5. Dose Escalation Scheme and Transition to Next Dose Cohort

  1. The dose increment between two dose levels should be guided by the dose/toxicity or dose/effect relationship defined in non-clinical studies, depending on whichever is steeper where this information is available.

  2. The steeper the increase in the dose/toxicity or dose/effect curves, the lower the dose increment that should be selected.

  3. Information on exposure, effect, and safety from the preceding dose in human should be taken into account. Since the initial doses may be very low, it is anticipated that early cohorts may not show any pharmacological effects. Where there is no response in a cohort the precautions for the next cohort should be the same as for the previous cohort.
The protocol should define stopping rules based on safety criteria for the cohort and trial.