Deep historical borrowing framework to prospectively and simultaneously synthesize control information in confirmatory clinical trials with multiple endpoints.
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ABSTRACT:
SUBMITTER: Zhan T
PROVIDER: S-EPMC9257992 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Assessment of efficacy in important subgroups - such as those defined by sex, age, race and region - in confirmatory trials is typically performed using separate analysis of the specific subgroup. This ignores relevant information from the complementary subgroup. Bayesian dynamic borrowing uses an informative prior based on analysis of the complementary subgroup and a weak prior distribution centred on a mean of zero to construct a robust mixture prior. This combination of priors allows for dynamic borrowing of prior information; the analysis learns how much of the complementary subgroup prior information to borrow based on the consistency between the subgroup of interest and the complementary subgroup. A tipping point analysis can be carried out to identify how much prior weight needs to be placed on the complementary subgroup component of the robust mixture prior to establish efficacy in the subgroup of interest. An attractive feature of the tipping point analysis is that it enables the evidence from the source subgroup, the evidence from the target subgroup, and the combined evidence to be displayed alongside each other. This method is illustrated with an example trial in severe asthma where efficacy in the adolescent subgroup was assessed using a mixture prior combining an informative prior from the adult data in the same trial with a non-informative prior.
| S-EPMC8247867 | biostudies-literature
Project description:Basket trials are an innovative precision medicine clinical trial design evaluating a single targeted therapy across multiple diseases that share a common characteristic. To date, most basket trials have been conducted in early-phase oncology settings, for which several Bayesian methods permitting information sharing across subtrials have been proposed. With the increasing interest of implementing randomised basket trials, information borrowing could be exploited in two ways; considering the commensurability of either the treatment effects or the outcomes specific to each of the treatment groups between the subtrials. In this article, we extend a previous analysis model based on distributional discrepancy for borrowing over the subtrial treatment effects ('treatment effect borrowing', TEB) to borrowing over the subtrial groupwise responses ('treatment response borrowing', TRB). Simulation results demonstrate that both modelling strategies provide substantial gains over an approach with no borrowing. TRB outperforms TEB especially when subtrial sample sizes are small on all operational characteristics, while the latter has considerable gains in performance over TRB when subtrial sample sizes are large, or the treatment effects and groupwise mean responses are noticeably heterogeneous across subtrials. Further, we notice that TRB, and TEB can potentially lead to different conclusions in the analysis of real data.
| S-EPMC9827857 | biostudies-literature
Project description:The purpose of this paper is to demonstrate and evaluate the use of Bayesian dynamic borrowing (Viele et al, in Pharm Stat 13:41-54, 2014) as a means of systematically utilizing historical information with specific applications to large-scale educational assessments. Dynamic borrowing via Bayesian hierarchical models is a special case of a general framework of historical borrowing where the degree of borrowing depends on the heterogeneity among historical data and current data. A joint prior distribution over the historical and current data sets is specified with the degree of heterogeneity across the data sets controlled by the variance of the joint distribution. We apply Bayesian dynamic borrowing to both single-level and multilevel models and compare this approach to other historical borrowing methods such as complete pooling, Bayesian synthesis, and power priors. Two case studies using data from the Program for International Student Assessment reveal the utility of Bayesian dynamic borrowing in terms of predictive accuracy. This is followed by two simulation studies that reveal the utility of Bayesian dynamic borrowing over simple pooling and power priors in cases where the historical data is heterogeneous compared to the current data based on bias, mean squared error, and predictive accuracy. In cases of homogeneous historical data, Bayesian dynamic borrowing performs similarly to data pooling, Bayesian synthesis, and power priors. In contrast, for heterogeneous historical data, Bayesian dynamic borrowing performed at least as well, if not better, than other methods of borrowing with respect to mean squared error, percent bias, and leave-one-out cross-validation.
| S-EPMC9185721 | biostudies-literature
Project description:BackgroundClinical trial investigators may need to evaluate treatment effects in a specific subgroup (or subgroups) of participants in addition to reporting results of the entire study population. Such subgroups lack power to detect a treatment effect, but there may be strong justification for borrowing information from a larger patient group within the same trial, while allowing for differences between populations. Our aim was to develop methods for eliciting expert opinions about differences in treatment effect between patient populations, and to incorporate these opinions into a Bayesian analysis.MethodsWe used an interaction parameter to model the relationship between underlying treatment effects in two subgroups. Elicitation was used to obtain clinical opinions on the likely values of the interaction parameter, since this parameter is poorly informed by the data. Feedback was provided to experts to communicate how uncertainty about the interaction parameter corresponds with relative weights allocated to subgroups in the Bayesian analysis. The impact on the planned analysis was then determined.ResultsThe methods were applied to an ongoing non-inferiority trial designed to compare antiretroviral therapy regimens in 707 children living with HIV and weighing ≥ 14 kg, with an additional group of 85 younger children weighing < 14 kg in whom the treatment effect will be estimated separately. Expert clinical opinion was elicited and demonstrated that substantial borrowing is supported. Clinical experts chose on average to allocate a relative weight of 78% (reduced from 90% based on sample size) to data from children weighing ≥ 14 kg in a Bayesian analysis of the children weighing < 14 kg. The total effective sample size in the Bayesian analysis was 386 children, providing 84% predictive power to exclude a difference of more than 10% between arms, whereas the 85 younger children weighing < 14 kg provided only 20% power in a standalone frequentist analysis.ConclusionsBorrowing information from a larger subgroup or subgroups can facilitate estimation of treatment effects in small subgroups within a clinical trial, leading to improved power and precision. Informative prior distributions for interaction parameters are required to inform the degree of borrowing and can be informed by expert opinion. We demonstrated accessible methods for obtaining opinions.
| S-EPMC8858505 | biostudies-literature
Project description:The group sequential design has been well understood and widely applied in designs of late phase clinical trial to enable potentially early stopping for efficacy or futility. The information fraction (IF) is one of the key elements to determine the decision boundary at the interim analyses. The family-wise error rate (FWER) control is highly critical for clinical trials with multiple endpoints to be tested. In this article, we illustrate the importance of properly defining the information fraction for each individual endpoint regarding the FWER control through the numerical evaluation and a case study.
| S-EPMC5898546 | biostudies-literature
Project description:ObjectivesMany trials investigate potential effects of treatments for coronavirus disease 2019. To provide sufficient information for all involveddecision-makers (clinicians, public health authorities, and drug regulatory agencies), a multiplicity of endpoints must be considered. The objectives are to provide hands-on statistical guidelines for harmonizing heterogeneous endpoints in coronavirus disease 2019 clinical trials.DesignRandomized controlled trials for patients infected with coronavirus disease 2019.SettingGeneral methods that apply to any randomized controlled trial for patients infected with coronavirus disease 2019.PatientsCoronavirus disease 2019 positive individuals.InterventionsNone.Measurements and main resultsWe develop a multistate model that is based on hospitalization, mechanical ventilation, death, and discharge. These events are both categories of the ordinal endpoint recommended by the World Health Organization and also within the core outcome set of the Core Outcome Measures in Effectiveness Trials initiative for coronavirus disease 2019 trials. To support our choice of states in the multistate model, we also perform a brief review of registered coronavirus disease 2019 clinical trials. Based on the multistate model, we give recommendation for compact, informative illustration of time-dynamic treatment effects and explorative statistical analysis. A majority of coronavirus disease 2019 clinical trials collect information on mechanical ventilation, hospitalization, and death. Using reconstructed and real data of coronavirus disease 2019 trials, we show how a stacked probability plot provides a detailed understanding of treatment effects on the patients' course of hospital stay. It contributes to harmonizing multiple endpoints and differing lengths of follow-up both within and between trials.ConclusionsAll ongoing clinical trials should include a stacked probability plot in their statistical analysis plan as descriptive analysis. While primary analysis should be on an early endpoint with appropriate capability to be a surrogate (parameter), our multistate model provides additional detailed descriptive information and links results within and between coronavirus disease 2019 trials.
| S-EPMC7737851 | biostudies-literature
Project description: Not available
| S-EPMC10703472 | biostudies-literature
Project description:BackgroundInterventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials.MethodsAs part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials.FindingsCurrent surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)-thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators.InterpretationThere is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence.FundingSPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded.
| S-EPMC10590868 | biostudies-literature
Project description:A marker's capacity to predict risk of a disease depends on disease prevalence in the target population and its classification accuracy, i.e. its ability to discriminate diseased subjects from non-diseased subjects. The latter is often considered an intrinsic property of the marker; it is independent of disease prevalence and hence more likely to be similar across populations than risk prediction measures. In this paper, we are interested in evaluating the population-specific performance of a risk prediction marker in terms of positive predictive value (PPV) and negative predictive value (NPV) at given thresholds, when samples are available from the target population as well as from another population. A default strategy is to estimate PPV and NPV using samples from the target population only. However, when the marker's classification accuracy as characterized by a specific point on the receiver operating characteristics (ROC) curve is similar across populations, borrowing information across populations allows increased efficiency in estimating PPV and NPV. We develop estimators that optimally combine information across populations. We apply this methodology to a cross-sectional study where we evaluate PCA3 as a risk prediction marker for prostate cancer among subjects with or without previous negative biopsy.
| S-EPMC3196635 | biostudies-literature
Project description:Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan-Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation.
| S-EPMC2943524 | biostudies-literature