The FDA and New Safety Warnings FREE

In response to postmarket drug safety surveillance and research data, the US Food and Drug Administration (FDA) and drug manufacturer may take 1 of 2 types of action. In extreme cases the FDA may remove a drug from the market. More often the product label or package insert is revised to reflect newly discovered risks. The most clinically significant new information is added to 1 of 3 legally defined sections of the prescribing information¹: (1) a boxed warning (information that is essential to be considered when prescribing the drug); (2) a contraindication (clinical situations when a drug's risks clearly outweigh its benefits); and (3) a warning (adverse reactions with reasonable evidence of a causal association, reactions that may require discontinuation, or reactions that interfere with a laboratory test).

We analyzed 1 calendar year of these major label changes to provide insights into this safety program. We report the number of actions, severity of events, and nature and scope of the safety information. We also describe the types of drugs affected, whether they were recently approved drugs or established treatments, and what type and level of scientific evidence was used to support of these label changes.

Major safety regulatory actions during 2009 were defined as drug withdrawals for safety, new or revised boxed warnings, contraindications, or warnings for approved prescription drugs.² For each action we calculated the years since initial drug approval and identified the brand name or generic status. We categorized the cited evidence source (ie, clinical trial, meta-analysis, epidemiological study, adverse event report). We also evaluated whether the scientific evidence was derived directly from studies of the target drug or inferred from studies of other drugs either with similar chemical structure and mechanism of action or that were indicated for use in the same patient population. A complete description of the study methods is available in the eAppendix.

In 2009, the FDA approved 181 major safety regulatory actions, including 1 drug safety withdrawal, 25 new boxed warnings, 19 new contraindications, 90 new warnings, and 46 revisions of previous actions (Table). Among the newly identified adverse effects were suicidal behavior, life-threatening viral infections, renal failure, and increased cancer risk in children. Adverse event reports from drug manufacturers or through the MedWatch program were the predominant source of scientific information and formed the basis of 77 of 135 new regulatory actions (57%) and 19 of 25 new boxed warnings (76%). Clinical studies were cited as the evidence source for 26 of 135 actions (19%) but only 2 were derived from statistically significant differences and 1 was based on a single study case. A large FDA meta-analysis of suicidal behavior and antiepileptic drugs generated warnings for 19 drugs.³ In 23 of 135 new actions (17%), the scientific evidence was derived from other drugs, with 15 based on similar chemical structure and mechanism, and 8 based on the same indication and/or patient population. The safety actions occurred a median of 11 years after initial approval and included 61 drugs marketed for 15 years or more; only 36 actions involved drugs within first 5 years after approval.

These major safety regulatory actions disclose clinically significant risks of widely used drugs, typically many years after approval. Scientific evidence cited to alert physicians about new risks for marketed drugs used notably less rigorous methods than the well-controlled, blinded, and randomized clinical trials used to document benefit prior to approval. When reported adverse events supported the warning, little or no detail was provided about the number and type of reports relied on or any systematic analysis performed.

Some of the most extensive changes involved class warnings applied to a group of drugs without distinguishing between them. All drugs indicated for epilepsy treatment got the same suicidal behavior warning, even those not included in the meta-analysis and drugs with markedly different mechanisms of action. The class warning was extended to 1 benzodiazepine—clonazepam (Klonopin; F. Hoffmann-La Roche Ltd) with an indication in epilepsy treatment—but not to other benzodiazepines. In another case the FDA announced and put similar suicidal behavior and violence warnings on 2 smoking cessation treatments—varenicline (Chantix; Pfizer Inc) and bupropion hydrochloride (Zyban; GlaxoSmithKline)—even though the FDA's unpublished but publicly available studies revealed that varenicline accounted for 10 times as many reports as bupropion and had higher risks.^4- 5

The 11-year median time since approval for actions in this 1-year study was markedly higher than the 7 years reported in a 2002 study of boxed warnings or withdrawals since 1975.⁶ Improving postmarket drug safety requires timelier ascertainment of drug risks together with higher quality and better documented scientific evidence.