Pharmaceutical Statistics最新文献

Immunotherapies and targeted therapies have gained popularity due to their promising therapeutic effects across multiple treatment areas. The focus of early phase dose-finding clinical trials has shifted from finding the maximum tolerated dose (MTD) to identifying the optimal biological dose (OBD), which aims to balance the toxicity and efficacy outcomes, thus optimizing the risk-benefit trade-off. These trials often collect multiple pharmacokinetics (PK) outcomes to assess drug exposure, which has shown correlations with toxicity and efficacy outcomes but has not been utilized in the current dose-finding designs for OBD selection. Moreover, PK outcomes are usually available within days after initial treatment, much faster than toxicity and efficacy outcomes. To bridge this gap, we introduce the innovative model-assisted PKBOIN-12 design, which enhances BOIN12 by integrating PK information into both the dose-finding algorithm and the final OBD determination process. We further extend PKBOIN-12 to TITE-PKBOIN-12 to address the challenges of late-onset toxicity and efficacy outcomes. Simulation results demonstrate that PKBOIN-12 more effectively identifies the OBD and allocates a greater number of patients to it than BOIN12. Additionally, PKBOIN-12 decreases the probability of selecting inefficacious doses as the OBD by excluding those with low drug exposure. Comprehensive simulation studies and sensitivity analysis confirm the robustness of both PKBOIN-12 and TITE-PKBOIN-12 in various scenarios.

When multiple historical controls are available, it is necessary to consider the conflicts between current and historical controls and the relationships among historical controls. One of the assumptions concerning the relationships between the parameters of interest of current and historical controls is known as the "Potential biases." Within the "Potential biases" assumption, the differences between the parameters of interest of the current control and of each historical control are defined as "potential bias parameters." We define a class of models called "potential biases model" that encompass several existing methods, including the commensurate prior. The potential bias model incorporates homogeneous historical controls by shrinking the potential bias parameters to zero. In scenarios where multiple historical controls are available, a method that uses a horseshoe prior was proposed. However, various other shrinkage priors are also available. In this study, we propose methods that apply spike-and-slab, Dirichlet-Laplace, and spike-and-slab lasso priors to the potential bias model. We conduct a simulation study and analyze clinical trial examples to compare the performances of the proposed and existing methods. The horseshoe prior and the three other priors make the strongest use of historical controls in the absence of heterogeneous historical controls and reduce the influence of heterogeneous historical controls in the presence of a few historical controls. Among these four priors, the spike-and-slab prior performed the best for heterogeneous historical controls.

In this article, we present interval estimation methods for the Youden index and the optimal cut-off point in the context of AUC-based optimal combinations of multivariate normally distributed biomarkers, considering the presence of covariates. We propose a generalized pivotal confidence interval, a Bayesian credible interval, and several bootstrap confidence intervals for both the Youden index and its corresponding cut-off point. To evaluate the performance of these confidence and credible intervals, we conducted a Monte Carlo simulation study. Finally, we illustrate the proposed methods using a diabetic dataset.

With the development of targeted therapy, immunotherapy, and antibody-drug conjugates (ADCs), there is growing concern over the "more is better" paradigm developed decades ago for chemotherapy, prompting the US Food and Drug Administration (FDA) to initiate Project Optimus to reform dose optimization and selection in oncology drug development. For early-phase oncology trials, given the high variability from sparse data and the rigidity of parametric model specifications, we use Bayesian dynamic models to borrow information across doses with only vague order constraints. Our proposed adaptive design simultaneously incorporates toxicity and efficacy outcomes to select the optimal dose (OD) in Phase I/II clinical trials, utilizing Bayesian model averaging to address the uncertainty of dose-response relationships and enhance the robustness of the design. Additionally, we extend the proposed design to handle delayed toxicity and efficacy outcomes. We conduct extensive simulation studies to evaluate the operating characteristics of the proposed method under various practical scenarios. The results demonstrate that the proposed designs have desirable operating characteristics. A trial example is presented to demonstrate the practical implementation of the proposed designs.

The number of clinical trials that include a binary biomarker in design and analysis has risen due to the advent of personalised medicine. This presents challenges for medical decision makers because a drug may confer a stronger effect in the biomarker positive group, and so be approved either in this subgroup alone or in the all-comer population. We develop and evaluate Bayesian methods that can be used to assess this. All our methods are based on the same statistical model for the observed data but we propose different prior specifications to express differing degrees of knowledge about the extent to which the treatment may be more effective in one subgroup than the other. We illustrate our methods using some real examples. We also show how our methodology is useful when designing trials where the size of the biomarker negative subgroup is to be determined. We conclude that our Bayesian framework is a natural tool for making decisions, for example, whether to recommend using the treatment in the biomarker negative subgroup where the treatment is less likely to be efficacious, or determining the number of biomarker positive and negative patients to include when designing a trial.

Bayesian meta-analysis is a promising approach for rare events meta-analysis. However, the inference of the overall effect in rare events meta-analysis is sensitive to the choice of prior distribution for the heterogeneity parameter. Therefore, it is crucial to assign a convincing prior specification and ensure that it is both plausible and transparent. Various priors for the heterogeneity parameter have been proposed; however, the comparative performance of alternative prior specifications in rare events meta-analysis is poorly understood. Based on a binomial-normal hierarchical model, we conducted a comprehensive simulation study to compare seven heterogeneity prior specifications for binary outcomes, using the odds ratio as the metric. We compared their performance in terms of coverage, median percentage bias, width of the 95% credible interval, and root mean square error (RMSE). We illustrate the results with two recently published rare events meta-analyses of a few studies. The results show that the half-normal prior (with a scale of 0.5), the prior proposed by Turner et al. for the general healthcare setting (without restriction to a specific type of outcome) and for the adverse event setting perform well when the degree of heterogeneity is not relatively high, yielding smaller bias and shorter interval widths with similar coverage and RMSE in most cases compared to other prior specifications. None of the priors performed better when the heterogeneity between-studies were significantly extreme.

The method of power prior has long been used as a tool for leveraging external data to augment a traditional clinical study. More recently, it has been found that integrating propensity scoring into its application has the potential for improved operating characteristics. In this paper, we introduce a new propensity score-integrated power prior strategy which uses propensity score weighting and is distinctive from other such proposals in the literature. This strategy replaces the sufficient statistic in the original expression of power prior with a propensity score weighted version of it. A simulation study shows that the operating characteristics of the proposed weighting strategy compare favorably to those of the original power prior method when there is covariate imbalance, like the stratification strategy we first introduced.

Dose-finding studies in oncology often include an up-and-down dose transition rule that assigns a dose to each cohort of patients based on accumulating data on dose-limiting toxicity (DLT) events. In making a dose transition decision, a key scientific question is whether the true DLT rate of the current dose exceeds the target DLT rate, and the statistical question is how to evaluate the statistical evidence in the available DLT data with respect to that scientific question. This article introduces generalized likelihood ratios (GLRs) that can be used to measure statistical evidence and support dose transition decisions. Applying this approach to a single-dose likelihood leads to a GLR-based interval design with three parameters: the target DLT rate and two GLR cut-points representing the levels of evidence required for dose escalation and de-escalation. This design gives a likelihood interpretation to each existing interval design and provides a unified framework for comparing different interval designs in terms of how much evidence is required for escalation and de-escalation. A GLR-based comparison of commonly used interval designs reveals important differences and motivates alternative designs that reduce over-treatment while maintaining MTD estimation accuracy. The GLR-based approach can also be applied to a joint likelihood based on a nonparametric (e.g., isotonic regression) model or a parametric model. Simulation results indicate that the isotonic GLR performs similarly to the single-dose GLR but the GLR based on a parsimonious model can improve MTD estimation when the underlying model is correct.

An informed estimate of subject-level variance is a key determinate for accurate estimation of the required sample size for clinical trials. Evaluating completed adult Type 2 diabetes studies submitted to the FDA for accuracy of the variance estimate at the planning stage provides insights to inform the sample size requirements for future studies. From the U.S. Food and Drug Administration (FDA) database of new drug applications containing 14,106 subjects from 26 phase 3 randomized studies submitted to the FDA in support of drug approvals in adult type 2 diabetes studies reviewed between 2013 and 2017, we obtained estimates of subject-level variance for the primary endpoint-change in glycated hemoglobin (HbA1c) from baseline to 6 months. In addition, we used nine additional studies to examine the impact of clinically meaningful covariates on residual standard deviation and sample size re-estimation. Our analyses show that reduced sample sizes can be used without interfering with the validity of efficacy results for adult type 2 diabetes drug trials. This finding has implications for future research involving the adult type 2 diabetes population, including the potential to reduce recruitment period length and improve the timeliness of results. Furthermore, our findings could be utilized in the design of future endocrinology clinical trials.

The primary purpose of an oncology dose-finding trial for novel anticancer agents has been shifting from determining the maximum tolerated dose to identifying an optimal dose (OD) that is tolerable and therapeutically beneficial for subjects in subsequent clinical trials. In 2022, the FDA Oncology Center of Excellence initiated Project Optimus to reform the paradigm of dose optimization and dose selection in oncology drug development and issued a draft guidance. The guidance suggests that dose-finding trials include randomized dose-response cohorts of multiple doses and incorporate information on pharmacokinetics (PK) in addition to safety and efficacy data to select the OD. Furthermore, PK information could be a quick alternative to efficacy data to predict the minimum efficacious dose and decide the dose assignment. This article proposes a model-based trial design for dose optimization with a randomization scheme based on PK outcomes in oncology. A simulation study shows that the proposed design has advantages compared to the other designs in the percentage of correct OD selection and the average number of patients assigned to OD in various realistic settings.