Escalation with Overdose Control is More Efficient and Safer than Accelerated Titration for Dose Finding
The standard 3 + 3 or “modified Fibonacci” up-and-down (MF-UD) method of dose escalation is by far the most used design in dose-finding cancer trials. However, MF-UD has always shown inferior performance when compared with its competitors regarding number of patients treated at optimal doses. A cons...
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MDPI AG
2015-07-01
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| Online Access: | http://www.mdpi.com/1099-4300/17/8/5288 |
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| author | André Rogatko Galen Cook-Wiens Mourad Tighiouart Steven Piantadosi |
| author_facet | André Rogatko Galen Cook-Wiens Mourad Tighiouart Steven Piantadosi |
| author_sort | André Rogatko |
| collection | DOAJ |
| description | The standard 3 + 3 or “modified Fibonacci” up-and-down (MF-UD) method of dose escalation is by far the most used design in dose-finding cancer trials. However, MF-UD has always shown inferior performance when compared with its competitors regarding number of patients treated at optimal doses. A consequence of using less effective designs is that more patients are treated with doses outside the therapeutic window. In June 2012, the U S Food and Drug Administration (FDA) rejected the proposal to use Escalation with Overdose Control (EWOC), an established dose-finding method which has been extensively used in FDA-approved first in human trials and imposed a variation of the MF-UD, known as accelerated titration (AT) design. This event motivated us to perform an extensive simulation study comparing the operating characteristics of AT and EWOC. We show that the AT design has poor operating characteristics relative to three versions of EWOC under several practical scenarios. From the clinical investigator’s perspective, lower bias and mean square error make EWOC designs preferable than AT designs without compromising safety. From a patient’s perspective, uniformly higher proportion of patients receiving doses within an optimal range of the true MTD makes EWOC designs preferable than AT designs. |
| first_indexed | 2024-12-10T08:02:24Z |
| format | Article |
| id | doaj.art-decae53d612949bc8f82f61c199babc4 |
| institution | Directory Open Access Journal |
| issn | 1099-4300 |
| language | English |
| last_indexed | 2024-12-10T08:02:24Z |
| publishDate | 2015-07-01 |
| publisher | MDPI AG |
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| spelling | doaj.art-decae53d612949bc8f82f61c199babc42022-12-22T01:56:45ZengMDPI AGEntropy1099-43002015-07-011785288530310.3390/e17085288e17085288Escalation with Overdose Control is More Efficient and Safer than Accelerated Titration for Dose FindingAndré Rogatko0Galen Cook-Wiens1Mourad Tighiouart2Steven Piantadosi3Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., PACT, Suite 900C, Los Angeles, CA 90048, USABiostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., PACT, Suite 900C, Los Angeles, CA 90048, USABiostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., PACT, Suite 900C, Los Angeles, CA 90048, USABiostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., PACT, Suite 900C, Los Angeles, CA 90048, USAThe standard 3 + 3 or “modified Fibonacci” up-and-down (MF-UD) method of dose escalation is by far the most used design in dose-finding cancer trials. However, MF-UD has always shown inferior performance when compared with its competitors regarding number of patients treated at optimal doses. A consequence of using less effective designs is that more patients are treated with doses outside the therapeutic window. In June 2012, the U S Food and Drug Administration (FDA) rejected the proposal to use Escalation with Overdose Control (EWOC), an established dose-finding method which has been extensively used in FDA-approved first in human trials and imposed a variation of the MF-UD, known as accelerated titration (AT) design. This event motivated us to perform an extensive simulation study comparing the operating characteristics of AT and EWOC. We show that the AT design has poor operating characteristics relative to three versions of EWOC under several practical scenarios. From the clinical investigator’s perspective, lower bias and mean square error make EWOC designs preferable than AT designs without compromising safety. From a patient’s perspective, uniformly higher proportion of patients receiving doses within an optimal range of the true MTD makes EWOC designs preferable than AT designs.http://www.mdpi.com/1099-4300/17/8/5288dose findingcancer early trialsphase I trialsescalation with overdose controlaccelerated titrationEWOC |
| spellingShingle | André Rogatko Galen Cook-Wiens Mourad Tighiouart Steven Piantadosi Escalation with Overdose Control is More Efficient and Safer than Accelerated Titration for Dose Finding Entropy dose finding cancer early trials phase I trials escalation with overdose control accelerated titration EWOC |
| title | Escalation with Overdose Control is More Efficient and Safer than Accelerated Titration for Dose Finding |
| title_full | Escalation with Overdose Control is More Efficient and Safer than Accelerated Titration for Dose Finding |
| title_fullStr | Escalation with Overdose Control is More Efficient and Safer than Accelerated Titration for Dose Finding |
| title_full_unstemmed | Escalation with Overdose Control is More Efficient and Safer than Accelerated Titration for Dose Finding |
| title_short | Escalation with Overdose Control is More Efficient and Safer than Accelerated Titration for Dose Finding |
| title_sort | escalation with overdose control is more efficient and safer than accelerated titration for dose finding |
| topic | dose finding cancer early trials phase I trials escalation with overdose control accelerated titration EWOC |
| url | http://www.mdpi.com/1099-4300/17/8/5288 |
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