gms | German Medical Science

Background: The time to progression ratio (TTPr) is a novel endpoint in Phase I/II oncology trials, which is frequently applied to evaluate the efficacy of molecular targeted treatments in late stage patients. The general idea of the design is that a patient serves as their own control.

To calculate the TTPr for an individual, the time to progression (TTP) under the experimental targeted treatment is divided by the last TTP under standard treatment. If the TTPr exceeds a certain value (typically 1.3), the person is considered a responder. Subsequently, a binomial test is performed, investigating if the proportion of responders is significantly higher than a certain threshold (typically 15%).

In this work, the current practice for the TTPr is critically examined.

Methods: Using elementary calculations and simulations based on reasonable assumptions, we point out numerous shortcomings of the current methodology. As a remedy to these shortcomings, we propose a new approach for evaluating trials in which patients serve as each owns control.

Results: Notably, the applied threshold values will often lead to rejection of the null hypothesis even if the experimental treatment is harmful. On the other hand, the approach features little power under appropriately chosen thresholds. In contrast to this, our methodology allows the formulation of meaningful null hypotheses and markedly outperforms the current approach in terms of power.

Conclusion: The newly derived testing procedure for treatment efficacy based on intrapatient comparisons of progression times outperforms currently used binomial tests in terms of power while controlling its nominal type I level.

The authors declare that they have no competing interests.

The authors declare that an ethics committee vote is not required.