A comprehensive comparison of the continual reassessment method to the standard 3 + 3 dose escalation scheme in Phase I dose-finding studies Journal Article
| Authors: | Iasonos, A.; Wilton, A. S.; Riedel, E. R.; Seshan, V. E.; Spriggs, D. R. |
| Article Title: | A comprehensive comparison of the continual reassessment method to the standard 3 + 3 dose escalation scheme in Phase I dose-finding studies |
| 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. © Society for Clinical Trials 2008. |
| Keywords: | controlled study; treatment duration; accuracy; biological markers; clinical protocol; practice guideline; dose-response relationship, drug; algorithms; publication; confidence interval; simulation; standard; statistical analysis; clinical research; intermethod comparison; safety; drug toxicity; maximum tolerated dose; clinical trials, phase i as topic; drug dose regimen; sample size; process optimization; process model; process control; continual reassessment method; oscillation; process design |
| Journal Title: | Clinical Trials |
| Volume: | 5 |
| Issue: | 5 |
| ISSN: | 1740-7745 |
| Publisher: | Sage Publications |
| Date Published: | 2008-10-01 |
| Start Page: | 465 |
| End Page: | 477 |
| Language: | English |
| DOI: | 10.1177/1740774508096474 |
| PUBMED: | 18827039 |
| PROVIDER: | scopus |
| PMCID: | PMC2637378 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 10" - "Export Date: 17 November 2011" - "Source: Scopus" |
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