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A key drawback of the traditional 3+3 design in dose escalation is its slow processing of data to reach the target dose. In contrast, the Continual Reassessment Method designs produce an expedited convergence to the target dose or the doses near target.
The primary objective of a phase I clinical trial is to establish the maximum tolerated dose (MTD). Dose-finding trials are essential in drug development as they establish recommended doses for later-phase testing. This will then ultimately be used in the new drug application (NDA). We need reliable, efficient phase I trial designs for faster, cheaper drug development.
When creating the optimal dose, there is an onus on researchers to treat each patient ethically. By incorporating efficacy and toxicity into their assessment, they reach the targeted toxicity level (TTL) or the probability of toxicity. The TTL is then used to discover the maximum tolerated dose (MTD).
A wide variety of dose finding approaches are available to researchers. These consist of algorithm or model-based designs.
Algorithm-based designs such as the 3+3 design (Carter, 1987), use rules fixed during trial design to select the MTD and allocate patients to a dose level. Dose levels are assigned using information from patients at one dose level.
Model-based designs such as continual reassessment (CRM) (O'Quigley), allocate patients to a dose level using a targeted toxicity rate and a statistical model describing the dose–toxicity relationship between the dose levels.
It is the opinion of many researchers that the CRM and model based designs would have a far larger uptake in Phase I clinical trials if an easy to use software application is available for CRM.
Cheung (2013) formulated and tested a specific method for sample size calculation for the CRM, which is now available in the latest version of nQuery.
A key drawback of the traditional 3+3 design in dose escalation is slow processing of data to reach the target dose. In contrast, CRM designs show an expedited convergence to the target dose or the doses near target.
However, the determination of the appropriate sample size remains a challenge.
Some general rules for calculating sample size are provided for CRM but are ad hoc. As a result, both researchers and reviewers alike may tend to be wary of the CRM due to safety concerns. There is a definite need for support and guidance on sample size justification early in the planning stage. This is why we have implemented this feature into the latest release of nQuery.
There are several commonly used stopping rules for CRM designs:
The calculation implemented in nQuery is based on an empirical approximation for the CRM using the power dose-toxicity function, F(d, β) = dexp(β), where d is the dose and β has a normal prior with mean 0 and variance 1.34. The sample size is found using an iteration procedure, where the smallest sample size required to achieve Bn(DLT, ψ, nLevel) ≥ APCS, for some prespecified APCS, is selected. B is the benchmark index for the MTD estimator, and it is assumed that the first patient starts at the median dose level.
The table provides an initial lower bound for the sample size, and can be used as a benchmark for further efficiency calculations. It is calibrated for the most useful and common values for phase I trials, and gives the option of calculating the APCS for a given sample size.
In addition, the relationship between the various parameters in the model and the sample size or APCS can be examined. This particular method finds its use in facilitating a quick assessment of the sample size in a phase I trial, and gives an insight as to whether a phase I dose finding trial is sufficiently powered.
Below we see how effectively the Continual Reassessment Method
can be completed in nQuery
Further Reading:
http://biostats.bepress.com/cgi/viewcontent.cgi?article=1074&context=jhubiostat
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3843987/
https://www.nature.com/articles/bjc2017186
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Bayesian Assurance: Formalizing Sensitivity Analysis For Sample Size.
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In this webinar you’ll learn about:
These Stories on Guide to Sample Size
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