An adaptive dose-finding design incorporating both toxicity and efficacy

Wei Zhang, Daniel J. Sargent, Sumithra J Mandrekar

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Novel therapies are challenging the standards of drug development. Agents with specific biologic targets and limited toxicity require novel designs to determine doses to be taken forward into larger studies. In this paper, we describe an approach that incorporates both toxicity and efficacy data into the estimation of the biologically optimal dose of an agent in a phase I trial. The approach is based on the flexible continuation-ratio model, and uses straightforward optimal dose selection criteria. Dose selection is based on all patients treated up until that time point, using a continual reassessment method approach. Dose-outcome curves considered include monotonically increasing, monotonically decreasing, and unimodal curves. Our simulation studies demonstrate that the proposed design, which we call TriCRM, has favourable operating characteristics.

Original languageEnglish (US)
Pages (from-to)2365-2383
Number of pages19
JournalStatistics in Medicine
Volume25
Issue number14
DOIs
StatePublished - Jul 30 2006

Fingerprint

Dose Finding
Toxicity
Patient Selection
Efficacy
Dose
Pharmaceutical Preparations
Continual Reassessment Method
Phase I Trial
Therapeutics
Curve
Operating Characteristics
Continuation
Therapy
Drugs
Design
Simulation Study
Target
Demonstrate

Keywords

  • Bayesian method
  • Continual reassessment method
  • Continuation-ratio model
  • Phase I trail
  • Proportional odds model
  • Trinomial

ASJC Scopus subject areas

  • Epidemiology

Cite this

An adaptive dose-finding design incorporating both toxicity and efficacy. / Zhang, Wei; Sargent, Daniel J.; Mandrekar, Sumithra J.

In: Statistics in Medicine, Vol. 25, No. 14, 30.07.2006, p. 2365-2383.

Research output: Contribution to journalArticle

Zhang, Wei ; Sargent, Daniel J. ; Mandrekar, Sumithra J. / An adaptive dose-finding design incorporating both toxicity and efficacy. In: Statistics in Medicine. 2006 ; Vol. 25, No. 14. pp. 2365-2383.
@article{41c2fb1c234241148f384c5f09c5c36a,
title = "An adaptive dose-finding design incorporating both toxicity and efficacy",
abstract = "Novel therapies are challenging the standards of drug development. Agents with specific biologic targets and limited toxicity require novel designs to determine doses to be taken forward into larger studies. In this paper, we describe an approach that incorporates both toxicity and efficacy data into the estimation of the biologically optimal dose of an agent in a phase I trial. The approach is based on the flexible continuation-ratio model, and uses straightforward optimal dose selection criteria. Dose selection is based on all patients treated up until that time point, using a continual reassessment method approach. Dose-outcome curves considered include monotonically increasing, monotonically decreasing, and unimodal curves. Our simulation studies demonstrate that the proposed design, which we call TriCRM, has favourable operating characteristics.",
keywords = "Bayesian method, Continual reassessment method, Continuation-ratio model, Phase I trail, Proportional odds model, Trinomial",
author = "Wei Zhang and Sargent, {Daniel J.} and Mandrekar, {Sumithra J}",
year = "2006",
month = "7",
day = "30",
doi = "10.1002/sim.2325",
language = "English (US)",
volume = "25",
pages = "2365--2383",
journal = "Statistics in Medicine",
issn = "0277-6715",
publisher = "John Wiley and Sons Ltd",
number = "14",

}

TY - JOUR

T1 - An adaptive dose-finding design incorporating both toxicity and efficacy

AU - Zhang, Wei

AU - Sargent, Daniel J.

AU - Mandrekar, Sumithra J

PY - 2006/7/30

Y1 - 2006/7/30

N2 - Novel therapies are challenging the standards of drug development. Agents with specific biologic targets and limited toxicity require novel designs to determine doses to be taken forward into larger studies. In this paper, we describe an approach that incorporates both toxicity and efficacy data into the estimation of the biologically optimal dose of an agent in a phase I trial. The approach is based on the flexible continuation-ratio model, and uses straightforward optimal dose selection criteria. Dose selection is based on all patients treated up until that time point, using a continual reassessment method approach. Dose-outcome curves considered include monotonically increasing, monotonically decreasing, and unimodal curves. Our simulation studies demonstrate that the proposed design, which we call TriCRM, has favourable operating characteristics.

AB - Novel therapies are challenging the standards of drug development. Agents with specific biologic targets and limited toxicity require novel designs to determine doses to be taken forward into larger studies. In this paper, we describe an approach that incorporates both toxicity and efficacy data into the estimation of the biologically optimal dose of an agent in a phase I trial. The approach is based on the flexible continuation-ratio model, and uses straightforward optimal dose selection criteria. Dose selection is based on all patients treated up until that time point, using a continual reassessment method approach. Dose-outcome curves considered include monotonically increasing, monotonically decreasing, and unimodal curves. Our simulation studies demonstrate that the proposed design, which we call TriCRM, has favourable operating characteristics.

KW - Bayesian method

KW - Continual reassessment method

KW - Continuation-ratio model

KW - Phase I trail

KW - Proportional odds model

KW - Trinomial

UR - http://www.scopus.com/inward/record.url?scp=33745956991&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745956991&partnerID=8YFLogxK

U2 - 10.1002/sim.2325

DO - 10.1002/sim.2325

M3 - Article

C2 - 16220478

AN - SCOPUS:33745956991

VL - 25

SP - 2365

EP - 2383

JO - Statistics in Medicine

JF - Statistics in Medicine

SN - 0277-6715

IS - 14

ER -