Journal of Biopharmaceutical Statistics

In recent years, clinical trials utilizing a two-stage seamless adaptive trial design have become very popular in drug development. A typical example is a phase 2/3 adaptive trial design, which consists of two stages. As an example, stage 1 is for a phase 2 dose-finding study and stage 2 is for a phase 3 efficacy confirmation study. Depending upon whether or not the target patient population, study objectives, and study endpoints are the same at different stages, Chow (2020) classified two-stage seamless adaptive design into eight categories...

Adaptive designs, such as group sequential designs (and the ones with additional adaptive features) or adaptive platform trials, have been quintessential efficient design strategies in trials of unmet medical needs, especially for generating evidence from global regions. Such designs allow interim decision making and making adjustment to study design when necessary, meanwhile maintaining study integrity and operating characteristics. However, driven by the heightened competitive landscape and the desire to bring effective treatment to patients faster, innovation in the already functional designs is still germane to further propel drug development to a more efficient path...

There is growing interest in understanding geographic patterns of medical device-related adverse events (AEs). A spatial scan method combined with the likelihood ratio test (LRT) for spatial-cluster signal detection over the geographical region is universally used. The spatial scan method used a moving window to scan the entire study region and collected some candidate sub-regions from which the spatial-cluster signal(s) will be found. However, it has some challenges, especially in computation. First, the computational cost increased when the number of sub-regions increased...

Multi-regional clinical trial (MRCT) has become an increasing trend for its supporting simultaneous global drug development. After MRCT, consistency assessment needs to be conducted to evaluate regional efficacy. The weighted Z-test approach is a common consistency assessment approach in which the weighting parameter W does not have a good practical significance; the discounting factor approach improved from the weighted Z-test approach by converting the estimation of W in original weighted Z-test approach to the estimation of discounting factor D ...

For the approval of a drug product, the United States Food and Drug Administration requires substantial evidence (SE) regarding effectiveness and safety of the test drug to be provided. In recent years, the use of real-world data in support of regulatory submission of pharmaceutical development has received much attention, and real-world evidence (RWE) is treated as complementary to SE by evaluating the real-world performance of the test treatment. In this article, we start by summarizing current regulatory perspectives on drug evaluation and some potential challenges in using RWE...

China's accession to the ICH has accelerated the advancement of its regulatory science. To foster innovation and improve the efficiency of pharmaceutical research and development, the China National Medical Products Administration (NMPA) encourages the use of real-world evidence (RWE) to support drug regulatory decision-making and has constructed a series of real-world study (RWS) related guidance, reflecting the contribution of the NMPA to the field of RWS in drug clinical development. Based on the four guidelines on RWE, real-world data (RWD), RWS design and protocol development, and communication with regulatory authorities, the guidance has been extended to more specific clinical applications, such as oncology, rare diseases, pediatric drugs, and traditional Chinese medicine...

Combination therapy, a treatment modality that involves multiple treatment agents, has become imperative for improving treatment effectiveness and addressing resistance in the field of oncology. However, determining the most effective dose for these combinations, particularly when dealing with intricate drug interactions and diverse toxicity patterns, presents a substantial challenge. This paper introduces a novel Bayesian <u>do</u>se-finding <u>d</u>esign for <u>comb</u>inati<u>o</u>n therapies with information borrowing, named the DOD-Combo design...

The motivation for this paper is to account for subject specific variations in a Cox proportional hazard model for alternating recurrent events. This is done through two sets of frailty components, whose marginal distributions are bound together by a copula function. The likelihood function involves unobservable variables, which requires the use of the EM algorithm. This leads to intractable integrals, which after some approximations, are solved using computationally intensive techniques. The results are applied to a real-life data...

It is well known a basket trial consisting of multiple cancer types has the potential of borrowing strength across the baskets defined by the cancer types, leading to an efficient design in terms of sample size and trial duration. The treatment effects in those baskets are often heterogeneous and categorized by the cancer types being sensitive or insensitive to the treatment. Hence, the assumption of exchangeability in many existing basket trials may be violated, and there is a need to design trials without this assumption...

There has been an increasing use of master protocols in oncology clinical trials because of its efficiency to accelerate cancer drug development and flexibility to accommodate multiple substudies. Depending on the study objective and design, a master protocol trial can be a basket trial, an umbrella trial, a platform trial, or any other form of trials in which multiple investigational products and/or subpopulations are studied under a single protocol. Master protocols can use external data and evidence (e.g...

Regulatory agencies are advancing the use of systematic approaches to collect patient experience data, including patient-reported outcomes (PROs), in cancer clinical trials to inform regulatory decision-making. Due in part to clinician under-reporting of symptomatic adverse events, there is a growing recognition that evaluation of cancer treatment tolerability should include the patient experience, both in terms of the overall side effect impact and symptomatic adverse events. Methodologies around implementation, analysis, and interpretation of "patient" reported tolerability are under development, and current approaches are largely descriptive...

BACKGROUND: Daily diaries are an important modality for patient-reported outcome assessment. They typically comprise multiple questions, so understanding their underlying structure is key to appropriate analysis and interpretation. Structural evaluation of such measures poses challenges due to the high volume of repeated measurements. Potential strategies include selecting a single day, averaging item-level observations over time, or using all data while accounting for its multilevel structure...

Combination therapies with multiple mechanisms of action can offer improved efficacy and/or safety profiles when compared to a single therapy with one mechanism of action. Consequently, the number of combination therapy studies have increased multi-fold, both in oncology and non-oncology indications. However, identifying the optimal doses of each drug in a combination therapy can require a large sample size and prolong study timelines, especially when full factorial designs are used. In this paper, we extend the MCP-Mod design of Bretz, Pinheiro, and Branson to a three-dimensional space to model the dose-response surface of a two-drug combination under the framework of Combination (Comb) MCP-Mod...

It is commonly necessary to perform inferences on the difference, ratio, and odds ratio of two proportions p 1 and p 2 based on two independent samples. For this purpose, the most common asymptotic statistics are based on the score statistics ( S -type statistics). As these do not correct the bias of the estimator of the product p i (1- p i ), Miettinen and Nurminen proposed the MN -type statistics, which consist of multiplying the statistics S by ( N -1)/ N , where N is the sum of the two sample sizes. This paper demonstrates that the factor ( N -1)/ N is only correct in the case of the test of equality of two proportions, providing the estimation of the correct factor ( AU -type statistics) and the minimum value of the same ( AUM- type statistics)...

In epidemiology and clinical research, recurrent events refer to individuals who are likely to experience transient clinical events repeatedly over an observation period. Examples include hospitalizations in patients with heart failure, fractures in osteoporosis studies and the occurrence of new lesions in oncology. We provided an in-depth analysis of the sample size required for the analysis of recurrent time-to-event data using multifrailty or multilevel survival models. We covered the topic from the simple shared frailty model to models with hierarchical or joint frailties...

In contemporary exploratory phase of oncology drug development, there has been an increasing interest in evaluating investigational drug or drug combination in multiple tumor indications in a single basket trial to expedite drug development. There has been extensive research on more efficiently borrowing information across tumor indications in early phase drug development including Bayesian hierarchical modeling and the pruning-and-pooling methods. Despite the fact that the Go/No-Go decision for subsequent Phase 2 or Phase 3 trial initiation is almost always a multi-facet consideration, the statistical literature of basket trial design and analysis has largely been limited to a single binary endpoint...

Measurements are generally collected as unilateral or bilateral data in clinical trials, epidemiology, or observational studies. For example, in ophthalmology studies, the primary outcome is often obtained from one eye or both eyes of an individual. In medical studies, the relative risk is usually the parameter of interest and is commonly used. In this article, we develop three confidence intervals for the relative risk for combined unilateral and bilateral correlated data under the equal dependence assumption...

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In clinical trials, unilateral or bilateral data can usually be encountered if a subject contributes one or both of paired organs. For the bilateral data, responses from two paired body parts are correlated. In this paper, we study various confidence intervals of common risk difference in stratified unilateral and bilateral data based on the Dallal's model. Simulation results show that the score method outperforms other methods and provides coverage probability close to the nominal level and satisfactory coverage width...

Making the go/no-go decision is critical in Phase II (or Ib) clinical trials. The conventional decision-making framework based on a binary hypothesis testing has been gradually replaced by the TODeM (Triple Outcome Decision-Making) which has three zones of outcomes: go, no-go, and consider. The TODeM provides more flexibility in decision-making with considering both of statistical significance and clinical relevance. However, Bayesian methods (e.g. EXNEX, MUCE, etc.) for the information borrowing are still based on the binary decision-making framework...