Login / Signup

Beyond the two-trials rule.

Leonhard Held
Published in: Statistics in medicine (2024)
The two-trials rule for drug approval requires "at least two adequate and well-controlled studies, each convincing on its own, to establish effectiveness." This is usually implemented by requiring two significant pivotal trials and is the standard regulatory requirement to provide evidence for a new drug's efficacy. However, there is need to develop suitable alternatives to this rule for a number of reasons, including the possible availability of data from more than two trials. I consider the case of up to three studies and stress the importance to control the partial Type-I error rate, where only some studies have a true null effect, while maintaining the overall Type-I error rate of the two-trials rule, where all studies have a null effect. Some less-known P $$ P $$ -value combination methods are useful to achieve this: Pearson's method, Edgington's method and the recently proposed harmonic mean χ 2 $$ {\chi}^2 $$ -test. I study their properties and discuss how they can be extended to a sequential assessment of success while still ensuring overall Type-I error control. I compare the different methods in terms of partial Type-I error rate, project power and the expected number of studies required. Edgington's method is eventually recommended as it is easy to implement and communicate, has only moderate partial Type-I error rate inflation but substantially increased project power.
Keyphrases
  • case control
  • systematic review
  • randomized controlled trial
  • quality improvement
  • transcription factor
  • big data
  • stress induced