Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Bayesian procedures for phase I/II clinical trials investigating the safety and efficacy of drug combinations
AU - Whitehead, John
AU - Thygesen, Helene
AU - Whitehead, Anne
PY - 2011/7/20
Y1 - 2011/7/20
N2 - Many formal statistical procedures for phase I dose-finding studies have been proposed. Most concern a single novel agent available at a number of doses and administered to subjects participating in a single treatment period and returning a single binary indicator of toxicity. Such a structure is common when evaluating cytotoxic drugs for cancer. This paper concerns studies of combinations of two agents, both available at several doses. Subjects participate in one treatment period and provide two binary responses: one an indicator of benefit and the other of harm. The word “benefit” is used loosely here: the response might be an early indicator of physiological change which, if induced in patients, is of potential therapeutic value. The context need not be oncology, but might be any study intended to meet both the phase I aim of establishing which doses are safe and the phase II goal of exploring potential therapeutic activity. A Bayesian approach is used based on an assumption of monotonicity in the relationship between the strength of the dose combination and the distribution of the bivariate outcome. Special cases are described, and the procedure is evaluated using simulation. The parameters that define the model have immediate and simple interpretation. Graphical representations of the posterior opinions about model parameters are shown, and these can be used to inform the discussions of the trial safety committee.
AB - Many formal statistical procedures for phase I dose-finding studies have been proposed. Most concern a single novel agent available at a number of doses and administered to subjects participating in a single treatment period and returning a single binary indicator of toxicity. Such a structure is common when evaluating cytotoxic drugs for cancer. This paper concerns studies of combinations of two agents, both available at several doses. Subjects participate in one treatment period and provide two binary responses: one an indicator of benefit and the other of harm. The word “benefit” is used loosely here: the response might be an early indicator of physiological change which, if induced in patients, is of potential therapeutic value. The context need not be oncology, but might be any study intended to meet both the phase I aim of establishing which doses are safe and the phase II goal of exploring potential therapeutic activity. A Bayesian approach is used based on an assumption of monotonicity in the relationship between the strength of the dose combination and the distribution of the bivariate outcome. Special cases are described, and the procedure is evaluated using simulation. The parameters that define the model have immediate and simple interpretation. Graphical representations of the posterior opinions about model parameters are shown, and these can be used to inform the discussions of the trial safety committee.
KW - combination therapies
KW - decision procedure
KW - dose-finding
KW - phase I/II clinical trials
U2 - 10.1002/sim.4267
DO - 10.1002/sim.4267
M3 - Journal article
VL - 30
SP - 1952
EP - 1970
JO - Statistics in Medicine
JF - Statistics in Medicine
SN - 1097-0258
IS - 16
ER -