Characteristics of trials and regulatory pathways leading to US approval of innovative vs. non-innovative oncology drugs

Health Policy. 2019 Aug;123(8):721-727. doi: 10.1016/j.healthpol.2019.06.002. Epub 2019 Jun 12.


Background: Successful first-generation drugs can be converted with small alterations to "second-generation drugs," which are cheaper to develop and may pose less financial risk for manufacturers due to already validated action mechanism and a well-defined consumer market.

Methods: We found four classes of cancer drugs for first- and second generation products approved in the US: BCR-ABL tyrosine kinase inhibitors (TKI) for treatment of CML, ALK + TKI for NSCLC, CD20 monoclonal antibodies for CLL, and HER2 monoclonal antibodies for breast cancer. We analyzed the characteristics of the clinical trials and the approval pathways for these 14 drugs.

Results: First-generation and 4 out of 5 s-generation BCR-ABL TKI drugs were granted expedited approval, while all drugs were approved based on single-arm trials. Both ALK + TKI drugs were based on single-arm trials and expedited approval. The first-generation CD20 monoclonal antibody drug was approved based on single-arm trials, and one of the second-generation drugs had pivotal trials that were randomized. All benefited from expedited approval. All HER2 monoclonal antibodies in the sample were based on randomized trials and expedited pathways.

Conclusion: Second-generation TKI and monoclonal antibodies were often approved through expedited regulatory pathways and studied in single-arm trials. This helps to facilitate the approval for earlier use by patients, but is also associated with greater risk of post-approval safety-related labeling changes or unanticipated adverse events.

Keywords: Cancer; Drug approval; First-generation drug; Health policy; Public health; Second generation drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / standards*
  • Clinical Trials as Topic / standards*
  • Drug Approval / organization & administration*
  • Humans
  • Neoplasms / drug therapy
  • United States
  • United States Food and Drug Administration


  • Antineoplastic Agents