![[PDF]](/pb-assets/Icons/adobe-pdf-icon-1498649896243.png){kind=icon}
Abstract
Background An extensive literature has covered the statistical properties of the Continual Reassessment Method (CRM) and the modifications of this method. While there are some applications of CRM designs in recent Phase I trials, the standard method (SM) of escalating doses after three patients with an option for an additional three patients SM remains very popular, mainly due to its simplicity. From a practical perspective, clinicians are interested in designs that can estimate the MTD using fewer patients for a fixed number of doses, or can test more dose levels for a given sample size.
Purpose This article compares CRM-based methods with the SM in terms of the number of patients needed to reach the MTD, total sample size required, and trial duration.
Methods The comparisons are performed under two alternative schemes: a fixed or a varying sample approach with the implementation of a stopping rule. The stopping rule halts the trial if the confidence interval around the MTD is within a pre-specified bound. Our simulations evaluated several CRM-based methods under different scenarios by varying the number of dose levels from five to eight and the location of the true MTD.
Results CRM and SM are comparable in terms of how fast they reach the MTD and the total sample size required when testing a limited number of dose levels (≤5), but as the number of dose levels increases, CRM reaches the MTD in fewer patients when used with a fixed sample of 20 patients. However, a sample size of 20—25 patients is not sufficient to achieve a narrow precision around the estimated toxicity rate at the MTD.
Limitations We focused on methods with practical design features that are of interest to clinicians. However, there are several alternative CRM-based designs that are not investigated in this manuscript, and hence our results are not generalizable to other designs.
Conclusions We show that CRM-based methods are an improvement over the SM in terms of accuracy and optimal dose allocation in almost all cases, except when the true dose is among the lower levels. Clinical Trials 2008; 5: 465—477. http://ctj.sagepub.com
|
O'Quigley J. , Pepe M. , Fisher L. Continual reassessment method: a practical design for Phase 1 clinical
trials in cancer. Biometrics 1990; 46(1):
33-48. Google Scholar | Crossref | Medline | ISI | |
|
O'Quigley J. Estimating the probability of toxicity at the recommended dose
following a Phase I clinical trial in cancer.
Biometrics 1992; 48(3):
853-863. Google Scholar | Crossref | Medline | ISI | |
|
O'Quigley J. , Shen L. Continual reassessment method: a likelihood approach.
Biometrics 1996; 52(2):
673-684. Google Scholar | Crossref | Medline | ISI | |
|
Shen L. , O'Quigley J. Consistency of continual reassessment method under model
misspecification . Biometrika 1996; 83(2):
395-405. Google Scholar | Crossref | ISI | |
|
O'Quigley J. , Reiner E. A stopping rule for the continual reassessment method.
Biometrika 1998; 85(3):
741-748. Google Scholar | Crossref | ISI | |
|
Babb J. , Rogatko A. , Zacks S. Cancer phase I clinical trials: efficient dose escalation with
overdose control . Statistics in Medicine 1999; 17:
1103-1120. Google Scholar | Crossref | ISI | |
|
O'Quigley J. , Shen LZ , Gamst A. Two-sample continual reassessment method.
Journal Biopharmaceutical Statistics 1999; 9(1):
17-44. Google Scholar | Crossref | Medline | |
|
Leung D. , Wang Y. An extension of the continual reassessment method using decision
theory. Statistics in Medicine 2002; 21(1):
51-63. Google Scholar | Crossref | Medline | ISI | |
|
O'Quigley J. Continual reassessment designs with early termination
. Biostatistics 2002; 3(1):
87-99. Google Scholar | Crossref | Medline | ISI | |
|
Rosenberger W. , Haines L. Competing designs for phase I clinical trials: a
review. Statistics in Medicine 2002 ; 21(18):
2757-2770. Google Scholar | Crossref | Medline | ISI | |
|
Potter DM Phase I studies of chemotherapeutic agents in cancer patients: a
review of the designs. Journal of Biopharmaceutical
Statistics 2006; 16(5):
579-604. Google Scholar | Crossref | Medline | ISI | |
|
Goodman S. , Zahurak M. , Piantadosi S. Some practical improvements in the continual reassessment method for
phase I studies. Statistics in Medicine 1995 ; 14(11):
1149-1161. Google Scholar | Crossref | Medline | ISI | |
|
Heyd J. , Carlin B. Adaptive design improvements in the continual reassessment method for
phase I studies. Statistics in Medicine 1999; 18:
1307-1321. Google Scholar | Crossref | Medline | ISI | |
|
Moller S. An extension of the continual reassessment methods using a preliminary
up-and down desigh in a dose findings study in cancer patients, in order to
investigate a greater range of doses. Statistics in
Medicine 1995; 14(9):
911-922. Google Scholar | Crossref | Medline | ISI | |
|
Eisenhauer EA , O'Dwyer PJ , Christian M. , Humphrey JS Phase I clinical trial design in cancer drug
development. Journal of Clinical Oncology 2000; 18(3):
684-92. Google Scholar | Crossref | Medline | ISI | |
|
Eder Jr JP , Garcia-Carbonero R. , Clark JW et al. A phase I trial of daily oral
4'-N-benzoyl-staurosporine in combination with protracted continuous infusion
5-fluorouracil in patients with advanced solid malignancies.
Investigational New Drugs 2004; 22(2):
139-50. Google Scholar | Crossref | Medline | ISI | |
|
Paoletti X. , Baron B. , Schoffski P. et al. Using the continual reassessment method: lessons
learned from an EORTC phase I dose finding study .
European Journal Cancer 2006; 42(10):
1362-8. Google Scholar | Crossref | Medline | ISI | |
|
Cheng JD , Babb JS , Langer C. et al. Individualized patient dosing in phase I clinical
trials: the role of escalation with overdose control in
PNU-214936. Journal of Clinical Oncology 2004; 22(4):
602-609. Google Scholar | Crossref | Medline | ISI | |
|
Rogatko A. , Schoeneck D. , Jonas W. et al. Translation of innovative designs into phase I
trials. J Clin Oncol 2007; 25(31):
4982-6. Google Scholar | Crossref | Medline | ISI | |
|
He W. , Liu J. , Binkowitz B. , Quan H. A model-based approach in the estimation of the maximum tolerated dose
in phase I cancer clinical trials. Statistics in
Medicine 2006; 25(12):
2027-42. Google Scholar | Crossref | Medline | ISI | |
|
Korn E. , Midthune D. , Chen T. et al. A comparison of two phase I trial
designs. Statistics in Medicine 1994; 13(18):
1799-1806. Google Scholar | Crossref | Medline | ISI | |
|
Zohar S. , Chevret S. The continual reassessment method: comparison of Bayesian stopping
rules for dose-ranging studies. Statistics in
Medicine 2001; 20(19):
2827-43. Google Scholar | Crossref | Medline | ISI | |
|
Chevret S. The continual reassessment method in cancer phase I clinical trials: a
simulation study. Statistics in Medicine 1993; 12(12):
1093-108. Google Scholar | Crossref | Medline | ISI | |
|
Ishizuka N. , Ohashi Y. The continual reassessment method and its applications: a Bayesian
methodology for phase I cancer clinical trials .
Statistics in Medicine 2001; 20 (17-18):
2661-81. Google Scholar | Crossref | Medline | ISI | |
|
Gelman A. , Carlin BJ , Stern SH , Rubin BD Bayesian data analysis. In Chatfield V , Tanner M , Zidek J. (eds). Texts in Statistical Science (2nd
edn). Chapman and Hall/
CRC, USA, 2004. Google Scholar | |
|
Cheung YK , Chappell R. A simple technique to evaluate model sensitivity in the continual
reassessment method. Biometrics 2002; 58(3):
671-4. Google Scholar | Crossref | Medline | ISI | |
|
Reiner E. , Paoletti X. , O'Quigley J. Operating characteristics of the standard phase I clinical trial
design . Computational Statistics and Data
Analysis 1999; 30:
303-315. Google Scholar | Crossref | ISI | |
| O'Quigley J. Phase I and phase I/II dose finding algorithms using continual reassessment
method. In Crowley J. (ed.). Handbook of Statistics in Clinical Oncology.
Marcel Dekker , New
York, 2005. Google Scholar | |
|
Cheng J. , Babb J. , Langer C. et al. Individualized patient dosing in phase I clinical
trials: the role of escalation with overdose control in
PNU-214936. Journal of Clinical Oncology 2004; 22(4):
602-609. Google Scholar | Crossref | Medline | ISI | |
|
Braun T.M. The bivariate continual reassessment method. Extending the CRM to
phase I trials of two competing outcomes. Controlled
Clinical Trials 2002; 23(3):
240-256. Google Scholar | Medline | |
|
Zohar S. , O'Quigley J. Identifying the most successful dose (MSD) in dose-finding studies in
cancer . Pharmaceutical Statistics 2006 ; 5:
187-199. Google Scholar | Crossref | Medline | ISI |
