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Abstract:
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When a new treatment regimen is expected to have comparable efficacy to the standard of care (SOC), but benefit over the SOC in other domains such as safety and tolerability, a non-inferiority (NI) trial may be appropriate, but is fraught with difficulty in justifying an acceptable NI margin that is based on both clinical and statistical input. To overcome this, we propose to utilize a composite ordinal outcome that combines elements from several domains of importance (e.g. efficacy, safety, and tolerability). The composite outcome itself may be analyzed using a superiority framework, or it can solely be used at the design stage for selecting a NI margin that balances risks and benefits. In the latter case, the choice of NI margin may be based on a novel quantity called the maximum allowable difference in efficacy (MADE), defined as the marginal difference in efficacy between arms that would yield a null treatment effect for the composite outcome given its assumed distribution. We compare the power of a superiority test for the composite outcome with a non-inferiority test for efficacy (using the MADE as the NI margin), and apply the methods to a TB treatment trial.
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