Accelerated Titration Designs

Dancey, Janet; Freidlin, Boris; Rubinstein, Larry

doi:10.1002/0470861258.ch4

Cited by 11 publications

(2 citation statements)

References 40 publications

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“…To assess the use and utility of the ATDs in the evaluation of novel oncology therapeutics, Dancey et al (10) conducted a literature search and an analysis of 36 identified ATD trials. Approximately half of the studies utilized intra-patient dose escalation.…”

Section: Overviewmentioning

confidence: 99%

Approaches to Phase 1 Clinical Trial Design Focused on Safety, Efficiency, and Selected Patient Populations: A Report from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee

Ivy

Siu

Garrett‐Mayer

et al. 2010

Clinical Cancer Research

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163

106

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The goals and objectives of phase 1 clinical trials are changing to include further evaluation of endpoints such as molecular targeted effects, in addition to dose/toxicity profile of the investigational agent. Because of these changes in focus, the National Cancer Institute/Investigational Drug Steering Committee’s Task Force on Clinical Trial Design met to evaluate the most efficient ways to design and implement early clinical trials with novel therapeutics. Clinical approaches discussed included the conventional 3 + 3 cohort expansion phase 1 design, multi-institutional phase 1 studies, accelerated titration designs, continual reassessment methods, the study of specific target patient populations and phase 0 studies. Each of these approaches uniquely contributes to some aspect of the phase 1 study, with all focused on dose and schedule determination, patient safety, and limited patient exposure to ineffective doses of investigational agent. The benefit of labor-intensive generation of preliminary biomarker evidence of target inhibition, as well as the value of molecular profiling of the study population, is considered. New drug development is expensive and the failure rate remains high. By identifying patient populations expected to respond to the study agent and tailoring the treatment with a novel drug, investigators will be one step closer to personalizing cancer treatment. The ‘fail early and fast’ approach is acceptable if the appropriate patient population is evaluated in the phase 1 trial. The approaches outlined in this overview address the merits, advantages, disadvantages and obstacles encountered during first in human studies.

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Section: Overviewmentioning

confidence: 99%

Approaches to Phase 1 Clinical Trial Design Focused on Safety, Efficiency, and Selected Patient Populations: A Report from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee

Ivy

Siu

Garrett‐Mayer

et al. 2010

Clinical Cancer Research

Self Cite

163

106

View full text Add to dashboard Cite

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“…One appreciates immediately that precautionary coherence (PC) entails what is often called 'intra-patient dose escalation' (Simon et al 1997;Dancey, Freidlin, and Rubinstein 2006), but which I will here call simply dose titration. 1 Under this simplified terminology, a dose-escalation trial, when modified to achieve precautionary coherence, necessarily becomes a dose titration trial.…”

Section: The 3+3/pc Designmentioning

confidence: 99%

Precautionary Coherence Unravels Dose Escalation Designs

Norris¹

2017

Preprint

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Background: Coherence notions have a long history in statistics, as rhetorical devices that support the critical examination of statistical doctrines and practices. Within the special domain of dose-finding methodology, a widely-discussed coherence criterion has been advanced as a means to guard the conceptual integrity of formal dose-finding designs from ad hoc tinkering. This is not, however, the only possible coherence criterion relevant to dose finding. Indeed, a new coherence criterion emerges naturally when the near-universal practice of cohort-wise dose escalation is examined from a clinical perspective. Methods: The practice of enrolling drug-naive patients into an escalation cohort is considered from a realistic perspective that acknowledges patients' heterogeneity with respect to pharmacokinetics and pharmacodynamics. A new coherence criterion thereby emerges, requiring that an escalation dose be tried preferentially in participants who have already tolerated a lower dose, rather than in new enrollees who are drug-naive. The logical implications of this 'precautionary coherence' (PC) criterion are worked out in the setting of a 3+3 design. A '3+3/PC' design that satisfies this criterion is described and visualized. A simulation study is performed, evaluating the long-run performance of this new design, relative to optimal 1-size-fits-all dosing. Results: Under the PC criterion, the 3+3 dose-escalation design necessarily transmutes into a dose titration design. Two simple rules suffice to enable abandonment of low starting doses, and termination of escalation. The process of conducting the 3+3/PC trial itself models the application of a dose titration algorithm (DTA) that carries over readily into clinical care. The 3+3/PC trial also yields an interval-censored 'dose-survival curve' having a semantics that should prove familiar to oncology trialists. Simulated 3+3/PC trials yield DTAs over a median of 6 dose levels, achieving 50% improved population-level efficacy compared to optimal 1-size-fits-all dosing. Conclusions: Dose individualization can be accomplished within a trial conducted along 'algorithmic' lines resembling those of the inveterate 3+3 design. The dose-survival curve arising from this '3+3/PC' design has semantics that should prove familiar and conceptually accessible to oncology trialists, and also seems capable of supporting more formal statistical treatments of the design. In the presence of sufficient heterogeneity in individualized optimal dosing, a 3+3/PC trial outperforms any conceivable 1-size-fits-all dose-finding design. This fact eliminates the rationale for the latter designs, and should put an end to the further development and promulgation of 1-size-fits-all dose finding.

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Algorithm‐Based Designs

2005

Encyclopedia of Statistical Sciences

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First, we describe the traditional algorithm‐based A + B designs and the modifications of A + B designs, along with the advantages and drawbacks of these designs. Accelerated designs and a modification of the accelerated designs are delineated in the next section, then we introduce a model‐based approach in the estimation of the maximum tolerated dose following an algorithm‐based design. Finally, design properties for commonly used and less commonly used algorithm‐based designs are provided.

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Accelerated Titration Designs

Cited by 11 publications

References 40 publications

Approaches to Phase 1 Clinical Trial Design Focused on Safety, Efficiency, and Selected Patient Populations: A Report from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee

Approaches to Phase 1 Clinical Trial Design Focused on Safety, Efficiency, and Selected Patient Populations: A Report from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee

Precautionary Coherence Unravels Dose Escalation Designs

Algorithm‐Based Designs

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