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Abstract:
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Two crossover designs have been proposed in order to demonstrate disease modification in clinical trials: the Randomized Withdrawal and the Staggered Start studies. An effect that continues after the drug is removed is disease modifying, but this Randomized Withdrawal design is difficult to implement due to ethical concerns. A Staggered Start design avoids this issue, but requires a long trial period. These study designs are compared mathematically and are shown to be equivalent with minimal assumptions. A new 'natural history staggered start' design using parallel groups is shown under certain conditions to be equivalent to or more stringent than the crossover designs. In these conditions it is superior, because it allows measurement of the same underlying patterns of drug effect, without the operational complications of longer trials, drop-out bias, and ethical concerns.
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