Correlates of Labeling Changes and Serious Safety Outcomes for New Molecular Entities (NMEs) Approved by the Food and Drug Administration (FDA)

Abstract

The Food and Drug Administration (FDA) monitors safety profiles of drugs through premarket evaluation and approval and continued postmarket surveillance; the latter aims to identify new drug safety outcomes not detected in premarket clinical trials, and to communicate the risks to healthcare providers and consumers through changes to the drug's label. Investigations of premarket characteristics, such drug review and approval times, approval pathways (e.g. priority review, breakthrough designation, fast track designation, and accelerated approval), and the use of a surrogate endpoint in the clinical trial, and their potential associations with postmarket safety outcomes can assist FDA in designing and implementing an effective postmarket safety program. We evaluated the associations between premarket product information and review characteristics and postmarket safety-related outcomes (label changes, withdrawals) and their timing for New Molecular Entities (NMEs). We assessed NMEs approved by the FDA between 10/1/2002 and 12/31/2014, and the resulting safety-related outcomes through 12/31/2015, by estimating odds ratios (OR), hazard ratios (HR) and 95% confidence interval (CI). A cohort of 278 approved NME drugs was followed from 377 to 4815 days. Safety outcomes were identified in 202 (72.7%) drugs; and of those 35 had at least one serious postmarket safety outcome (one withdrawn and 34 receiving an additional warning). We found that safety-related label changes occur throughout a drug's lifespan. An increase of any postmarket safety outcomes, albeit not statistically significant, was seen in fast track NMEs (Adjusted OR =1.53, 95% CI 0.72, 3.24) but not in other review pathways. NMEs with accelerated approval, composed primarily of drugs approved using a surrogate endpoint also had an increase in any postmarket safety outcomes (HR =1.58; 95% CI 1.01, 2.49). Small significant differences were seen for NMEs with shorter review time; a 10 day decrease in approval time was associated with a 3% increase in risk of safety outcomes only for drugs with priority review. The association of shorter review time with postmarket safety outcomes among NME drugs indicates the importance of continued rigorous monitoring for approved priority drugs once they are made available to the public.