A sequential enriched design for target patient population in psychiatric
clinical trials.
Author(s): Chen YF(1), Zhang X, Tamura RN, Chen CM.
Affiliation(s): Author information:
(1)Division of Biometrics I, Office of Biostatistics, Office of Translational
Sciences, Center of Drug Evaluation and Research (CDER), US Food and Drug
Administration, Silver Spring, MD, U.S.A.
Publication date & source: 2014, Stat Med. , 33(17):2953-67
High placebo response is widely believed to be one major reason why many
psychiatric clinical trials fail to demonstrate drug efficacy. In order to
alleviate this problem, research has developed several enrichment designs,
including the parallel design with a placebo lead-in phase, the sequential
parallel design, and a recently proposed two-way enriched design. While these
designs have been evaluated and discussed individually, their effectiveness
against each other has not been rigorously compared. The current study examines
the various enrichment designs simultaneously. Building on their strengths, we
introduce a new improved design named' sequential enriched design' (SED) aimed at
removing not only patients with high placebo response but also patients who do
not respond to any treatment from the study. The SED begins with a double-blind
placebo lead-in phase followed by a traditional parallel design in the first
stage. Only patients who respond to the drug in the first stage are re-randomized
to the drug or placebo at the second stage. We simulate data for a mixed
population composed of four subgroups of patients who are predetermined as to
whether they respond to drug or not as well as to placebo or not. By focusing on
the target patients whose responses reflect the drug's efficacy,we evaluate the
bias, mean squared error, and power for different designs. We demonstrate that
the SED produces a less biased estimate for the target treatment effect and
yields reasonably high power in general compared with the other designs.
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