning. 9 A striking example of an older drug class associated with numerous "late" emerging safety concerns, is the flouroquinolone class of antibiotics that includes 6 FDAapproved agents (e.g. ciprofloxacin, levofloxacin).…”