Dose Finding Experiments

In a past entry, I spoke about some issues in clinical trial design, explaining their structure and different phases.  Now, I am focusing in a part of these trials, the two first phases, which could be also a complete experiment by themselves, i.e. dose finding experiments.

The aim of a dose-finding experiment is a safe and efficient drug administration in humans. When a new drug (or procedure) is under study, we want to determine a safe dose of the drug for application but this dose should also be efficient. A balance between these two goals, non-toxicity and efficiency, is required in clinical trials.

Ethical concerns become essential in these experiments, same as in any experiment conducted on human beings, but especially because they are first-in-man studies, so the safety of the participants is the main worry. They also have a very small sample size, usually about 20 patients, therefore becoming a problem for the statistical analysis.

In phase 1 trials, the target is the evaluation of the maximum tolerated dose (MTD), the highest dose level with a pre-established observed toxicity rate. Depending on the risk of the experiment, a toxicity rate is fixed and the maximum dose level which does not exceed this toxicity rate is chosen. Then the recommended dose for the next phases of the study is either the MTD or one dose level less than the MTD. In phase 2 trials, we have an analogous experiment but now the target is the minimal effective dose, MED, which is the minimum dose level with a fixed efficiency rate. It is also common to try to combine these two targets in a single experiment, estimating a toxicity-efficiency curve and looking for an optimal dose that mixes these two goals.

A wide catalogue of designs for dose-finding experiments could be found in the statistical literature. The initial dose, the dose escalation, the stopping point and accuracy in the estimation of the MTD and MED are the main concerns in a design and they still are a fertile area for ​​research. A classical design in phase 1 is the traditional 3+3 design, very used in oncology experiments. In this design, patients are assigned in groups of three and the trial starts in the lowest dose level.  The first three patients are assigned and if it does not show any toxicity, we assign the next patients to the next level; if there is one case of toxicity, we repeat the experiment in the same level, and if there are two or more toxicities in the same level, we conclude that we have exceeded the MTD. This procedure is repeated until we exceed the MTD.

Phases 1 and 2  have been much less treated theoretically than phase 3 of clinical trials, but with this post I wanted to show up their  importance and try to make them more understandable to people who work in statistics.


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