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Bias induced by adaptive dose-finding designs.

Nancy Flournoy¹, Assaf P Oron²

¹Department of Statistics, University of Missouri, Columbia, MO, USA.

Journal of Applied Statistics

|June 16, 2022

Summary

This summary is machine-generated.

Adaptive dose-finding methods, like Continual Reassessment Methods, can introduce bias in estimating response rates. This bias, positive above and negative below the target dose, can be mitigated using shrinkage estimation.

Keywords:

Bernoulli regression analysis continual reassessment method inference following stochastic processes interval designs phase I clinical trials up-and-down procedures

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Area of Science:

Biostatistics
Clinical Trial Design
Pharmacometrics

Background:

Maximum likelihood estimators are known to exhibit bias in statistical literature.
Adaptive dose-finding designs are increasingly used in clinical trials for efficiency.

Purpose of the Study:

To demonstrate that adaptive dose-finding procedures inherently induce bias.
To provide an explicit formula for the bias of observed response rates in such designs.
To investigate the implications of this bias and propose mitigation strategies.

Main Methods:

Analysis of adaptive dose-finding procedures with Bernoulli responses.
Derivation of an explicit mathematical formula for bias in observed response rates.
Simulation and illustration of bias patterns for designs targeting a specific quantile.

Main Results:

Adaptive dose-finding procedures (Continual Reassessment Methods, Up-and-Down, Interval Designs) were shown to induce bias.
Bias tends to be positive above the target dose and negative below it for designs concentrating dose allocations.
This bias property in dose-finding designs appears to be a novel finding.

Conclusions:

Adaptive dose-finding designs introduce a previously unrecognized bias in response rate estimation.
Understanding and quantifying this bias is crucial for accurate dose selection in clinical trials.
A simple shrinkage formula is proposed to mitigate bias and improve estimation accuracy, especially away from the target dose.