Therapeutic value of first versus supplemental indications of drugs in US and Europe (2011-20): retrospective cohort study

BMJ. 2023 Jul 5:382:e074166. doi: 10.1136/bmj-2022-074166.


Objective: To analyze the therapeutic value of supplemental indications compared with first indications for drugs approved in the US and Europe.

Design: Retrospective cohort study.

Setting: New and supplemental indications approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) between 2011 and 2020.

Main outcome measures: Proportion of first and supplemental indications rated as having high therapeutic value using ratings from the French and German national, independent health authorities.

Results: The cohort study included 124 first and 335 supplemental indications approved by the FDA and 88 first and 215 supplemental indications approved by the EMA between 2011 and 2020; the largest subset was for cancer disorders. Therapeutic ratings were available for 107 (86%) first and 179 (53%) supplemental indications in the US and for 87 (99%) first and 184 (86%) supplemental indications in Europe. Among FDA approved indications with available ratings, 41% (44/107) had high therapeutic value ratings for first indications compared with 34% (61/179) for supplemental indications. In Europe, 47% (41/87) of first and 36% (67/184) of supplemental indications had high therapeutic value ratings. Among FDA approvals, when the sample was restricted to the first three approved indications, second indication approvals were 36% less likely to have a high value rating (relative ratio 0.64, 95% confidence interval 0.43 to 0.96) and third indication approvals were 45% less likely (0.55, 0.29 to 1.01) compared with the first indication approval. Similar findings were observed for Europe and when weighting by the inverse number of indications for each drug.

Conclusions: The proportion of supplemental indications rated as having high therapeutic value was substantially lower than for first indications. When first or supplemental indications do not offer added therapeutic value over other available treatments, that information should be clearly communicated to patients and physicians and reflected in the price of the drugs.

MeSH terms

  • Antineoplastic Agents* / therapeutic use
  • Cohort Studies
  • Drug Approval
  • Europe
  • Humans
  • Neoplasms* / drug therapy
  • Pharmaceutical Preparations
  • Retrospective Studies
  • United States
  • United States Food and Drug Administration


  • Pharmaceutical Preparations
  • Antineoplastic Agents