TY - JOUR
T1 - Reducing placebo exposure in trials
AU - Fureman, Brandy E.
AU - Friedman, Daniel
AU - Baulac, Michel
AU - Glauser, Tracy
AU - Moreno, Jonathan
AU - Dixon-Salazar, Tracy
AU - Bagiella, Emilia
AU - Connor, Jason
AU - Ferry, Jim
AU - Farrell, Kathleen
AU - Fountain, Nathan B.
AU - French, Jacqueline A.
N1 - Publisher Copyright:
© 2017 American Academy of Neurology.
PY - 2017/10/3
Y1 - 2017/10/3
N2 - The randomized controlled trial is the unequivocal gold standard for demonstrating clinical efficacy and safety of investigational therapies. Recently there have been concerns raised about prolonged exposure to placebo and ineffective therapy during the course of an add-on regulatory trial for new antiepileptic drug approval (typically ∼6 months in duration), due to the potential risks of continued uncontrolled epilepsy for that period. The first meeting of the Research Roundtable in Epilepsy on May 19-20, 2016, focused on "Reducing placebo exposure in epilepsy clinical trials," with a goal of considering new designs for epilepsy regulatory trials that may be added to the overall development plan to make it, as a whole, safer for participants while still providing rigorous evidence of effect. This topic was motivated in part by data from a meta-analysis showing a 3-to 5-fold increased rate of sudden unexpected death in epilepsy in participants randomized to placebo or ineffective doses of new antiepileptic drugs. The meeting agenda included rationale and discussion of different trial designs, including active-control add-on trials, placebo add-on to background therapy with adjustment, time to event designs, adaptive designs, platform trials with pooled placebo control, a pharmacokinetic/pharmacodynamic approach to reducing placebo exposure, and shorter trials when drug tolerance has been ruled out. The merits and limitations of each design were discussed and are reviewed here.
AB - The randomized controlled trial is the unequivocal gold standard for demonstrating clinical efficacy and safety of investigational therapies. Recently there have been concerns raised about prolonged exposure to placebo and ineffective therapy during the course of an add-on regulatory trial for new antiepileptic drug approval (typically ∼6 months in duration), due to the potential risks of continued uncontrolled epilepsy for that period. The first meeting of the Research Roundtable in Epilepsy on May 19-20, 2016, focused on "Reducing placebo exposure in epilepsy clinical trials," with a goal of considering new designs for epilepsy regulatory trials that may be added to the overall development plan to make it, as a whole, safer for participants while still providing rigorous evidence of effect. This topic was motivated in part by data from a meta-analysis showing a 3-to 5-fold increased rate of sudden unexpected death in epilepsy in participants randomized to placebo or ineffective doses of new antiepileptic drugs. The meeting agenda included rationale and discussion of different trial designs, including active-control add-on trials, placebo add-on to background therapy with adjustment, time to event designs, adaptive designs, platform trials with pooled placebo control, a pharmacokinetic/pharmacodynamic approach to reducing placebo exposure, and shorter trials when drug tolerance has been ruled out. The merits and limitations of each design were discussed and are reviewed here.
UR - http://www.scopus.com/inward/record.url?scp=85030751523&partnerID=8YFLogxK
U2 - 10.1212/WNL.0000000000004535
DO - 10.1212/WNL.0000000000004535
M3 - Article
C2 - 28878049
AN - SCOPUS:85030751523
SN - 0028-3878
VL - 89
SP - 1507
EP - 1515
JO - Neurology
JF - Neurology
IS - 14
ER -