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Adaptive designs in randomized clinical trials: reanalysis of the HOVON87/NMSG18 multiple myeloma trial
Maarten R Seefat1, Niek G van der Maas2, Kazem Nasserinejad2,3
1Department of Haematology, Amsterdam UMC, Cancer Centre Amsterdam, the Netherlands.
Background:
Randomized controlled trials are the gold standard to assess clinical efficacy of novel drugs, but improved survival extends follow-up time and challenges their feasibility. Adaptive trial designs, offering earlier outcome assessments, may enhance efficiency and accelerate decision-making. We retrospectively evaluated whether applying adaptive designs to the randomized HOVON87/NMSG18 phase III trial (inclusion between January 2009 and October 2012), which failed to meet its primary endpoint, could have indicated futility earlier.
Methods:
We modelled two adaptive trial designs: (1) group sequential and (2) sample size re-estimation. Each design recommends early trial termination for strong efficacy or futility, or continuation if signals are inconclusive. Interim analyses for the group sequential design were defined at 33% and 67% of events required for the final analysis, using O'Brien-Fleming, Pocock, and gamma spending functions to control for false positive or negative results. Sample size re-estimation design was evaluated after 67% of events.
Findings:
Group sequential design: Hazard ratios (HRs) at both interim analyses were within futility/efficacy boundaries with the more conservative O'Brien-Fleming and gamma spending functions, indicating trial continuation as planned. However, the more aggressive Pocock spending function indicated trial termination at the second interim analysis with a HR of 0.88 exceeding the futility boundary of HR > 0.85. Sample size re-estimation design: At 67% of events, the observed HR of 0.86 was in the unfavourable zone, whereas the promising zone required a HR between ≥0.76 and ≤0.83. The observed HR indicated trial continuation without sample size expansion.
Interpretation:
This reanalysis of a MM trial suggests that adaptive designs indicate earlier futility detection and thereby facilitate decision-making. Early signals could reduce follow-up time or potentially offer sample size expansion if the effect is promising but not yet conclusive. Our findings highlight the value of implementing adaptive designs to enhance the efficiency and ethical conduct of future RCTs.
Funding:
The HOVON87/NMSG18 trial was supported by Dutch Cancer Society grant 2008-4246, the Norwegian Cancer Society and Celgene.
Insights
Adaptive trial designs could have detected futility earlier in a multiple myeloma trial, improving efficiency. These designs enhance decision-making and ethical conduct for future randomized controlled trials.
Area of Science:
- Clinical Trials Methodology
- Biostatistics
- Oncology Drug Development
Background:
- Randomized controlled trials (RCTs) are crucial for drug efficacy assessment but face challenges with extended follow-up times.
- Adaptive trial designs offer earlier outcome assessments, potentially improving efficiency and accelerating decision-making.
- This study retrospectively evaluated adaptive designs' ability to detect futility earlier in a phase III multiple myeloma trial that missed its primary endpoint.
Purpose of the Study:
- To assess if adaptive trial designs could have identified futility earlier in the HOVON87/NMSG18 phase III trial.
- To evaluate the performance of group sequential and sample size re-estimation adaptive designs.
Main Methods:
- Two adaptive designs were modeled: group sequential and sample size re-estimation.
- Group sequential design used interim analyses at 33% and 67% of events with O'Brien-Fleming, Pocock, and gamma spending functions.
- Sample size re-estimation design was evaluated after 67% of events.
Main Results:
- The group sequential design with the Pocock spending function indicated early trial termination due to futility (HR=0.88 > 0.85).
- The sample size re-estimation design indicated trial continuation without sample size expansion (HR=0.86 in the unfavorable zone).
- More conservative O'Brien-Fleming and gamma spending functions suggested trial continuation as planned.
Conclusions:
- Adaptive designs can facilitate earlier futility detection in clinical trials, aiding decision-making.
- Early futility signals can reduce follow-up time and potentially allow for sample size expansion if results are promising.
- Implementing adaptive designs enhances the efficiency and ethical conduct of future randomized controlled trials.
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