Post-Marketing Benefit-Risk Assessment of Rotavirus Vaccination in Japan: A Simulation and Modelling Analysis.

INTRODUCTION: Rotarix™, GSK's live attenuated rotavirus vaccine, was introduced in Japan in 2011. A recent trend in reduction of rotavirus gastroenteritis (RVGE) due to this vaccine was described. However, an observed/expected analysis showed a temporal association with intussusception within 7 days post dose 1. OBJECTIVE: In this paper, we compare the benefit and risk of vaccination side-by-side in a benefit-risk analysis. METHODS: The number of vaccine-preventable RVGE-associated hospitalizations and deaths (benefit) and intussusception-associated hospitalizations and deaths (risk) following two doses of Rotarix™ in Japan was compared using simulations. Source data included peer-reviewed clinical and epidemiological publications, Japanese governmental statistics (Statistics Bureau, Ministry of Internal Affairs and Communications), and market survey data. RESULTS: For a birth cohort of 1 million vaccinated Japanese children followed for 5 years, the benefit-risk analysis suggested that the vaccine would prevent ~17,900 hospitalizations and ~6.3 deaths associated with RVGE. At the same time, vaccination would be associated with about ~50 intussusception hospitalizations and ~0.017 intussusception deaths. Therefore, for every intussusception hospitalization caused by vaccination and for one intussusception-associated death, 350 (95 % CI 69-2510) RVGE-associated hospitalizations and 366 (95 % CI 59-3271) RVGE-associated deaths are prevented, respectively, by vaccination. CONCLUSIONS: The benefit-risk balance for Rotarix™ is favorable in Japan. From a public health perspective, the benefits in terms of prevented RVGE hospitalizations and deaths for the vaccinated population far exceed the estimated risks due to intussusception.

Recommendations for benefit-risk assessment methodologies and visual representations.

PURPOSE: The purpose of this study is to draw on the practical experience from the PROTECT BR case studies and make recommendations regarding the application of a number of methodologies and visual representations for benefit-risk assessment. METHODS: Eight case studies based on the benefit-risk balance of real medicines were used to test various methodologies that had been identified from the literature as having potential applications in benefit-risk assessment. Recommendations were drawn up based on the results of the case studies. RESULTS: A general pathway through the case studies was evident, with various classes of methodologies having roles to play at different stages. Descriptive and quantitative frameworks were widely used throughout to structure problems, with other methods such as metrics, estimation techniques and elicitation techniques providing ways to incorporate technical or numerical data from various sources. Similarly, tree diagrams and effects tables were universally adopted, with other visualisations available to suit specific methodologies or tasks as required. Every assessment was found to follow five broad stages: (i) Planning, (ii) Evidence gathering and data preparation, (iii) Analysis, (iv) Exploration and (v) Conclusion and dissemination. CONCLUSIONS: Adopting formal, structured approaches to benefit-risk assessment was feasible in real-world problems and facilitated clear, transparent decision-making. Prior to this work, no extensive practical application and appraisal of methodologies had been conducted using real-world case examples, leaving users with limited knowledge of their usefulness in the real world. The practical guidance provided here takes us one step closer to a harmonised approach to benefit-risk assessment from multiple perspectives.

Literature review of visual representation of the results of benefit-risk assessments of medicinal products.

BACKGROUND: The PROTECT Benefit-Risk group is dedicated to research in methods for continuous benefit-risk monitoring of medicines, including the presentation of the results, with a particular emphasis on graphical methods. METHODS: A comprehensive review was performed to identify visuals used for medical risk and benefit-risk communication. The identified visual displays were grouped into visual types, and each visual type was appraised based on five criteria: intended audience, intended message, knowledge required to understand the visual, unintentional messages that may be derived from the visual and missing information that may be needed to understand the visual. RESULTS: Sixty-six examples of visual formats were identified from the literature and classified into 14 visual types. We found that there is not one single visual format that is consistently superior to others for the communication of benefit-risk information. In addition, we found that most of the drawbacks found in the visual formats could be considered general to visual communication, although some appear more relevant to specific formats and should be considered when creating visuals for different audiences depending on the exact message to be communicated. CONCLUSION: We have arrived at recommendations for the use of visual displays for benefit-risk communication. The recommendation refers to the creation of visuals. We outline four criteria to determine audience-visual compatibility and consider these to be a key task in creating any visual. Next we propose specific visual formats of interest, to be explored further for their ability to address nine different types of benefit-risk analysis information.

Quantifying factors for the success of stratified medicine.

Co-developing a drug with a diagnostic to create a stratified medicine - a therapy that is targeted to a specific patient population on the basis of a clinical characteristic such as a biomarker that predicts treatment response - presents challenges for product developers, regulators, payers and physicians. With the aim of developing a shared framework and tools for addressing these challenges, here we present an analysis using data from case studies in oncology and Alzheimer's disease, coupled with integrated computational modelling of clinical outcomes and developer economic value, to quantify the effects of decisions related to key issues such as the design of clinical trials. This illustrates how such analyses can aid the coordination of diagnostic and drug development, and the selection of optimal development and commercialization strategies. It also illustrates the impact of the interplay of these factors on the economic feasibility of stratified medicine, which has important implications for public policy makers.

Informing the selection of futility stopping thresholds: case study from a late-phase clinical trial.

In an environment where (i) potential risks to subjects participating in clinical studies need to be managed carefully, (ii) trial costs are increasing, and (iii) there are limited research resources available, it is necessary to prioritize research projects and sometimes re-prioritize if early indications suggest that a trial has low probability of success. Futility designs allow this re-prioritization to take place. This paper reviews a number of possible futility methods available and presents a case study from a late-phase study of an HIV therapeutic, which utilized conditional power-based stopping thresholds. The two most challenging aspects of incorporating a futility interim analysis into a trial design are the selection of optimal stopping thresholds and the timing of the analysis, both of which require the balancing of various risks. The paper outlines a number of graphical aids that proved useful in explaining the statistical risks involved to the study team. Further, the paper outlines a decision analysis undertaken which combined expectations of drug performance with conditional power calculations in order to produce probabilities of different interim and final outcomes, and which ultimately led to the selection of the final stopping thresholds.

Tularemia outbreak investigation in Kosovo: case control and environmental studies.

A large outbreak of tularemia occurred in Kosovo in the early postwar period, 1999-2000. Epidemiologic and environmental investigations were conducted to identify sources of infection, modes of transmission, and household risk factors. Case and control status was verified by enzyme-linked immunosorbent assay, Western blot, and microagglutination assay. A total of 327 serologically confirmed cases of tularemia pharyngitis and cervical lymphadenitis were identified in 21 of 29 Kosovo municipalities. Matched analysis of 46 case households and 76 control households suggested that infection was transmitted through contaminated food or water and that the source of infection was rodents. Environmental circumstances in war-torn Kosovo led to epizootic rodent tularemia and its spread to resettled rural populations living under circumstances of substandard housing, hygiene, and sanitation.