Friday, October 8, 2010

Trials with bolted on adaptive components

All too often, I get a request to make a trial adaptive. In a lot of cases, adaptations were considered but rejected, but the sample size was too large given considerations such as dropout. Of course, this is a delicate time in sponsor-CRO relations, because emotions are already running high due to the frustration in spending the time considering a lot of alternatives that are already rejected. There is further danger in that the sponsor is, in fact, asking for a fundamental change to a trial that has already been designed.

Adaptive trials are best designed with the adaptation already in mind. This is because the adaptive component affects many aspects of the trial. In addition, the additional planning required for an additive trial can be more easily done if it is worked in from the beginning.

In the case where adaptation is used to rescue a trial, it's probably best to take the time to effectively start from the beginning, at least in making sure the time and events table makes sense. Barring that, I will often recommend one futility analysis be performed. The reason I do this are as follows:

* no adjustment to stated Type 1 error rate is required

* it's relatively easy to "bolt on" to an existing trial

* under the most common circumstances under which this late consideration is done (late Phase 1 or Phase 2 trial) this strategy will prevent wasting too much money on a worthless compound

Of course, not all trials benefit from a futility analysis, but I recommend this strategy almost categorically in cases where a sponsor wants to add one interim analysis to an otherwise designed trial.

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