Progression-free survival in oncological clinical studies: Assessment time bias and methods for its correction

Progression-free survival (PFS) is a frequently used endpoint in oncological clinical studies. In case of PFS, potential events are progression and death. Progressions are usually observed delayed as they can be diagnosed not before the next study visit. For this reason potential bias of treatment effect estimates for progression-free survival is a concern. In randomized trials and for relative treatment effects measures like hazard ratios, bias-correcting methods are not necessarily required or have been proposed before. However, less is known on cross-trial comparisons of absolute outcome measures like median survival times. This paper proposes a new method for correcting the assessment time bias of progression-free survival estimates to allow a fair cross-trial comparison of median PFS. Using median PFS for example, the presented method approximates the unknown posterior distribution by a Bayesian approach based on simulations. It is shown that the proposed method leads to a substantial reduction of bias as compared to estimates derived from maximum likelihood or Kaplan–Meier estimates. Bias could be reduced by more than 90% over a broad range of considered situations differing in assessment times and underlying distributions. By coverage probabilities of at least 94% based on the credibility interval of the posterior distribution the resulting parameters hold common confidence levels. In summary, the proposed approach is shown to be useful for a cross-trial comparison of median PFS.     

On assessing the presence of evaluation‐time bias in progression‐free survival in randomized trials

Evaluation (or assessment)–time bias can arise in oncology trials that study progression‐free survival (PFS) when randomized groups have different patterns of timing of assessments. Modelling or computer simulation is sometimes used to explore the extent of such bias; valid results require building such simulations under realistic assumptions concerning the timing of assessments. This paper considers a trial that used a logrank test where computer simulations were based on unrealistic assumptions that severely overestimated the extent of potential bias. The paper shows that seemingly small differences in assumptions can lead to dramatic differences in the apparent operating characteristics of logrank tests. Copyright © 2010 John Wiley & Sons, Ltd.     

Determination of hazard ratio for progression‐free survival considering the tumor assessment schedule in sample size calculation

Progression‐free survival is recognized as an important endpoint in oncology clinical trials. In clinical trials aimed at new drug development, the target population often comprises patients that are refractory to standard therapy with a tumor that shows rapid progression. This situation would increase the bias of the hazard ratio calculated for progression‐free survival, resulting in decreased power for such patients. Therefore, new measures are needed to prevent decreasing the power in advance when estimating the sample size. Here, I propose a novel calculation procedure to assume the hazard ratio for progression‐free survival using the Cox proportional hazards model, which can be applied in sample size calculation. The hazard ratios derived by the proposed procedure were almost identical to those obtained by simulation. The hazard ratio calculated by the proposed procedure is applicable to sample size calculation and coincides with the nominal power. Methods that compensate for the lack of power due to biases in the hazard ratio are also discussed from a practical point of view.     

Designing historical control studies with survival endpoints using exact statistical inference

Historical control trials compare an experimental treatment with a previously conducted control treatment. By assigning all recruited samples to the experimental arm, historical control trials can better identify promising treatments in early phase trials compared with randomized control trials. Existing designs of historical control trials with survival endpoints are based on asymptotic normal distribution. However, it remains unclear whether the asymptotic distribution of the test statistic is close enough to the true distribution given relatively small sample sizes in early phase trials. In this article, we address this question by introducing an exact design approach for exponentially distributed survival endpoints, and compare it with an asymptotic design in both real examples and simulation examples. Simulation results show that the asymptotic test could lead to bias in the sample size estimation. We conclude the proposed exact design should be used in the design of historical control trials.     

Bayesian Semiparametric Regression for Median Residual Life

Abstract.  With survival data there is often interest not only in the survival time distribution but also in the residual survival time distribution. In fact, regression models to explain residual survival time might be desired. Building upon recent work of Kottas & Gelfand [ J. Amer. Statist. Assoc. 96 (2001) 1458], we formulate a semiparametric median residual life regression model induced by a semiparametric accelerated failure time regression model. We utilize a Bayesian approach which allows full and exact inference. Classical work essentially ignores covariates and is either based upon parametric assumptions or is limited to asymptotic inference in non-parametric settings. No regression modelling of median residual life appears to exist. The Bayesian modelling is developed through Dirichlet process mixing. The models are fitted using Gibbs sampling. Residual life inference is implemented extending the approach of Gelfand & Kottas [ J. Comput. Graph. Statist. 11 (2002) 289]. Finally, we present a fairly detailed analysis of a set of survival times with moderate censoring for patients with small cell lung cancer.     

Bias corrected MLEs under progressive type-II censoring scheme

ABSTRACT

Censoring frequently occurs in survival analysis but naturally observed lifetimes are not of a large size. Thus, inferences based on the popular maximum likelihood (ML) estimation which often give biased estimates should be corrected in the sense of bias. Here, we investigate the biases of ML estimates under the progressive type-II censoring scheme (pIIcs). We use a method proposed in Efron and Johnstone [Fisher's information in terms of the hazard rate. Technical Report No. 264, January 1987, Stanford University, Stanford, California; 1987] to derive general expressions for bias corrected ML estimates under the pIIcs. This requires derivation of the Fisher information matrix under the pIIcs. As an application, exact expressions are given for bias corrected ML estimates of the Weibull distribution under the pIIcs. The performance of the bias corrected ML estimates and ML estimates are compared by simulations and a real data application.     

Small Sample Bias in the Gamma Frailty Model for Univariate Survival

The gamma frailty model is a natural extension of the Cox proportional hazards model in survival analysis. Because the frailties are unobserved, an E-M approach is often used for estimation. Such an approach is shown to lead to finite sample underestimation of the frailty variance, with the corresponding regression parameters also being underestimated as a result. For the univariate case, we investigate the source of the bias with simulation studies and a complete enumeration. The rank-based E-M approach, we note, only identifies frailty through the order in which failures occur; additional frailty which is evident in the survival times is ignored, and as a result the frailty variance is underestimated. An adaption of the standard E-M approach is suggested, whereby the non-parametric Breslow estimate is replaced by a local likelihood formulation for the baseline hazard which allows the survival times themselves to enter the model. Simulations demonstrate that this approach substantially reduces the bias, even at small sample sizes. The method developed is applied to survival data from the North West Regional Leukaemia Register.     

Urn Sampling and the Proportional Hazard Model

This paper investigates the urn sampling analogue for the score statistic relating survival to covariates assuming a proportional hazard model. The exact permutation distribution can be calculated as well as the exact low order moments for arbitrary censoring patterns. The asymptotic distribution of the score statistic is an easy consequence. The method is naturally extended to deal with the multivariate case, time varying covariates and interval censoring. Finally the relationship between the censoring process, the survival times and covariates are studied considering different reference sets for the distribution of the score statistic. Some assumptions about the censoring process are investigated and as a consequence the effect of censoring is clarified.     

Estimation of Survival Function Subject to Time-Dependent Covariates and Left Truncation

Abstract

Satten et al. [Satten, G. A., Datta, S., Robins, J. M. (2001). Estimating the marginal survival function in the presence of time dependent covariates. Statis. Prob. Lett. 54: 397--403] proposed an estimator [denoted by ?(t)] of survival function of failure times that is in the class of survival function estimators proposed by Robins [Robins, J. M. (1993). Information recovery and bias adjustment in proportional hazards regression analysis of randomized trials using surrogate markers. In: Proceedings of the American Statistical Association-Biopharmaceutical Section. Alexandria, VA: ASA, pp. 24--33]. The estimator is appropriate when data are subject to dependent censoring. In this article, it is demonstrated that the estimator ?(t) can be extended to estimate the survival function when data are subject to dependent censoring and left truncation. In addition, we propose an alternative estimator of survival function [denoted by ? _w (t)] that is represented as an inverse-probability-weighted average Satten and Datta [Satten, G. A., Datta, S. (2001). The Kaplan–Meier estimator as an inverse-probability-of-censoring weighted average. Amer. Statist. Ass. 55: 207--210]. Simulation results show that when truncation is not severe the mean squared error of ?(t) is smaller than that of ? _w (t), except for the case when censoring is light. However, when truncation is severe, ? _w (t) has the advantage of less bias and the situation can be reversed.     

Accuracy of approximate progressively censored reliability sampling plans for exponential models

Reliability sampling plans provide an efficient method to determine the acceptability of a product based upon the lifelengths of some test units. Usually, they depend on the producer and consumer’s quality requirements and do not admit closed form solutions. Acceptance sampling plans for one- and two-parameter exponential lifetime models, derived by approximating the operating characteristic curve, are presented in this paper. The accuracy of these approximate plans, which are explicitly expressible and valid for failure and progressive censoring, is assessed. The approximation proposed in the one-parameter case is found to be practically exact. Explicit lower and upper bounds on the smallest sample size are given in the two-parameter case. Some additional advantages are also pointed out.     

Using categorical markers as auxiliary variables in log‐rank tests and hazard ratio estimation

Markers, which are prognostic longitudinal variables, can be used to replace some of the information lost due to right censoring. They may also be used to remove or reduce bias due to informative censoring. In this paper, the authors propose novel methods for using markers to increase the efficiency of log‐rank tests and hazard ratio estimation, as well as parametric estimation. They propose a «plug‐in» methodology that consists of writing the test statistic or estimate of interest as a functional of Kaplan–Meier estimators. The latter are then replaced by an efficient estimator of the survival curve that incorporates information from markers. Using simulations, the authors show that the resulting estimators and tests can be up to 30% more efficient than the usual procedures, provided that the marker is highly prognostic and that the frequency of censoring is high.     

A likelihood based approach for joint modeling of longitudinal trajectories and informative censoring process

We propose a joint modeling likelihood-based approach for studies with repeated measures and informative right censoring. Joint modeling of longitudinal and survival data are common approaches but could result in biased estimates if proportionality of hazards is violated. To overcome this issue, and given that the exact time of dropout is typically unknown, we modeled the censoring time as the number of follow-up visits and extended it to be dependent on selected covariates. Longitudinal trajectories for each subject were modeled to provide insight into disease progression and incorporated with the number follow-up visits in one likelihood function.     

Progressive censoring with fixed censoring times

In this paper, we revisit the progressive Type-I censoring scheme as it has originally been introduced by Cohen [Progressively censored samples in life testing. Technometrics. 1963;5(3):327–339]. In fact, original progressive Type-I censoring proceeds as progressive Type-II censoring but with fixed censoring times instead of failure time based censoring times. Apparently, a time truncation has been added to this censoring scheme by interpreting the final censoring time as a termination time. Therefore, not much work has been done on Cohens's original progressive censoring scheme with fixed censoring times. Thus, we discuss distributional results for this scheme and establish exact distributional results in likelihood inference for exponentially distributed lifetimes. In particular, we obtain the exact distribution of the maximum likelihood estimator (MLE). Further, the stochastic monotonicity of the MLE is verified in order to construct exact confidence intervals for both the scale parameter and the reliability.     

Inference for two-stage adaptive treatment strategies using mixture distributions

Summary.  Treatment of complex diseases such as cancer, leukaemia, acquired immune deficiency syndrome and depression usually follows complex treatment regimes consisting of time varying multiple courses of the same or different treatments. The goal is to achieve the largest overall benefit defined by a common end point such as survival. Adaptive treatment strategy refers to a sequence of treatments that are applied at different stages of therapy based on the individual's history of covariates and intermediate responses to the earlier treatments. However, in many cases treatment assignment depends only on intermediate response and prior treatments. Clinical trials are often designed to compare two or more adaptive treatment strategies. A common approach that is used in these trials is sequential randomization. Patients are randomized on entry into available first-stage treatments and then on the basis of the response to the initial treatments are randomized to second-stage treatments, and so on. The analysis often ignores this feature of randomization and frequently conducts separate analysis for each stage. Recent literature suggested several semiparametric and Bayesian methods for inference related to adaptive treatment strategies from sequentially randomized trials. We develop a parametric approach using mixture distributions to model the survival times under different adaptive treatment strategies. We show that the estimators proposed are asymptotically unbiased and can be easily implemented by using existing routines in statistical software packages.     

Estimand framework: Are we asking the right questions? A case study in the solid tumor setting

The estimand framework requires a precise definition of the clinical question of interest (the estimand) as different ways of accounting for “intercurrent” events post randomization may result in different scientific questions. The initiation of subsequent therapy is common in oncology clinical trials and is considered an intercurrent event if the start of such therapy occurs prior to a recurrence or progression event. Three possible ways to account for this intercurrent event in the analysis are to censor at initiation, consider recurrence or progression events (including death) that occur before and after the initiation of subsequent therapy, or consider the start of subsequent therapy as an event in and of itself. The new estimand framework clarifies that these analyses address different questions (“does the drug delay recurrence if no patient had received subsequent therapy?” vs “does the drug delay recurrence with or without subsequent therapy?” vs “does the drug delay recurrence or start of subsequent therapy?”). The framework facilitates discussions during clinical trial planning and design to ensure alignment between the key question of interest, the analysis, and interpretation. This article is a result of a cross-industry collaboration to connect the International Council for Harmonisation E9 addendum concepts to applications. Data from previously reported randomized phase 3 studies in the renal cell carcinoma setting are used to consider common intercurrent events in solid tumor studies, and to illustrate different scientific questions and the consequences of the estimand choice for study design, data collection, analysis, and interpretation.     

Practical statistical considerations for investigating anti-tumor treatments in mice

Anti-tumor treatment outcomes in mouse experiments can be challenging to interpret and communicate accurately. In reporting these experiments, rigorous statistical considerations are commonly absent, although statistical applications have been proposed. We investigated the practicality and utility of different statistical strategies for the analysis of anti-tumor responses in a longitudinal mouse case study. Each analysis that we performed had different endpoints, investigated different questions, and was based on different assumptions. We found rudimentary visual and risk analysis insufficient without additional considerations, and upon further investigation we found improvements in key anti-tumor parameter estimates associated with a drug combination in our case study. We offer practical statistical considerations for investigating anti-cancer treatments in mice, applying a multi-tier statistical approach.     

How to choose a time zero for patients in external control arms

When a sponsor carries out a single-arm trial of a novel oncology compound, it may wish to assess the efficacy of the compound via comparison of overall survival to an external control arm, constructed using patients included in some retrospective registry. If efficacy of the novel compound is compared to efficacy of physician's choice of chemotherapy, patients in the retrospective registry might qualify for inclusion in the external control arm at multiple different points in time, when they receive different chemotherapy treatments. For example, a patient might qualify at the start of their second, third and fourth lines of therapy. From the start of which line of therapy should this patient's survival be compared to survival of participants in the single-arm trial? Some sponsors have elected to include patients in the external control arm from the last available line of therapy in the retrospective database. Another possibility is to randomly select a line of therapy for each external control arm patient from among those available. In this paper, we show, via probabilistic arguments and also via simulation based on real data, that both of these methods give rise to a bias in favor of the single-arm trial. We further show that this bias can be avoided by instead including external control arm patients multiple times in the external control arm, once for each time they receive qualifying treatment.     

The application of bespoke spending functions in group‐sequential designs and the effect of delayed treatment switching in survival trials

For a group‐sequential trial with two pre‐planned analyses, stopping boundaries can be calculated using a simple SAS? programme on the basis of the asymptotic bivariate normality of the interim and final test statistics. Given the simplicity and transparency of this approach, it is appropriate for researchers to apply their own bespoke spending function as long as the rate of alpha spend is pre‐specified. One such application could be an oncology trial where progression free survival (PFS) is the primary endpoint and overall survival (OS) is also assessed, both at the same time as the analysis of PFS and also later following further patient follow‐up. In many circumstances it is likely, if PFS is significantly extended, that the protocol will be amended to allow patients in the control arm to start receiving the experimental regimen. Such an eventuality is likely to result in the diminution of any effect on OS. It is shown that spending a greater proportion of alpha at the first analysis of OS, using either Pocock or bespoke boundaries, will maintain and in some cases result in greater power given a fixed number of events. Copyright © 2009 John Wiley & Sons, Ltd.