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Drug Safety, Post-FDA Approval: What to Look For

Drug Safety, Post-FDA Approval: What to Look For

  • The danger which is least expected soonest comes to us.—French dramatist, poet, and reformer Voltaire

  • Boxed Warnings are Most Common. Of the 222 novel therapeutics the FDA approved 2001–2010 (183 pharmaceuticals, 39 biologics), 71 (32%) were affected by a postmarket safety event. Of 123 new postmarket safety events, 61 were boxed warnings, 59 safety communications, and 3 withdrawals.

  • Highest Risk Therapeutics. Significantly associated with higher rates of postmarket safety events were biologics, therapeutics indicated for the treatment of psychiatric disease, those receiving accelerated approval, and those with near–regulatory deadline approval. Events were significantly less frequent in therapeutics that had regulatory review times less than 200 days.

  • The Withdrawals. Withdrawn from the market were the anti-inflammatory valdecoxib in 2005 and tegaserod for irritable bowel syndrome in 2007—both because of cardiovascular concerns—and efalizumab for psoriasis in 2009 because of progressive multifocal leukoencephalopathy risk.

  • Classwide Warnings. Included in the 61 incremental boxed warnings, affecting 43 novel therapeutics, were classwide warnings for antipsychotics (ziprasidone, aripiprazole) in 2005, selective serotonin reuptake inhibitors (duloxetine, atomoxetine) in 2006, and monoclonal antibodies acting against tumor necrosis factor α (adalimumab, certolizumab, golimumab) in 2009. Safety communications preceded 8 boxed warnings, but only 4 described the safety risk that triggered the boxed warning.

  • Safety Communications for Entire Drug Classes. The 59 safety communications affected 44 novel therapeutics, in some cases entire drug classes: triptans (almotriptan, frovatriptan, eletriptan) in 2006, phosphodiesterase 5 inhibitors (vardenafil, tadalifil) in 2007, bisphosphonates (zolendronic acid, ibandronate) in 2008, and dipeptidyl peptidase 4 inhibitors (saxagliptin, sitagliptin) in 2015.

  • Mean Times. Mean time from a novel therapeutic’s approval to first event: 4.2 years. Withdrawal mean times: 3.4, 4.7, and 5.4 years. Boxed warning median time: 4.0 years. Safety communication median time: 4.9 years. At 10 years, 30.8% of the therapeutics had 1 or more safety events.

  • Safety Events by Disease Category. Therapeutics were classified in 8 therapeutic areas: (1) autoimmune, musculoskeletal, and dermatology; (2) cancer and hematology; (3) cardiovascular disease, diabetes, and hyperlipidemia; (4) genitourinary and renal; (5) infectious disease; (6) neurology; (7) psychiatry; and (8) other. Postmarket safety events were most common in psychiatric disease therapeutics, least common in cancer and hematologic disease therapeutics.

  • Call for Continuous Monitoring. Safety risks may become evident only when novel therapeutics are used in larger patient populations and for longer durations in the postmarket period. A high frequency of postmarket safety events in novel therapeutics after FDA approval highlights the need for continuous monitoring throughout their life cycle. Knowledge of these safety events can change how novel therapeutics are used in clinical practice and inform patient and clinician decision making.

At least 1 new safety issue was detected in the years after FDA approval in 1 of every 3 novel therapeutics that received approval during a recent decade. Four therapeutic areas were affected by classwide safety communications between 2006 and 2015: triptans, phosphodiesterase-5 inhibitors, bisphosphonates, and dipeptidyl 4 peptidase inhibitors.

Researchers conducted a cohort study of novel therapeutics approved between 2001 and 2010 to determine the frequency of postmarket safety events: withdrawals because of safety concerns, issuance of boxed warnings, and issuance of safety communications.

They also wanted to find out whether any novel therapeutic characteristics known at the time of approval—drug class, therapeutic area, priority review, accelerated approval, orphan status, near–regulatory deadline approval, and regulatory review time—were associated with increased risk.

Click on the slides above for highlights of their findings and conclusions. 



Downing NS, Shah ND, Aminawung JA, et al. Postmarket safety events among novel therapeutics approved by the US Food and Drug Administration between 2001 and 2010. JAMA. 2017;317(18):1854-1863.


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