Dose-finding: why start at the lowest dose?

You’ve got a new drug and it’s time to test it on patients. How much of the drug do you give? That’s the question dose-finding trials attempt to answer.

The typical dose-finding procedure starts by selecting a small number of dose levels, say four or five. The trial begins by giving the lowest dose to the first few patients, and there is some procedure for deciding when to try higher doses. Convention says it is unethical to start at any dose other than lowest dose. I will give several reasons to question convention.

Suppose you want to run a clinical trial to test the following four doses of Agent X: 10 mg, 20 mg, 30 mg, 50 mg. You want to start with 20 mg. Your trial goes for statistical review and the reviewer says your trial is unethical because you are not starting at the lowest dose. You revise your protocol saying you only want to test three doses: 20 mg, 30 mg, and 50 mg. Now suddenly it is perfectly ethical to start with a dose of 20 mg because it is the lowest dose.

The more difficult but more important question is whether a dose of 20 mg of Agent X is medically reasonable. The first patient in the trial does not care whether higher or lower doses will be tested later. He only cares about the one dose he’s about to receive. So rather than asking “Why are you starting at dose 2?” reviewers should ask “How did you come up with this list of doses to test?”

A variation of the start-at-the-lowest-dose rule is the rule to always start at “dose 1″. Suppose you revise the original protocol to say dose 1 is 20 mg, dose 2 is 30 mg, and dose 3 is 50 mg. The protocol also includes a “dose -1″ of 10 mg. You explain that you do not intend to give dose -1, but have included it as a fallback in case the lowest dose (i.e. 20 mg) turns out to be too toxic. Now because you call 20 mg “dose 1″ it is ethical to begin with that dose. You could even begin with 30 mg if you were to label the two smaller doses “dose -2″ and “dose -1.” With this reasoning, it is ethical to start at any dose, as long as you call it “dose 1.” This approach is justified only if the label “dose 1″ carries the implicit endorsement of an expert that it is a medically reasonable starting dose.

Part of the justification for starting at the lowest dose is that the earliest dose-finding methods would only search in one direction. This explains why some people still speak of “dose escalation” rather than “dose-finding.” More modern dose-finding methods can explore up and down a dose range.

The primary reason for starting at the lowest dose is fear of toxicity. But when treating life-threatening diseases, one could as easily justify starting at the highest dose for fear of under treatment. (Some trials do just that.) Depending on the context, it could be reasonable to start at the lowest, highest, or any dose in between.

The idea of first selecting a range of doses and then deciding where to start exploring seems backward. It makes more sense to first pick the starting dose, then decide what other doses to consider.

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Posted in Clinical trials, Statistics