It is difficult to design valid and well-controlled monotherapy trials that
satisfy regulatory requirements and, at the same time, demonstrate the use
fulness of a new drug in clinical practice. The conversion design is a drug
-substitution trial in which patients with uncontrolled seizures are assign
ed to add-on treatment with an investigational drug and, usually, an approp
riate control, after which pre-existing treatment is gradually discontinued
. In the most utilised design, patients are randomised to receive a high do
se versus low dose of the new drug, while concomitant medication is gradual
ly discontinued. Exit criteria are predetermined to prevent excessive deter
ioration of seizures, and treatment retention time is used as the primary o
utcome variable to measure the effectiveness of the allocated treatments: t
he goal is to demonstrate higher retention rates in the high-dosage group.
Conversion studies may help to fill some gaps in knowledge regarding effica
cy and tolerability as monotherapy before larger-scale de-novo studies are
started. In the de-novo design, newly diagnosed patients ale randomised to
receive the investigational drug or an active control. In equivalence (or n
on-inferiority) trials, the active control is usually an established antiep
ileptic drug (AED) such as carbamazepine or valproate, and outcome paramete
rs may include proportion of patients achieving a predefined (for example,
B-month) seizure remission or the proportion of patients remaining in the t
rial (retention rate, a combined measure of efficacy and tolerability). In
regulatory trials designed to show a difference, newly diagnosed patients a
re randomised to a high versus a low dose of the investigational drug, and
exit criteria are again predetermined for patients whose seizures are not a
dequately controlled. In this case, outcome parameters may include time to
first seizure in addition to retention in the trial. Comparative monotherap
y trials in newly diagnosed patients are relevant to approximately 50% of t
he patients who develop epilepsy and can be satisfactorily managed with a s
ingle drug. These trials allow direct head-to-head comparisons and avoid th
e confounding effects of baseline drugs and co-medication withdrawal presen
t in conversion studies. Long-term follow-up of patients who are receiving
a drug in monotherapy at adequate doses gives the most clinically relevant
answers regarding the usefulness of a new drug. It is concluded that the de
-novo design is the gold standard when studying AEDs as monotherapy, but th
e conversion-to-monotherapy design can be used before starting the de-novo
program in order to obtain estimates of efficacy and tolerability of the AE
D as monotherapy in a population of difficult-to-treat patients. With both
designs, the use of suboptimal comparators incorporated into some of the re
gulatory trials is a cause of ethical concern. (C) 2001 Published by Elsevi
er Science B.V.