Estimands and Causality
Johns Hopkins Bloomberg School of Public Health, USA
Closing: Andreas Faldum, Werner Brannath / Annette Kopp-Schneider
Adaptive group sequential survival comparisons based on log-rank and pointwise test statistics
Jannik Feld, Andreas Faldum, Rene Schmidt
Institute of Biostatistics and Clinical Research, University of Münster
Whereas the theory of confirmatory adaptive designs is well understood for uncensored data, implementation of adaptive designs in the context of survival trials remains challenging. Commonly used adaptive survival tests are based on the independent increments structure of the log-rank statistic. These designs suffer the limitation that effectively only the interim log-rank statistic may be used for design modifications (such as data-dependent sample size recalculation). Alternative approaches based on the patient-wise separation principle have the common disadvantage that the test procedure may either neglect part of the observed survival data or tends to be conservative. Here, we instead propose an extension of the independent increments approach to adaptive survival tests. We present a confirmatory adaptive two-sample log-rank test of no difference in a survival analysis setting, where provision is made for interim decision making based on both the interim log-rank statistic and/or pointwise survival-rates, while avoiding aforementioned problems. The possibility to include pointwise survival-rates eases the clinical interpretation of interim decision making and is a straight forward choice for seamless phase II/III designs. We will show by simulation studies that the performance does not suffer using the pointwise survival-rates and exemplary consider application of the methodology to a two-sample log-rank test with binding futility criterion based on the observed short-term survival-rates and sample size recalculation based on conditional power. The methodology is motivated by the LOGGIC Europe Trial from pediatric oncology. Distributional properties are derived using martingale techniques in the large sample limit. Small sample properties are studied by simulation.
Single-stage, three-arm, adaptive test strategies for non-inferiority trials with an unstable reference
Werner Brannath, Martin Scharpenberg, Sylvia Schmidt
University of Bremen, Germany
For indications where only unstable reference treatments are available and use of placebo is ethically justified, three-arm `gold standard‘ designs with an experimental, reference and placebo arm are recommended for non-inferiority trials. In such designs, the demonstration of efficacy of the reference or experimental treatment is a requirement. They have the disadvantage that only little can be concluded from the trial if the reference fails to be efficacious. To overcome this, we investigate a novel single-stage, adaptive test strategies where non-inferiority is tested only if the reference shows sufficient efficacy and otherwise delta-superiority of the experimental treatment over placebo is tested. With a properly chosen superiority margin, delta-superiority indirectly shows non-inferiority. We optimize the sample size for several decision rules and find that the natural, data driven test strategy, which tests with non-inferiority if the reference’s efficacy test is significant, leads to the smallest overall and placebo sample sizes. Under specific constraints on the sample sizes, this procedure controls the family-wise error rate. All optimal sample sizes are found to meet this constraint. We finally show how to account for a relevant placebo drop-out rate in an efficient way and apply the new test strategy to a real life data set.
Sample size re-estimation based on the prevalence in a randomized test-treatment study
Amra Hot, Antonia Zapf
Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg
Patient benefit should be the primary criterion in evaluating diagnostic tests. If a new test has shown sufficient accuracy, its application in clinical practice should yield to a patient benefit. Randomized test-treatment studies are needed to assess the clinical utility of a diagnostic test as part of a broader management regimen in which test-treatment strategies are compared in terms of their impact on patient relevant outcomes . Due to their increased complexity compared to common intervention trials the implementation of such studies poses practical challenges which might affect the validity of the study. One important aspect is the sample size determination. It is a special feature of these designs that they combine information on the disease prevalence and accuracy of the diagnostic tests, i.e. sensitivity and specificity of the investigated tests, with assumptions on the expected treatment effect. Due to the lack of empirical information or uncertainty regarding these parameters sample size consideration will always be based on a rather weak foundation, thus leading to an over- or underpowered trial. Therefore, it is reasonable to consider adaptations in earlier phases of the trial based on a pre-specified interim analysis in order to solve this problem. A blinded sample size re-estimation based on the disease prevalence in a randomized test-treatment study was performed as part of a simulation study. The type I error, the empirical overall power as well as the bias of the estimated prevalence are assessed and presented.
 J. G. Lijmer, P.M. Bossuyt. Diagnostic testing and prognosis: the randomized controlled trial in test evaluation research. In: The evidence base of clinical diagnosis. Blackwell Oxford, 2009, 63-82.
Performance evaluation of a new “diagnostic-efficacy-combination trial design” in the context of telemedical interventions
Mareen Pigorsch1, Martin Möckel2, Jan C. Wiemer3, Friedrich Köhler4, Geraldine Rauch1
1Charité – Universitätsmedizin Berlin, Institute of Biometry and clinical Epidemiology; 2Charité – Universitätsmedizin Berlin, Division of Emergency and Acute Medicine, Cardiovascular Process Research; 3Clinical Diagnostics, Thermo Fisher Scientific; 4Charité – Universitätsmedizin Berlin, Centre for Cardiovascular Telemedicine, Department of Cardiology and Angiology
Telemedical interventions in heart failure patients intend to avoid unfavourable, treatment-related events by an early, individualized care, which reacts to the current patients need. However, telemedical support is an expensive intervention and only patients with a high risk for unfavourable follow-up events will profit from telemedical care. Möckel et al. therefore adapted a “diagnostic-efficacy-combination design” which allows to validate a biomarker and investigate a biomarker-selected population within the same study. For this, cut-off values for the biomarkers were determined based on the observed outcomes in the control group to define a high-risk subgroup. This defines the diagnostic design step. These cut-offs were subsequently applied to the intervention and the control group to identify the high-risk subgroup. The intervention effect is then evaluated by comparison of these subgroups. This defines the efficacy design step. So far, it has not been evaluated if this double use of the control group for biomarker validation and efficacy comparison leads to a bias in treatment effect estimation. In this methodological research work, we therefore want to evaluate whether the “diagnostic-efficacy-combination design” leads to biased treatment effect estimates. If there is a bias, we further want to analyse its impact and the parameters influencing its size.
We perform a systematic Monte-Carlo simulation study to investigate potential bias in various realistic trial scenarios that mimic and vary the true data of the published TIM‐HF2 Trial. In particular we vary the event rates, the sample sizes and the biomarker distributions.
The results show, that indeed the proposed design leads to some bias in the effect estimators, indicating an overestimation of the effect. But this bias is relatively small in most scenarios. The larger the sample size, the more the event rates differ in the control and the intervention group and the better the biomarker can separate the high-risk from the low-risk patients, the smaller is the resulting relative bias.
The “diagnostic-efficacy-combination design” can be recommended for clinical applications. We recommend ensuring a sufficient large sample size.
Möckel M, Koehler K, Anker SD, Vollert J, Moeller V, Koehler M, Gehrig S, Wiemer JC, von Haehling S, Koehler F. Biomarker guidance allows a more personalized allocation of patients for remote patient management in heart failure: results from the TIM-HF2 trial. Eur J Heart Fail. 2019;21(11):1445-58.
Valid sample size re-estimation at interim
Charité – Institute of Biometry and Clinical Epidemiology, Germany
Throughout this work, we consider the situation of a two-arm controlled clinical trial based on time-to-event data.
The aim of this thesis is to estimate a meaningful survival model in a robust way to observed data during an interim analysis in order to carry out a valid sample size recalculation.
Adaptive designs provide an attractive possibility of changing study design parameters in an ongoing trial. There are still many open questions with respect to adaptive designs for time-to-event data. Among other things, this is because survival data, unlike continuous or binary data, undertake a follow-up phase, so that the outcome is not directly observed after patient’s treatment.
Evaluating survival data at interim analyses leads to a patient overrun since the recruitment is usually not stopped at the same time. Another problem is that there must be an interim analysis during this recruitment phase to save patients. Moreover, the timing of the interim analysis is a crucial point build decisions upon a reasonable level of information.
A general issue about time-to-event data is that at an interim analysis one can only calculate the updated size of the required number of events. However, there is normally a greater need in the determination of the sample size to achieve that required number of events. Therefore, the underlying event-time distribution is needed, which may possibly be estimated from the interim data.
This however, is a difficult task for the following reasons: The number of observed events at interim is limited, and the survival curve at interim is truncated by the interim time point.
The goal of this research work is to fit a reasonable survival model to the observed data in a robust way. The fitted curve has the following advantages: The underlying hazards per group can be estimated which allows updating the required number of patients for achieving the respective number of events. Finally, the impact of overrun can be directly assessed and quantified.
The following problems were additionally evaluated in detail. How much do the hazards deviate if the wrong event-time distribution was estimated? At which point in time is a sample size re-estimation useful, or rather how many events are required, for a valid sample size re-estimation at interim?