A Regulatory View on Adaptive/Flexible Clinical Trial Design

Hung, H. M. James; O’Neill, Robert T.; Wang, Sue‐Jane; Lawrence, John

doi:10.1002/bimj.200610229

Cited by 67 publications

(45 citation statements)

References 35 publications

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“…This dilemma has led to the development of adaptive trial designs [9][10][11][12][13][14] . If investigators can determine early-on which types of patients are most likely to benefit from a novel treatment, then the trail can be re-targeted to favorable patients only.…”

Section: Discussionmentioning

confidence: 99%

Choosing inclusion criteria that minimize the time and cost of clinical trials

Babbs¹

2014

WJM

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AIM:To present statistical tools to model and optimize the cost of a randomized clinical trial as a function of the stringency of patient inclusion criteria. METHODS:We consider a two treatment, dichotomous outcome trial that includes a proportion of patients who are strong responders to the tested intervention. Patients are screened for inclusion using an arbitrary number of test results that are combined into an aggregate suitability score. The screening score is regarded as a diagnostic test for the responsive phenotype, having a specific cutoff value for inclusion and a particular sensitivity and specificity. The cutoff is a measure of stringency of inclusion criteria. Total cost is modeled as a function of the cutoff value, number of patients screened, the number of patients included, the case occurrence rate, response probabilities for control and experimental treatments, and the trial duration required to produce a statistically significant result with a specified power. Regression methods are developed to estimate relevant model parameters from pilot data in an adaptive trial design. RESULTS:The patient numbers and total cost are strongly related to the choice of the cutoff for inclusion. Clear cost minimums exist between 5.6 and 6.1 on a representative 10-point scale of exclusiveness. Potential cost savings for typical trial scenarios range in millions of dollars. As the response rate for controls approaches 50%, the proper choice of inclusion criteria can mean the difference between a successful trial and a failed trial. CONCLUSION:Early formal estimation of optimal inclusion criteria allows planning of clinical trials to avoid high costs, excessive delays, and moral hazards of Type II errors.© 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: Adaptive trial designs; Biomarkers; Clinical trials; Device; Drug therapy; Ethics; Methodology; Optimal allocation; Personalized medicine; Sequential design Core tip: This paper presents statistical tools to model and optimize the cost of a randomized clinical trial as a function of the stringency of patient inclusion criteria. The patient numbers and total cost are strongly related to the choice of the cutoff for inclusion. Clear cost minimums exist for many realistic scenarios. Potential cost savings for typical trial scenarios range in millions of dollars. Early formal estimation of optimal inclusion criteria allows planning of clinical trials to avoid high costs, excessive delays, and moral hazards of type Ⅱ errors.Babbs CF. Choosing inclusion criteria that minimize the time and cost of clinical trials. World

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Section: Discussionmentioning

confidence: 99%

Choosing inclusion criteria that minimize the time and cost of clinical trials

Babbs¹

2014

WJM

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“…Such research is currently done, e.g., in the area of adaptive design. On the other hand, it is made clear that these methods have to be applied in a convincing and transparent way to be acceptable in areas with impact on public health (Hung et al, 2006;Koch, 2006). My own experience is that this should be possible.…”

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confidence: 94%

“…Two further papers (Hung et al, 2006;Koch, 2006) mainly deal with regulatory concerns about adaptive designs. The authors of the first paper from the FDA have contributed innovative methodological research within this area themselves and so their arguments deserve special attention.…”

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confidence: 99%

Methodological Developments vs. Regulatory Requirements

Bauer

2006

Biometrical J

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This is a discussion of the following three papers appearing in this special issue on adaptive designs: 'FDA's critical path initiative: A perspective on contributions of biostatistics' by Robert T. O'Neill, 'A regulatory view on adaptive/flexible clinical trial design' by H. M. James Hung, Robert T. O'Neill, Sue-Jane Wang and John Lawrence; and 'Confirmatory clinical trials with an adaptive design' by Armin Koch.

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“…Thus, the papers by O'Neill (2006), by Hung et al (2006), and by Koch (2006) are welcome additions to the literature. Collectively, they strike a careful balance between encouraging adoption of these methods when appropriate, especially in early phase trials, but they warn the potential user against too eager use of these tools.…”

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confidence: 94%

Opening the Adaptive Toolbox

Wittes

Lachenbruch

2006

Biometrical J

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This is a discussion of the following three papers appearing in this special issue on adaptive designs: 'A regulatory view on adaptive/flexible clinical trial design' by H. M. James Hung, Robert T. O'Neill, Sue-Jane Wang and John Lawrence; 'Confirmatory clinical trials with an adaptive design' by Armin Koch; and 'FDA's critical path initiative: A perspective on contributions of biostatistics' by Robert T. O'Neill.

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A Regulatory View on Adaptive/Flexible Clinical Trial Design

Cited by 67 publications

References 35 publications

Choosing inclusion criteria that minimize the time and cost of clinical trials

Choosing inclusion criteria that minimize the time and cost of clinical trials

Methodological Developments vs. Regulatory Requirements

Opening the Adaptive Toolbox

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