Haijun Ma

Composite endpoints with censored data are commonly used as study outcomes in clinical trials. For example, progression-free survival is a widely used composite endpoint, with disease progression and death as the two components. Progression-free survival time is often defined as the time from randomization to the earlier occurrence of disease progression or death from any cause. The censoring times of the two components could be different for patients not experiencing the endpoint event. Conventional approaches, such as taking the minimum of the censoring times of the two components as the censoring time for progression-free survival time, may suffer from efficiency loss and could produce biased estimates of the treatment effect. We propose a new likelihood-based approach that decomposes the endpoints and models both the progression-free survival time and the time from disease progression to death. The censoring times for different components are distinguished. The approach makes full use of available information and provides a direct and improved estimate of the treatment effect on progression-free survival time. Simulations demonstrate that the proposed method outperforms several other approaches and is robust against various model misspecifications. An application to a prostate cancer clinical trial is provided.

Safety evaluation is a key aspect of medical product development. It is a continual and iterative process requiring thorough thinking, and dedicated time and resources. In this article, we discuss how safety data are transformed into evidence to establish and refine the safety profile of a medical product, and how the focus of safety evaluation, data sources, and statistical methods change throughout a medical product’s life cycle. Some challenges and statistical strategies for medical product safety evaluation are discussed. Examples of safety issues identified in different periods, that is, premarketing and postmarketing, are discussed to illustrate how different sources are used in the safety signal identification and the iterative process of safety assessment. The examples highlighted range from commonly used pediatric vaccine given to healthy children to medical products primarily used to treat a medical condition in adults. These case studies illustrate that different products may require different approaches, and once a signal is discovered, it could impact future safety assessments. Many challenges still remain in this area despite advances in methodologies, infrastructure, public awareness, international harmonization, and regulatory enforcement. Innovations in safety assessment methodologies are pressing in order to make the medical product development process more efficient and effective, and the assessment of medical product marketing approval more streamlined and structured. Health care payers, providers, and patients may have different perspectives when weighing in on clinical, financial and personal needs when therapies are being evaluated.

A structured benefit-risk assessment (BRA) is critical for drug development and lifecycle management. How to select B-R endpoints, determine weighting for these endpoints, and evaluate uncertainties are key aspects of the B-R decision-making process. In this article, we discuss key considerations on endpoint selection, challenges of double counting and correlated endpoints, and methods that can be used to address these challenges. In addition, we discuss the use of qualitative and quantitative weighting in BRA, techniques useful for weight construction, and weights based on empirical preferences. Potential sources for uncertainties in BRA, the approaches to illustrate and to address these uncertainties are described. Finally, we emphasize that benefit-risk assessment is a continuous process and requires cross-functional efforts.

This article is a result of the efforts of the American Statistical Association Biopharmaceutical Section Working Group on Safety. With representatives from different institutions, this group reviewed the drugs approved by the United States Food and Drug Administration (FDA) to treat Type 2 diabetes mellitus during 2002–2014 with a focus on the cardiovascular (CV) risk assessment. The main objective of this article is to understand the impact of FDA guidance of 2008 on assessment of CV risk in antidiabetes development programs, which are summarized and displayed in chronological order. Compared to New Drug Applications (NDAs) submitted prior to the FDA 2008 guidance, the number of patient-years significantly increased for NDAs approved in the post-guidance era. To meet guidance requirements on CV risk assessment, meta-analyses and large cardiovascular outcome trials (CVOTs) have been conducted. These CVOTs provide an opportunity to assess safety signals beyond CV risk and assess the benefit/risk ratio better in diabetic patients with a high risk for CV events, but they also present challenges. The advantages and disadvantages of different CV assessment strategies are summarized in this manuscript. Finally, we raise some emerging questions and discuss future opportunities for CV risk assessment research. Supplementary materials for this article are available online.

Multivariate data summarized over areal units (counties, zip codes, etc.) are common in the field of public health. Statistical methods for areal wombling (boundary analysis) must account for correlations across both diseases and locations. Utilizing recent developments in multivariate conditionally autoregressive (MCAR) distributions and spatial structural equation modeling, we suggest a variety of Bayesian hierarchical models for multivariate areal boundary analysis, including some that incorporate random neighborhood structure. We illustrate our methods using Minnesota county-level esophagus, larynx, and lung cancer data, using methods that permit identification of both composite and cancer-specific boundaries. Our results indicate primary boundaries in both the composite and cancer-specific response surface separating the miningand tourism-oriented northeast counties from the remainder of the state.