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Do single-arm trials have a role in drug development plans incorporating randomised trials?

Michael J Grayling1, Adrian P Mander1

  • 1MRC Biostatistics Unit Hub for Trials Methodology Research, Cambridge, UK.

Pharmaceutical Statistics
|November 27, 2015
PubMed

Insights

Single-arm trials in oncology drug development may offer biased results and are often inefficient. Direct progression to randomized trials can save sample sizes and avoid issues associated with single-arm studies.

Area of Science:

  • Oncology
  • Clinical Trial Design
  • Biostatistics

Background:

  • Phase II oncology trials frequently use single-arm designs to assess drug efficacy via tumor response (RECIST).
  • Subsequent randomized trials are common if initial efficacy is demonstrated.
  • Single-arm trials risk biased treatment effect estimation due to patient selection, potentially leading to inefficient development plans.

Purpose of the Study:

  • To compare the performance of development plans using single-arm trials followed by randomized trials against stand-alone randomized trials (single-stage or group sequential).
  • To investigate the utility of single-arm trials and identify the most efficient drug development strategies.
  • To evaluate the impact of investigator prior beliefs (sceptical vs. enthusiastic) on the suitability of single-arm trials.

Main Methods:

  • Comparative analysis of different clinical trial development plan structures.
  • Simulation or modeling of trial outcomes under various scenarios.
  • Application of reference priors to quantify investigator opinions.
  • Case study contextualized with a non-small-cell lung cancer trial.

Main Results:

  • Development plans incorporating single-arm trials were frequently found to be non-optimal.
  • Even pessimistic prior beliefs favored alternative development plans.
  • Significant potential for sample size savings (up to 25%) and avoidance of single-arm trial biases were identified.

Conclusions:

  • Single-arm trials in oncology drug development, especially when followed by randomized trials, may not be the most efficient approach.
  • Direct progression to group sequential randomized trials can offer advantages in terms of sample size and bias mitigation.
  • Careful consideration of trial design is crucial, particularly regarding the use of single-arm trials when randomization is planned.
Keywords:
optimal development plansphase II clinical trial designrandomised two-armsingle-arm

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