CRM Suite
(what was new in previous versions, known as BMA-CRM Simulator)

What was new BMA-CRM Simulator (V2.2.3)

• Menus are modernized; a minor bug in the “Recent Files” system is fixed.
• The .NET Framework used has been upgraded to 4.5.2.
• There are other improvements.

What was New in V2.2.2

• The Trial Conduct Tab is Operational! The Trial Conduct tab has been completely rewritten to improve it and to accommodate trials which use Data Augmentation. Now you can delete patients, get a trial conduct decision without committing to treating a patient, view the state of the trial at any point in its history, and more. Each trial decision now comes with an extensive description explaining the details of the decision and how it was obtained.
• Scenario Grid: Scenarios can now be given meaningful names and can be reordered.
• MTD Determination: The rules for determining the MTD have been changed to better match users' expectations and actual practice. Note that this change should not affect well-designed trials whose maximum sample size is reasonably large (see below). The MTD is now required to have had at least three patients treated on it. If the dose level closest to the target probability of toxicity without skipping untried dose levels has had fewer than three patients treated on it, the highest dose level lower than this dose level which has had at least three patients treated on it is determined to be the MTD. If no such dose level exists, the MTD is determined to be the dose level closest to the target probability of toxicity without skipping untried dose levels, but you are warned that the determination of the MTD has a high degree of uncertainty because there were too few patients treated at that dose level.
• Maximum Sample Size: We now recommend that the maximum sample size be at least three times the number of dose levels. If a lower maximum sample size is specified, we warn you and include a warning in the simulation output.
• Dose Level Escalation: For increased safety and to better match users' expectations and actual practice, we now limit dose level escalation in some circumstances. We now do not allow escalation away from a dose level for which the current raw proportion of toxicities is above the target probability of toxicity. That is to say, if the proportion of toxicities among all currently fully observed patient outcomes at a dose level is above the target probability of toxicity, we do not allow escalation away from that dose level. If escalation would otherwise be recommended but this rule applies, it is still recommended to treat a patient, but the dose level on which the patient should be treated is lower than it would otherwise be. Note that in the rare circumstance that this rule needs to be applied to a dose level at which no patient outcomes have been fully observed, it is assumed that the dose level does not have a raw proportion of toxicities above the target probability of toxicity. This is because this rare circumstance should only arise with trial designs which assume for other reasons that escalating away from such a dose level is acceptable.
• Power User Features: Some features have been added for use by experts investigating the Data Augmentation calculations. These features are not available by default.
• Many improvements and bug fixes.

What was New in V2.2.1

• Trial Design:
  • Data Augmentation: If desired, the trial design will use Data Augmentation (DA) when patient data are missing. This allows treatment decisions and trial safety decisions to be made without waiting for missing data to become known, greatly reducing the expected trial duration. When DA is chosen, you are limited to one set of prior probabilities of toxicity for the dose levels. More information about using Data Augmentation in CRM can be found in DA Method Description. When DA is chosen, you must specify additional trial design parameters specifically for DA.
  • Toxicity Assessment Period: You now must specify the toxicity assessment period. Of course this needs to be specified for DA, but it is also now used in simulation with or without DA so that we may estimate expected trial duration.
• Simulation:
  • Accrual Rate: You must specify the accrual rate when simulating, so that expected trial duration may be estimated. The accrual rate may also affect the operating characteristics when DA is chosen.
  • Proportion of Toxicities Observed in Second Half of Assessment Period: This, along with the probability of toxicity, parameterizes the Weibull distribution now used to simulate time to toxicity at each dose level.
  • Multithreading: The simulations are multithreaded on machines with more than two cores, greatly reducing the time required to perform them.
  • Trial Duration: Expected trial duration (total trial time) is estimated.
• Many other improvements.

What was New in V2.1.2

• IMPORTANT: The inputs for the sets of prior probability of toxicity at each dose level are now user-specified as prior MEDIANS. (Previous versions expected them to be prior means, and calculated the corresponding prior medians.) So what you input for these values has changed since it is a different statistic compared to versions older than v2.1. For the dose-toxicity model π_j(α) = p_j^exp(α), the inputs for the prior probabilities of toxicity at each dose level are now used directly as the p_j values, which are the prior medians. See this technical report for an explanation of the prior median, and note that the BMA Method Description describes the old method of using the inputs as prior means, but is otherwise correct.
• NOTE: Simulation files created with older versions will not open in v2.1. If you wish to use an old trial design you will need to re-enter your design, bearing in mind that the sets of prior probabilities of toxicity at each dose level are now prior medians. If you use the same input values with v2.1 as you used with an older version and re-simulate, you may obtain different results.
• Various updates and bug fixes.
• The program occasionally sends usage statistics and crash reports to our biostatistics software support team to improve your experience using the software.

References

1. Guosheng Yin, and Ying Yuan (2009). Bayesian Model Averaging Continual Reassessment Method in Phase I Clinical Trials. Journal of American Statistical Association, 104, 954-968.
2. Suyu Liu, Guosheng Yin, and Ying Yuan (2013). Bayesian Data Augmentation Dose Finding with Continual Reassessment Method and Delayed Toxicity. The Annals of Applied Statistics, Vol 7, No. 4, 2138-2156