A Structured Benefit-Risk Assessment Operating Model for Investigational Medicinal Products in the Pharmaceutical Industry

Abstract

Robust and transparent formal benefit-risk (BR) analyses for medicinal products represent a means to better understand the appropriate use of medicinal products, and to maximize their value to prescribers and patients. Despite regulatory and social imperatives to conduct structured BR (sBR) assessments, and the availability of a plethora of methodological tools, there exists large variability in the uptake and execution of sBR assessments among pharmaceutical companies. As such, in this paper we present an sBR assessment framework developed and implemented within a large global pharmaceutical company that aims to guide the systematic assessment of BR across the continuum of drug development activities, from first-time-in-human studies through to regulatory submission. We define and emphasize the concepts of Key Clinical Benefits and Key Safety Risks as the foundation for BR analysis. Furthermore, we define and foundationally employ the concepts of sBR and a Core Company BR position as the key elements for our BR framework. We outline 3 simple stages for how to perform the fundamentals of an sBR analysis, along with an emphasis on the weighting of Key Clinical Benefits and Key Safety Risks, and a focus on any surrounding uncertainties. Additionally, we clarify existing definitions to differentiate descriptive, semi-quantitative, and fully quantitative BR methodologies. By presenting our framework, we wish to stimulate productive conversation between industry peers and health authorities regarding best practice in the BR field. This paper may also help facilitate the pragmatic implementation of sBR methodologies for organizations without an established framework for such assessments.

Keywords: Benefit-risk; Health authorities; Key clinical benefits; Key safety risks; Structured benefit-risk.

Figure 1

Developmental milestone-specific sBR methodology framework. NNH Number needed to harm, NNT number needed to treat, RM risk management, sBR structured benefit-risk.

Figure 2

A Simple value tree. Example of a simple value tree. Content is fictive and for illustrative purposes only. Figure adapted from Fig. 2 in Coplan et al. [26]. B Weighted value tree. Example of a weighted value tree. Content is fictive and for illustrative purposes only. Figure adapted from Fig. 2 in Coplan et al. [26]. C Complete weighted value tree. Example of a complete weighted value tree. Content is fictive and for illustrative purposes only, and is not intended to represent actual medical judgments. Figure adapted from Fig. 2 in Coplan et al. [26].

Figure 3

BR methodology choice for regulatory submission. BR Benefit-risk, NNH number needed to harm, NNT number needed to treat.

Figure 4

Forest plot. AE Adverse event, CI confidence interval, CNS central nervous system. Content is fictive and for illustrative purposes only. Figure available at: https://protectbenefitrisk.eu/dotchartspatients.html.

Figure 5

MCDA results. BR Benefit-risk, EDSS expanded disability status scale, PML progressive multifocal leukoencephalopathy. Content is fictive and for illustrative purposes only. Figure available at: https://protectbenefitrisk.eu/waterfallplot.html.