Alternative names: Overall/biomarker-positive designs with sequential assessment, sequential designs, Fixed-sequence 2 designs, hierarchical fixed sequence testing procedure
Details
Utility
Might be useful in cases where the experimental treatment is expected to be effective in the overall population.
Methodology
- As these designs comprise two sequential stages, it follows that the sample size calculation should also be staged.
- At the first stage, the standard formula for a traditional randomized trial can be used for the biomarker-positive subgroup using the significance level α to estimate the treatment effect in that subgroup.
- The formula used in the enrichment designs for the required total number of events or the required number of patients can be used at the first stage of these designs.
- At the second stage, the sample size must be adjusted in order to yield appropriate power for the entire population.
Sample size Formula
- At the first stage, the standard formula for a traditional randomized trial which is the same as the formula proposed for enrichment designs can be applied for the biomarker-positive subgroup.
- At the second stage, the sample size formula proposed for marker stratified designs aiming to yield appropriate power for the entire population could be considered.
Statistical/Practical considerations
Advantages
- Can control the overall type I error α.
- Can require smaller sample size as compared to the subgroup-specific designs, especially when we assume that the novel treatment equally benefits both biomarker-defined subgroups.
Limitations
- Can be problematic for determining whether the treatment is beneficial in the biomarker-negative subgroup.
- Cannot control the probability of rejecting the null hypothesis of no treatment effect in the biomarker-negative subgroup when the treatment benefit is restricted to biomarker-positive patients. Consequently, there is a high risk of inappropriately recommending the novel treatment for biomarker-negative patients due to the large treatment effect in the biomarker-positive subgroup.
Key references
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- European Medicines Agency. Reflection Paper on Methodological Issues Associated with Pharmacogenomic Biomarkers in Relation to Clinical Development and Patient Selection. Available online: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/07/WC500108672.pdf (accessed on 10 October 2015).
- Matsui, S.; Choai, Y.; Nonaka, T. Comparison of statistical analysis plans in randomize-all phase III trials with a predictive biomarker. Clin. Cancer Res. 2014, 20, 2820–2830. [Google Scholar] [CrossRef] [PubMed]