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Characteristics of efficacy evidence supporting approval of supplemental indications for prescription drugs in United States, 2005-14: systematic review

BMJ 2015; 351 doi: (Published 23 September 2015) Cite this as: BMJ 2015;351:h4679
  1. Bo Wang, medical student1,
  2. Aaron S Kesselheim, associate professor of medicine1
  1. 1Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, 1620 Tremont St, Boston, MA 02120, USA
  1. Correspondence to: A S Kesselheim akesselheim{at}
  • Accepted 17 August 2015


Objective To characterize the types of comparators and endpoints used in efficacy trials for approvals of supplemental indications, compared with the data supporting these drugs’ originally approved indications.

Design Systematic review.

Setting Publicly accessible data on supplemental indications approved by the US Food and Drug Administration from 2005 to 2014.

Main outcome measures Types of comparators (active, placebo, historical, none) and endpoints (clinical outcomes, clinical scales, surrogate) in the efficacy trials for these drugs’ supplemental and original indication approvals.

Results The cohort included 295 supplemental indications. Thirty per cent (41/136) of supplemental approvals for new indications were supported by efficacy trials with active comparators, compared with 51% (47/93) of modified use approvals and 11% (7/65) of approvals expanding the patient population (P<0.001), almost all of which related to pediatric patients (61/65; 94%). Trials using clinical outcome endpoints led to approval for 32% (44/137) of supplemental approvals for new indications, 30% (28/93) of modified indication approvals, and 22% (14/65) of expanded population approvals (P=0.29). Orphan drugs had supplemental approvals for 40 non-orphan indications, which were supported by similar proportions of trials using active comparators (28% (11/40) for non-orphan supplemental indications versus 24% (10/42) for original orphan indications; P=0.70) and clinical outcome endpoints (25% (10/40) versus 31% (13/42); P=0.55).

Conclusions Wide variations were seen in the evidence supporting approval of supplemental indications, with the fewest active comparators and clinical outcome endpoints used in trials leading to supplemental approvals that expanded the patient population.


  • Contributors: Both authors conceived the study. Both authors analyzed and interpreted the data. Both authors drafted and revised the manuscript, and both approved the final version. ASK is the guarantor.

  • Funding: This investigator initiated study was not funded by industry. ASK’s work is supported by the Greenwall faculty scholars program in bioethics and the Harvard program in therapeutic science. The funders had no role in the conception, writing, or review of the manuscript.

  • Competing interests: Both authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Ethics approval was not required for this study because it was based on publicly available data and involved no individual patient data collection or analysis.

  • Transparency: The lead author (the manuscript’s guarantor) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

  • Data sharing: No additional data available.

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