Safety-related regulatory actions for biologicals approved in the United States and the European Union

JAMA. 2008 Oct 22;300(16):1887-96. doi: 10.1001/jama.300.16.1887.


Context: Biologicals are a relatively new class of medicines that carry specific risks (eg, immunogenicity). However, limited information is available on the nature and timing of safety problems with their use that were identified after approval.

Objective: To determine the nature, frequency, and timing of safety-related regulatory actions for biologicals following approval in the United States and/or the European Union.

Design and setting: Follow-up of a group of biologicals approved in the United States and/or European Union between January 1995 and June 2007. Vaccines, allergenic products, and products for further manufacture and transfusion purposes were excluded.

Main outcome measures: Nature, frequency, and timing of safety-related regulatory actions defined as (1) dear healthcare professional letters (United States) and direct healthcare professional communications (European Union), (2) black box warnings (United States), and (3) safety-related marketing withdrawals (United States and European Union) issued between January 1995 and June 2008.

Results: A total of 174 biologicals were approved (136 in the United States and 105 in the European Union, of which 67 were approved in both regions). Eighty-two safety-related regulatory actions (46 dear healthcare professional letters, 17 direct healthcare professional communications, 19 black box warnings, and no withdrawals) were issued for 41 of the 174 different biologicals (23.6%). The probability of a first safety-related regulatory action, derived from Kaplan-Meier analyses, was 14% (95% confidence interval [CI], 9%-19%) 3 years after approval and 29% (95% CI, 20%-37%) 10 years after approval. Biologicals first in class to obtain approval had a higher risk for a first safety-related regulatory action compared with later approved products in that class (12.0/1000 vs 2.9/1000 months, respectively; hazard ratio, 3.7 [95% CI, 1.5-9.5]). Warnings mostly concerned the classes general disorders and administration site conditions, infections and infestations, immune system disorders and neoplasms benign, malignant, and unspecified.

Conclusions: The nature of safety problems identified after approval for biologicals is often related to the immunomodulatory effect (infections). Because the biologicals first to be approved in a class were more likely to be subjected to regulatory action, close monitoring is recommended.

MeSH terms

  • Adverse Drug Reaction Reporting Systems*
  • Biological Products / adverse effects*
  • Drug Approval
  • Drug Labeling
  • European Union
  • Legislation, Drug*
  • United States


  • Biological Products