Proof of efficacy trials: choosing the dose

It is apparent from current usage of antiepileptic drugs (AEDs) and from retrospective review of their drug development programmes, that the doses currently used in clinical practice differ from those which were used in clinical trials. This raises the question of how dose and titration schedules are selected in early development. An integral component of a drug development programme should be an assessment of dose response. The International Council on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use [1994. Guidelines for industry: Dose-response information to support drug registration. ICH-E4. Federal Register] regulatory guidelines suggest that, at a minimum, three elements of dosing should be characterised: a maximum well tolerated dose, a minimum effective dose, and an appropriate rate of titration. Several specific designs can be utilised to assess dose response, which fall broadly into four categories, namely free titration, forced titration and dose escalation, parallel dose response, and dose reduction studies. In addition to these standard approaches, concentration-defined trials are an alternative in some circumstances and have been used with success in the development of newer AEDs. The designs chosen to address these elements are dependent upon the phase of development of the drug, and the severity of the disease, however, it is clear that conducting dose response studies earlier in the development programme may reduce the number of failed Phase 3 studies.