{
  "abstract": "Introduction Registrational trials are clinical trials which are used to justify regulatory approval of a new medication by the FDA. However, clinical trials may not be designed around patient-centred outcomes, like overall survival (OS) or quality of life. This disconnect raises concerns about whether current trial designs are truly aligned with the long-term needs and priorities of patients. A comprehensive analysis of trial designs and endpoints is necessary to ensure that future oncological therapies deliver meaningful clinical improvements. Our objective was to describe types of clinical trial design and primary endpoints used for registrational trials, and their trends over time.Research design and methods In this cohort study, the HemOnc database was used to identify registrational trials supporting cancer drug approval from 2004 through 2023. Clinical trial design (escalation, de-escalation, in-class switch, out-of-class switch) and primary endpoint (OS; time-to-event including progression-free survival; response-based endpoint) were characterized.Results Escalation trial designs were more common than in-class switches or out-of-class switches. De-escalation and mixed designs were exceedingly rare. The most common primary endpoint was a composite time-to-event endpoint.Conclusion Most clinical trials leading to FDA approval for cancer-directed therapies employ escalation designs with composite time-to-event endpoints. Designs reflecting paradigm shifts in therapy (in-class switches and out-of-class switches) are sparsely used. This approach raises the concern that trials may increase therapeutic toxicity without delivering meaningful improvements in OS or quality of life.",
  "authors": [
    {
      "affiliations": [
        "Department of Medicine, Brown University Health, Providence, Rhode Island, USA"
      ],
      "name": "Charles J Milrod"
    },
    {
      "affiliations": [
        "Department of Medicine, Northside Hospital, Lawrenceville, Georgia, USA"
      ],
      "name": "Aidan Petrovich"
    },
    {
      "affiliations": [
        "Children’s Healthcare of Atlanta Arthur M Blank Hospital, Atlanta, Georgia, USA"
      ],
      "name": "Wayne Haowei Liang"
    },
    {
      "affiliations": [
        "Internal Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA"
      ],
      "name": "Elizabeth Davis"
    },
    {
      "affiliations": [
        "Mayo Clinic Rochester Department of Artificial Intelligence and Informatics, Rochester, Minnesota, USA"
      ],
      "name": "Carolyn Petersen"
    },
    {
      "affiliations": [
        "Mayo Clinic, Rochester, Minnesota, USA"
      ],
      "name": "Talal Hilal"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital, Boston, Massachusetts, USA"
      ],
      "name": "Peter Yang"
    },
    {
      "affiliations": [
        "Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA"
      ],
      "name": "Jeremy Lyle Warner"
    },
    {
      "affiliations": [
        "UNC-Chapel Hill, Chapel Hill, North Carolina, USA"
      ],
      "name": "Samuel M Rubinstein"
    }
  ],
  "title": "Trends in the design of FDA registrational randomised clinical trials in haematology and oncology: a 20-year cohort study",
  "uid": "ac9ea1a2-3152-5f94-be8e-d48e57746df0"
}