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