Improved two-stage group sequential procedures for testing a secondary endpoint after the primary endpoint achieves
Huiling Li1, Jianming Wang1, Xiaolong Luo1
1Department of Biostatistics, Celgene Corporation, Berkeley Heights, NJ, USA.
Biometrical Journal. Biometrische Zeitschrift
|June 8, 2018
Summary
New group sequential testing procedures enhance power for secondary endpoints in clinical trials. These methods improve statistical significance testing for secondary outcomes while controlling overall error rates.
Area of Science:
- Biostatistics
- Clinical Trial Design
- Statistical Inference
Background:
- Group sequential trials commonly use alpha-level boundaries (e.g., O'Brien-Fleming, Pocock) for primary endpoints.
- Secondary endpoints are tested hierarchically, conditional on primary endpoint significance, often leading to power loss.
- Existing methods for secondary endpoint error control (e.g., Bonferroni) can be conservative, further reducing power.
Purpose of the Study:
- To propose novel group sequential testing procedures designed to increase statistical power for secondary endpoints.
- To develop methods that effectively transfer significance from primary to secondary endpoints while maintaining strong familywise error rate (FWER) control.
- To compare the performance of proposed procedures against existing methods regarding FWER and secondary hypothesis rejection power.
Main Methods:
- Development of two new procedures: the improved Bonferroni and improved Pocock procedures.
- Utilizing the correlation between interim and final statistics for the secondary endpoint.
- Application of graphical approaches to transfer alpha levels from the primary to the secondary endpoint.
- Validation of FWER control through simulation studies.
Main Results:
- The proposed improved Bonferroni and improved Pocock procedures strongly control the familywise error rate (FWER) by construction.
- Simulations confirm robust FWER control for the new procedures.
- The proposed methods demonstrate improved power for rejecting the secondary hypothesis compared to standard approaches.
Conclusions:
- The improved Bonferroni and improved Pocock procedures offer enhanced statistical power for secondary endpoints in group sequential trials.
- These methods provide a valuable alternative for optimizing clinical trial efficiency when both primary and secondary outcomes are of interest.
- The procedures maintain strong statistical rigor by ensuring FWER control.
Related Concept Videos
01:19Precipitation Titration: Endpoint Detection Methods
6.0K
In argentometric precipitation titrations, endpoints can be detected visually by the Mohr, Volhard, and Fajans methods. In the Mohr method, adding a soluble chromate indicator gives an initial yellow color to the analyte solution. As the titrant is added, the first excess of silver ions forms a red silver chromate precipitate, marking the endpoint. The solution pH should be maintained at about 8 by adding solid CaCO3.
In the Volhard method, a standard excess of AgNO3 is first added to the...
In the Volhard method, a standard excess of AgNO3 is first added to the...
6.0K
03:02Primary and Secondary Growth in Roots and Shoots
60.6K
Vascular plants, which account for over 90% of the Earth’s vegetation, all undergo primary growth—which lengthens roots and shoots. Many land plants, notably woody plants, also undergo secondary growth—which thickens roots and shoots.
60.6K
01:04Significance Testing: Overview
12.7K
Significance testing is a set of statistical methods used to test whether a claim about a parameter is valid. In analytical chemistry, significance testing is used primarily to determine whether the difference between two values comes from determinate or random errors. The effect of a particular change in the measurement protocol, analyst, or sample itself can cause a deviation from the expected result. In the case of a suspected deviation/outlier, we need to be able to confirm mathematically...
12.7K
01:27Secondary Motives: Power Motivation and Achievement Motivation
582
Power motivation and achievement motivation are two essential social motives identified by psychologist David McClelland. These motives influence behavior in various personal and professional contexts, shaping how individuals interact with others and pursue their goals.
Power motivation is characterized by the desire to influence, control, or have an impact on others. It is shaped by an individual's experiences, social environment, and cultural context. People with high power motivation are...
Power motivation is characterized by the desire to influence, control, or have an impact on others. It is shaped by an individual's experiences, social environment, and cultural context. People with high power motivation are...
582
01:23Primary and Secondary Reinforcers
1.0K
In psychology, reinforcement is a key concept in behavior modification. B.F. Skinner demonstrated this with his experiments involving rats in what is known as a Skinner box. The rats learned to press a lever to receive food, a primary reinforcer that fulfilled their innate need for nourishment.
Effective reinforcers for humans vary depending on the individual and the context. Primary reinforcers, such as food, water, sleep, shelter, and pleasure, have inherent value and satisfy basic biological...
Effective reinforcers for humans vary depending on the individual and the context. Primary reinforcers, such as food, water, sleep, shelter, and pleasure, have inherent value and satisfy basic biological...
1.0K
01:55Secondary Active Transport
138.1K
One example of how cells use the energy contained in electrochemical gradients is demonstrated by glucose transport into cells. The ion vital to this process is sodium (Na+), which is typically present in higher concentrations extracellularly than in the cytosol. Such a concentration difference is due, in part, to the action of an enzyme “pump” embedded in the cellular membrane that actively expels Na+ from a cell. Importantly, as this pump contributes to the high concentration of...
138.1K