Mathematical modeling of efficacy and safety for anticancer drugs clinical development

ABSTRACT

Introduction: Drug attrition in oncology clinical development is higher than in other therapeutic areas. In this context, pharmacometric modeling represents a useful tool to explore drug efficacy in earlier phases of clinical development, anticipating overall survival using quantitative model-based metrics. Furthermore, modeling approaches can be used to characterize earlier the safety and tolerability profile of drug candidates, and, thus, the risk-benefit ratio and the therapeutic index, supporting the design of optimal treatment regimens and accelerating the whole process of clinical drug development.

Areas covered: Herein, the most relevant mathematical models used in clinical anticancer drug development during the last decade are described. Less recent models were considered in the review if they represent a standard for the analysis of certain types of efficacy or safety measures.

Expert opinion: Several mathematical models have been proposed to predict overall survival from earlier endpoints and validate their surrogacy in demonstrating drug efficacy in place of overall survival. An increasing number of mathematical models have also been developed to describe the safety findings. Modeling has been extensively used in anticancer drug development to individualize dosing strategies based on patient characteristics, and design optimal dosing regimens balancing efficacy and safety.

KEYWORDS:

• Adverse events
• attrition rate
• clinical oncology
• efficacy
• mathematical modeling
• pharmacodynamics
• resistance
• safety

Article highlights

• The reduction of attrition in drug development is of paramount importance, in particular in the oncology field, where it is higher than in the other therapeutic areas.

• Mathematical models, by gathering and quantitatively integrating knowledge about the drug efficacy and safety profiles throughout every development phase, can provide a fundamental tool to reduce attrition and improve the decision-making process.

• Many relevant examples of modeling approaches applied to drug development in clinical oncology can be found in the recent literature.

• Approaches employed for the assessment of drug efficacy profile consist in models describing and/or linking the dynamics of: biomarkers of pharmacological activity, tumor size, tumor markers, and OS (or surrogate endpoints). Empirical and more mechanistic models accounting for the development of resistance in cancer patients have also been developed.

• A variety of models have been proposed for characterizing the drug safety profile, according to the type of data recorded during AEs monitoring: continuous, ordered categorical, and time-to-event.

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Declaration of interest

I Poggesi is an employee and holds stock with Janssen Pharmaceuticals shares. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.