Model-Based Drug Development: A Rational Approach to Efficiently Accelerate Drug Development

Abstract

The pharmaceutical industry continues to face significant challenges. Very few compounds that enter development reach the marketplace, and the investment required for each success can surpass $1.8 billion. Despite attempts to improve efficiency and increase productivity, total investment continues to rise whereas the output of new medicines declines. With costs increasing exponentially through each development phase, it is failure in phase II and phase III that is most wasteful. In today's development paradigm, late-stage failure is principally a result of insufficient efficacy. This is manifested as either a failure to differentiate sufficiently from placebo (shown for both novel and precedented mechanisms) or a failure to demonstrate sufficient differentiation from existing compounds. Set in this context, this article will discuss the role model-based drug development (MBDD) approaches can and do play in accelerating and optimizing compound development strategies through a series of illustrative examples.

Direct Oral Anticoagulants Vs. Enoxaparin for Prevention of Venous Thromboembolism Following Orthopedic Surgery: A Dose–Response Meta‐analysis

“…As part of a model‐informed drug development strategy,23, 24 a model‐based meta‐analysis was carried out to evaluate the dose–response relationships for efficacy end points (major VTE and total VTE) and safety end points (major, clinically relevant, and total bleeding) of anticoagulants used for the prevention of VTE following THR and TKR surgery. A similar analysis was previously used to compare the various classes of anticoagulants and demonstrated that the therapeutic index relative to enoxaparin was greater for direct FXa inhibitors than for other classes of anticoagulants 21.…”

“…As a key component of knowledge management,23, 24 these models can be used in conjunction with emerging data from investigational agents to help inform dose selection and study design, which will ensure efficient clinical development and adequate differentiation from current therapy.…”

Getting Innovative Therapies Faster to Patients at the Right Dose: Impact of Quantitative Pharmacology Towards First Registration and Expanding Therapeutic Use

“…However, most reports to date have summarized the return on investment of using QP approaches primarily in the domain of cost savings and efficiency gains 2, 3, 4. Here, we describe the potential of QP approaches to accelerate patient access to innovative therapies.…”

Agent-Based Modeling in Systems Pharmacology

“…There has been a near constant flow of new terms introduced into the literature1 in an attempt to capture this phenomenon: “MBDD,”2 “model‐facilitated” or “model‐informed drug development,”3 “Quantitative and Systems Pharmacology,”4 and “pharmacometrics.” Large pharmaceutical companies have begun to review, quantify, and report the successes derived from the adoption of a model‐based strategy, providing a thorough description of its implementation and impact 5, 6, 7. The US Food and Drug Administration (FDA) recently utilized mechanistic model‐based methodologies to design a postmarketing clinical trial8; serving as a clear demonstration of the increasing confidence in and adoption of model‐based techniques in pharmacology.…”