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Safety related label changes for new drugs after approval in the US through expedited regulatory pathways: retrospective cohort study

BMJ 2017; 358 doi: (Published 07 September 2017) Cite this as: BMJ 2017;358:j3837
  1. Sana R Mostaghim, researcher,
  2. Joshua J Gagne, associate professor of medicine,
  3. Aaron S Kesselheim, director
  1. Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 1620 Tremont St, Boston, MA 02120, USA
  1. Correspondence to: A S Kesselheim akesselheim{at}
  • Accepted 2 August 2017


Objective To determine if drugs approved through the Food and Drug Administration’s expedited development and review pathways have different rates of safety related label changes after approval compared with drugs approved through standard non-expedited pathways.

Design Retrospective cohort study.

Setting FDA public records, January 1997 to April 2016.

Participants 382 FDA approved drugs.

Main outcome measures The number of times a particular safety section of a label (boxed warning, contraindication, warning, precaution, or adverse reaction) was changed during a drug’s time on the market. The relative rate of safety related label changes per year for expedited pathway and non-expedited pathway drugs was compared by forming matched pairs of drugs in the same therapeutic class that were approved within three years of each other.

Results Among the 382 eligible new drugs, 135 (35%) were associated with an expedited development or review pathway, and matches were available for 96 (71%). The matched pairs were associated with a total of 1710 safety related label changes during the study period. Expedited pathway drugs were characterized by a rate of 0.94 safety related label changes for each drug per year, compared with 0.68 safety related label changes per year for non-expedited pathway drugs (rate ratio 1.38, 95% confidence interval 1.25 to 1.52). Compared with non-expedited pathway drugs, expedited pathway drugs had a 48% higher rate of changes to boxed warnings and contraindications, the two most clinically important categories of safety warnings (1.48, 95% confidence interval 1.07 to 2.06). A qualitative review of changes to the boxed warning sections revealed that less than 5% (3/67) were changed to describe reduced risks for patients.

Conclusions Expedited development and regulatory review pathways can accelerate the availability of new drugs, but drugs approved through these pathways are associated with increased safety related label changes after approval, particularly for the types of changes representing the highest risk warnings. To inform appropriate policy interventions, additional research should explore the causal factors contributing to these different rates.


  • Contributors: All authors conceived, designed, and executed the study, and approved the final draft for publication. SRM is guarantor.

  • Funding: This study was funded by the Laura and John Arnold Foundation. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

  • Competing interests: All authors have completed the uniform disclosure form at and declare that (within the past three years): ASK has received funding from the Harvard Program in Therapeutic Science and the FDA Office of Generic Drugs and Division of Health Communication. JJG has received salary support from grants from Novartis Pharmaceuticals Corporation and Eli Lilly to the Brigham and Women’s Hospital and is a consultant to Aetion and to Optum all for unrelated work.. SRM had field placements at Intermountain Healthcare and Takeda pharmaceuticals on unrelated projects as part of his doctoral studies.

  • Ethical approval: Not required.

  • Data sharing: All data are publicly available.

  • Transparency: The authors affirm that the manuscript is an honest, accurate, and transparent account of the study was reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

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