How Well Are We Applying Quantitative Methods to Reverse Translation to Inform Early Clinical Development?

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Excerpt

The Oxford English Dictionary defines reverse as move backwards; however, in the case of reverse translation we are defining it as moving backwards to go forwards. With each new molecule that is brought forward into humans, we generate enormous quantities of data, primarily in three categories—pharmacology, efficacy, and safety. The principle of “reverse translation” is to use these data to inform both drug discovery and development by 1) impacting the choice of new molecules/targets coming forward and 2) optimizing development paths and decision criteria to be pursued, such that patients can have access to life‐changing drugs more quickly. Indeed, taking the bedside‐to‐bench approach has previously yielded insights into molecular mechanisms across therapeutic areas.1 At the center of every drug development program are the patients we serve and we owe it to them to use our collective information and data in the most optimal way possible. The quantitative approaches presented in this Commentary build on a range of methods developed and implemented across industry for over a decade, culminating in the recent white paper on model‐informed drug discovery and development (MID3).2
Before a molecule enters humans for the first time, we have several categories of key information:
As a new drug enters the clinic, there are essentially five main questions to answer in early‐stage clinical development:
Although the above questions are stated qualitatively, there is a growing desire within drug development to underscore these questions with quantitative criteria. In other words, how are the “sufficient” exposure, “desired pharmacology,” “desired efficacy,” and “supportable” safety profile defined? There are scenarios where we simply do not know the answers to these questions; for instance, a new mechanism of action in an understudied disease. However, in the vast majority of circumstances each of these aspects can be informed by reverse translation wherein prior art is applied to the current investigation.
The methods that are used to support quantitative reverse translation can vary from the very simple to the extremely complex. Simple methods can simply involve targeting a plasma concentration with a new molecule (corrected for factors such as plasma protein binding and potency) that equals that associated with pharmacology/efficacy with a prior molecule (Case Study 4).8 An extremely complex method could invoke a multiscale model that relates systems pharmacology to efficacy and/or safety outcomes.6 The method employed should be “fit for purpose,” not just for the program under investigation, but for the resources and talents that are available to the organization. The quantitative integration of relevant data to help answer the relevant question is the most important aspect—the method is secondary.
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