Evaluation of performance of some enrichment designs dealing with high placebo response in psychiatric clinical trials

Chen, Yeh-Fong; Yang, Yang; Hung, H. M. James; Wang, Sue‐Jane

doi:10.1016/j.cct.2011.04.006

Cited by 69 publications

(99 citation statements)

References 10 publications

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“…9 Three of these elements are thought to represent the most critical factors in yielding high placebo response rates: diagnostic misclassification, misclassification of treatment outcome and study designs fostering high patient and clinician expectations. Clinical trial design is becoming more sophisticated including enrichment trials (see Fava et al 10 and Chen et al 11 ). New approaches include the ‘Sequential Parallel Comparison Design', 9 suitable for double-blind, placebo-controlled trials in CNS disorders.…”

Section: Subjective Ratings In Cns Disordersmentioning

confidence: 99%

Use of functional imaging across clinical phases in CNS drug development

2013

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The use of novel brain biomarkers using nuclear magnetic resonance imaging holds potential of making central nervous system (CNS) drug development more efficient. By evaluating changes in brain function in the disease state or drug effects on brain function, the technology opens up the possibility of obtaining objective data on drug effects in the living awake brain. By providing objective data, imaging may improve the probability of success of identifying useful drugs to treat CNS diseases across all clinical phases (I–IV) of drug development. The evolution of functional imaging and the promise it holds to contribute to drug development will require the development of standards (including good imaging practice), but, if well integrated into drug development, functional imaging can define markers of CNS penetration, drug dosing and target engagement (even for drugs that are not amenable to positron emission tomography imaging) in phase I; differentiate objective measures of efficacy and side effects and responders vs non-responders in phase II, evaluate differences between placebo and drug in phase III trials and provide insights into disease modification in phase IV trials.

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Section: Subjective Ratings In Cns Disordersmentioning

confidence: 99%

Use of functional imaging across clinical phases in CNS drug development

2013

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“…6 A systematic review from the Food and Drug Administration (FDA) database including 86 trials in major depressive disorder revealed that 30 trials did not have a placebo lead-in period, while 56 had. 7 The average placebo response in the first group was À9:24 (SD = 1:87) in Hamilton Rating Scale for Depression total score. Eight trials of the second group set absolute thresholds for one or more standard rating scales at the beginning and the end of the placebo leadin phase, while 48 applied both absolute and percent change criteria (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…A similar investigation of 34 schizophrenia trials provided a consistent result. 7 The sequential parallel comparison design combines a parallel group design with a placebo non-responder enriched second stage. 8 Originally described for binary endpoints, it was extended to continuous data.…”

Section: Introductionmentioning

confidence: 99%

Remarks on designs enriching for placebo non-responders

Rosenkranz

2016

Clinical Trials

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The results apply in the continuous case, and the binary or ordinary case is not studied. The findings explain to some extent the ambiguity in the assessments of the usefulness of placebo lead-in periods in clinical trials; however, besides the clear statement on variability reduction, it is not straightforward to judge upfront whether placebo lead-in is useful. Concerns relating to the conduct and interpretation of results of such trials are mentioned.

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“…A meta-analysis conducted on the FDA database (86 RCTs in major depressive disorders (MDD) and 34 RCTs in schizophrenia) indicated that the placebo lead-in design was an efficient approach in reducing the number of placebo responders and thus reducing the average response of placebo (Chen et al, 2011). However, an analysis of 75 RCTs conducted from 1981 to 2000 in MDD patients showed that the average placebo response rate of studies that used a placebo lead-in did not differ significantly from that of studies that did not use a placebo lead-in (Walsh et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

A Novel Methodology to Estimate the Treatment Effect in Presence of Highly Variable Placebo Response

Goméni¹,

Goyal

Bressolle³

et al. 2015

Neuropsychopharmacol

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One of the main reasons for the inefficiency of multicenter randomized clinical trials (RCTs) in depression is the excessively high level of placebo response. The aim of this work was to propose a novel methodology to analyze RCTs based on the assumption that centers with high placebo response are less informative than the other centers for estimating the 'true' treatment effect (TE). A linear mixed-effect modeling approach for repeated measures (MMRM) was used as a reference approach. The new method for estimating TE was based on a nonlinear longitudinal modeling of clinical scores (NLMMRM). NLMMRM estimates TE by associating a weighting factor to the data collected in each center. The weight was defined by the posterior probability of detecting a clinically relevant difference between active treatment and placebo at that center. Data from five RCTs in depression were used to compare the performance of MMRM with NLMMRM. The results of the analyses showed an average improvement of~15% in the TE estimated with NLMMRM when the center effect was included in the analyses. Opposite results were observed with MMRM: TE estimate was reduced by~4% when the center effect was considered as covariate in the analysis. The novel NLMMRM approach provides a tool for controlling the confounding effect of high placebo response, to increase signal detection and to provide a more reliable estimate of the 'true' TE by controlling false negative results associated with excessively high placebo response.

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Evaluation of performance of some enrichment designs dealing with high placebo response in psychiatric clinical trials

Cited by 69 publications

References 10 publications

Use of functional imaging across clinical phases in CNS drug development

Use of functional imaging across clinical phases in CNS drug development

Remarks on designs enriching for placebo non-responders

A Novel Methodology to Estimate the Treatment Effect in Presence of Highly Variable Placebo Response

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