Confirmatory Seamless Phase II/III Clinical Trials with Hypotheses Selection at Interim: Applications and Practical Considerations

Schmidli, Heinz; Bretz, Frank; Racine, Amy; Maurer, Willi

doi:10.1002/bimj.200510231

Cited by 105 publications

(97 citation statements)

References 16 publications

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“…One of the adaptive designs that has led to numerous studies [1,5,27,28] and which has been considered as one of the most promising [2] is the seamless phase 2-3 design. This design combines two development phases traditionally carried out in separate trials in one single study.…”

Section: Seamless Phase 2(b)-3 Trialsmentioning

confidence: 99%

“…The adaptive trial concept recently generated considerable interest both in biostatistical literature (special editions of the Journal of Biopharmaceutical Statistics in 2005 and the Biometrical Journal in 2006, literature reviews), [1][2][3][4][5] and with regulatory agencies. [6][7][8] According to the authors, this concept can group together extremely different ideas.…”

Section: Introductionmentioning

confidence: 99%

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Adaptive Methods: When and How Should They be Used in Clinical Trials?

2011

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-Adaptive clinical trial designs are defined as designs that use data cumulated during trial to possibly modify certain aspects without compromising the validity and integrity of the said trial. Compared to more traditional trials, in theory, adaptive designs allow the same information to be generated but in a more efficient manner. The advantages and limits of this type of design together with the weight of the constraints, in particular of a logistic nature, that their use implies, differ depending on whether the trial is exploratory or confirmatory with a view to registration. One of the key elements ensuring trial integrity is the involvement of an independent committee to determine adaptations in terms of experimental design during the study. Adaptive methods for clinical trials are appealing and may be accepted by the relevant authorities. However, the constraints that they impose must be determined well in advance.

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Section: Seamless Phase 2(b)-3 Trialsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adaptive Methods: When and How Should They be Used in Clinical Trials?

2011

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“…Recent work that can also be described under the heading of multivariate analyses is research into combining phases II and III into a single, seamless trial. Several authors have considered this question, taking a variety of different approaches [125][126][127][128].…”

Section: Multivariate Analysesmentioning

confidence: 99%

A 25‐year review of sequential methodology in clinical studies

Todd

2006

Statistics in Medicine

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SUMMARYThis paper explores the theoretical developments and subsequent uptake of sequential methodology in clinical studies in the 25 years since Statistics in Medicine was launched. The review examines the contributions which have been made to all four phases into which clinical trials are traditionally classified and highlights major statistical advancements, together with assessing application of the techniques. The vast majority of work has been in the setting of phase III clinical trials and so emphasis will be placed here. Finally, comments are given indicating how the subject area may develop in the future.

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“…Alternatively, a target subpopulation can be identified at the end of a broad eligibility trial under an adaptive signature design, [7][8][9][10] or at an interim analysis (with the possibility of restricting subsequent enrollment) under an adaptive enrichment design (AED). [11][12][13][14][15][16][17][18][19] The various approaches have been discussed and compared by Wang, O'Neill and Hun, 20 FDA, 21 Wang and Hung, 22 Chen et al, 23 and Simon. 24 Most of the existing literature on AEDs (cited above) deals with one or two predefined subgroups, although Lai, Liao, and Kim 17 and Magnusson and Turnbull 18 consider multiple predefined subgroups.…”

Section: Introductionmentioning

confidence: 99%

Treatment evaluation for a data‐driven subgroup in adaptive enrichment designs of clinical trials

Zhang

Chen

Soon

et al. 2017

Statistics in Medicine

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Adaptive enrichment designs (AEDs) of clinical trials allow investigators to restrict enrollment to a promising subgroup based on an interim analysis. Most of the existing AEDs deal with a small number of predefined subgroups, which are often unknown at the design stage. The newly developed Simon design offers a great deal of flexibility in subgroup selection (without requiring pre-defined subgroups) but does not provide a procedure for estimating and testing treatment efficacy for the selected subgroup. This article proposes a 2-stage AED which does not require predefined subgroups but requires a prespecified algorithm for choosing a subgroup on the basis of baseline covariate information. Having a prespecified algorithm for subgroup selection makes it possible to use cross-validation and bootstrap methods to correct for the resubstitution bias in estimating treatment efficacy for the selected subgroup. The methods are evaluated and compared in a simulation study mimicking actual clinical trials of human immunodeficiency virus infection.

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Confirmatory Seamless Phase II/III Clinical Trials with Hypotheses Selection at Interim: Applications and Practical Considerations

Cited by 105 publications

References 16 publications

Adaptive Methods: When and How Should They be Used in Clinical Trials?

Adaptive Methods: When and How Should They be Used in Clinical Trials?

A 25‐year review of sequential methodology in clinical studies

Treatment evaluation for a data‐driven subgroup in adaptive enrichment designs of clinical trials

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