Principles of New Trial Designs and their Practical Implications

Clinical trials for rare diseases are typically small out of necessity. Planning a small clinical trial, particularly for a rare disease, can present several challenges. Small trials exhibit more variability than larger trials, which implies that standard designs may lead to trials adequate only for large effects.

The specific requirements of rare disease trials make adaptive designs particularly appealing. Classical trials for rare disease are typically powered for large effects. The power of a statistical test is the ability of the test to detect an effect, if the effect actually exists. In statistical terms, it is the probability that it will correctly lead to the rejection of a null hypothesis.

In some cases we may not be able to reject the null hypothesis, not because it is true, but because we do not have sufficient evidence against it. This might be because the experiment is not large enough to reject the null hypothesis. As such, the power of a test can be described as the probability of not making a Type II error (not rejecting the null hypothesis when in fact it is false).

Adaptive designs provide an appealing alternative because:

• They shorten the development process without compromising validity or efficacy.
  
• Ineffective treatments can be identified earlier on.
• They permit a more efficient use of resources.
  

However, it is important to recognise what an adaptive design can or cannot do in the case of rare diseases. Most importantly, adaptive designs cannot make a medicine more effective. They can, however, identify ineffective treatments earlier. Such early identification can minimise the resources allocated to the study of an ineffective treatment and will allow the redistribution of resources to more promising treatments.