Reprioritizing Risk and Benefit: The Future of Study Design in Early-Phase Cancer Research

Ethics Hum Res. 2019 Nov;41(6):2-11. doi: 10.1002/eahr.500033.


The scientific purpose of phase I trials is to determine the maximum tolerated dose and/or optimal biological dose of experimental agents. Yet most participants in phase I oncology trials enroll hoping for direct medical benefit. The most common phase I trial designs use low starting doses and escalate cautiously in a "risk-escalation" model focused on minimizing risk for each participant. This approach ensures that a proportion of subjects will likely not receive any benefit, even if the intervention proves to be successful at appropriate doses. In this article, we propose that trial designs should employ dosing strategies that increase chances of providing benefit if the investigational agent should prove to be successful while limiting risk to reasonable levels. We then describe how adaptive trial designs can facilitate refined dose optimization based on both therapeutic benefit and toxicity, which can simultaneously decrease the risk of harm while increasing the chances of benefit.

Keywords: human subjects research; phase 1 oncology trials; research benefits; research risks.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Dose-Response Relationship, Drug*
  • Humans
  • Maximum Tolerated Dose*
  • Medical Oncology
  • Neoplasms / drug therapy*
  • Research Design*
  • Risk Assessment