Recent developments in the design of phase II clinical trials.

Clinical trials of new medical treatments may be classified into three successive phases. Phase I trials typically are small pilot studies to determine the therapeutic dose of a drug, biological agent, radiation schedule, or a combination of these regimens (cf. [1]). In cancer therapeutics, the underlying idea is that a higher dose of the therapeutic agent kills more cancer cells but also is more likely to harm and possibly kill the patient. Consequently, toxicity is the usual criterion for determining a maximum tolerable dose (MTD), and most phase I cancer trials involve very small groups of patients, usually three to six patients per dose, with each successive group receiving a higher dose until it is likely that the MTD has been reached. A more refined approach that continually updates an estimate of the probability of toxicity has also been proposed by O’Quigley, Pepe and Fisher [2].

[1]  P F Thall,et al.  An optimal three-stage design for phase II clinical trials. , 1994, Statistics in medicine.

[2]  B E Storer,et al.  A sequential phase II/III trial for binary outcomes. , 1990, Statistics in medicine.

[3]  T. Therneau,et al.  A two-stage design for randomized trials with binary outcomes. , 1987, Controlled clinical trials.

[4]  A. F. Smith,et al.  Bayesian Methods in Practice: Experiences in the Pharmaceutical Industry , 1986 .

[5]  D J Spiegelhalter,et al.  Comparison of Bayesian with group sequential methods for monitoring clinical trials. , 1989, Controlled clinical trials.

[6]  E. S. Pearson,et al.  THE USE OF CONFIDENCE OR FIDUCIAL LIMITS ILLUSTRATED IN THE CASE OF THE BINOMIAL , 1934 .

[7]  Terry M. Therneau,et al.  Optimal designs for a grouped sequential binomial trial , 1990 .

[8]  Terry M. Therneau,et al.  Optimal two-stage screening designs for survival comparisons , 1990 .

[9]  P. Thall,et al.  Bayesian sequential monitoring designs for single-arm clinical trials with multiple outcomes. , 1995, Statistics in medicine.

[10]  J Whitehead,et al.  Designing phase II studies in the context of a programme of clinical research. , 1985, Biometrics.

[11]  P. Thall,et al.  Incorporating historical control data in planning phase II clinical trials. , 1990, Statistics in medicine.

[12]  J Whitehead,et al.  Sample sizes for phase II and phase III clinical trials: an integrated approach. , 1986, Statistics in medicine.

[13]  T M Therneau,et al.  Designs for group sequential phase II clinical trials. , 1987, Biometrics.

[14]  J R Anderson,et al.  Analysis of survival by tumor response. , 1983, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  D. Spiegelhalter,et al.  The Assessment of the Subjective Opinion and its Use in Relation to Stopping Rules for Clinical Trials , 1983 .

[16]  S S Ellenberg,et al.  Randomized phase II clinical trials. , 1985, Cancer treatment reports.

[17]  B. K. Ghosh,et al.  A Comparison of Some Approximate Confidence Intervals for the Binomial Parameter , 1979 .

[18]  C R Palmer.  A comparative phase II clinical trials procedure for choosing the best of three treatments. , 1991, Statistics in medicine.

[19]  Richard Simon,et al.  Two-stage selection and testing designs for comparative clinical trials , 1988 .

[20]  B E Storer,et al.  Design and analysis of phase I clinical trials. , 1989, Biometrics.

[21]  Sylvester Rj,et al.  Design of phase II clinical trials in cancer using decision theory. , 1980 .

[22]  Donald A. Berry,et al.  Interim analysis in clinical trials; the role of the likelihood principle , 1987 .

[23]  Richard Simon,et al.  A Bayesian approach to establishang sample size and monitoring criteria for phase II clinical trials , 1994 .

[24]  Richard Sylvester.  A bayesian approach to the design of phase II clinical trials. , 1988 .

[25]  G. Elfring,et al.  Multiple-stage procedures for drug screening. , 1973, Biometrics.

[26]  S S Ellenberg,et al.  An efficient design for phase III studies of combination chemotherapies. , 1985, Cancer treatment reports.

[27]  J. Herson,et al.  Predictive probability early termination plans for phase II clinical trials. , 1979, Biometrics.

[28]  P F Thall,et al.  A two-stage design for choosing among several experimental treatments and a control in clinical trials. , 1989, Biometrics.

[29]  P F Thall,et al.  Practical Bayesian guidelines for phase IIB clinical trials. , 1994, Biometrics.

[30]  D. Spiegelhalter,et al.  A predictive approach to selecting the size of a clinical trial, based on subjective clinical opinion. , 1986, Statistics in medicine.

[31]  R. Simon,et al.  Confidence intervals for reporting results of clinical trials. , 1986, Annals of internal medicine.

[32]  Brown Bw,et al.  Confidence limits for probability of response in multistage phase II clinical trials. , 1985 .

[33]  Monitoring of a pilot toxicity study with two adverse outcomes. , 1994, Statistics in medicine.

[34]  A A Tsiatis,et al.  Exact confidence intervals following a group sequential test. , 1984, Biometrics.

[35]  Christopher Jennison,et al.  Confidence Intervals for a Binomial Parameter Following a Multistage Test With Application to MIL-STD 105D and Medical Trials , 1983 .

[36]  R. Simon,et al.  Optimal two-stage designs for phase II clinical trials. , 1989, Controlled clinical trials.

[37]  D. Berry,et al.  Interim analyses in clinical trials: classical vs. Bayesian approaches. , 1985, Statistics in medicine.

[38]  E. Gehan,et al.  The determinatio of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent. , 1961, Journal of chronic diseases.

[39]  P F Thall,et al.  A Bayesian strategy for screening cancer treatments prior to phase II clinical evaluation. , 1993, Statistics in medicine.

[40]  J Benichou,et al.  Application of the triangular test to phase II cancer clinical trials. , 1990, Statistics in medicine.

[41]  K C Cain,et al.  Charts for the early stopping of pilot studies. , 1984, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  T R Fleming,et al.  One-sample multiple testing procedure for phase II clinical trials. , 1982, Biometrics.

[43]  R Simon,et al.  Investigating a sequence of randomized phase II trials to discover promising treatments. , 1995, Statistics in medicine.

[44]  J O'Quigley,et al.  Continual reassessment method: a practical design for phase 1 clinical trials in cancer. , 1990, Biometrics.

[45]  P. Thall,et al.  Optimal two-stage designs for clinical trials with binary response. , 1988, Statistics in medicine.

[46]  D. Duffy,et al.  Confidence Intervals for a Binomial Parameter Based on Multistage Tests , 1987 .