The use of clinical trial simulation to support dose selection: application to development of a new treatment for chronic neuropathic pain.

PURPOSE: Pregabalin is being evaluated for the treatment of neuropathic pain. Two phase 2 studies were simulated to determine how precisely the dose that caused a one-point reduction in the pain score could be estimated. The likelihood of demonstrating at least a one-point change for each available dose strength was also calculated.
METHODS: A pharmacokinetic-pharmacodynamic (PK/PD) model relating pain relief to gabapentin plasma concentrations was derived from a phase 3 study. The PK component of the model was modified to reflect pregabalin PK. The PD component was modified by scaling the gabapentin concentration-effect relationship to reflect pregabalin potency, which was based on preclincal data. Uncertainty about the potency difference and the steepness of the concentration-response slope necessitated simulating a distribution of outcomes for a series of PK/PD models.
RESULTS: Analysis of the simulated data suggested that after accounting for the uncertainty, there was an 80% chance that the dose defining the clinical feature was within 45% of the true value. The likelihood of estimating a dose that was within an acceptable predefined precision range relative to a known value approximated 60%. The minimum dose that should be studied to have a reasonable chance of estimating the dose that caused a one-point change was 300 mg.
CONCLUSIONS: Doses that identify predefined response may be imprecisely estimated, suggesting that replication of a similar outcome may be elusive in a confirmatory study. Quantification of this precision provides a rationale for phase 2 trial design and dose selection for confirmatory studies.