Patient‐Centered Reverse Translation

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Excerpt

Reverse (adjective). Going in or turned towards the direction opposite to that previously stated.
Translation (noun). The process of translating words or text from one language into another.
oxforddictionaries.com
Reverse translation is an important and evolving concept in translational medicine. Since “reverse” essentially means the opposite direction, it is worth considering what “forward” translation means. Of course, the definition of translational medicine has been rigorously and extensively debated by many stakeholders over the years. One recent definition of translational medicine was developed for the strategic plan in service of the American Society for Clinical Pharmacology and Therapeutics.1 In this definition, the essential component of translational medicine is “to improve human health via a ‘bench‐to‐bedside’ approach.” Furthermore, “It may include application of research findings from genes, proteins, cells, tissues, organs, and animals, to clinical research in patient populations, all aimed at optimizing and predicting outcomes in specific patients.” The dictionary definition of translation relates to transitioning from one language to another (oxforddictionaries.com). And this is exactly what transpires in forward translational medicine, in which laboratory research concepts are translated into the language of medicine and clinical experiments. Bench‐to‐bedside is a common motif in definitions of translational medicine and can be taken as the main principle for forward translation. Figure1 displays forward translation as the process moving from identification of a therapeutic target to discovery and optimization of new potential therapies (and corresponding tools) to testing in patients. Drug development tools include biomarkers, assays, animal models, and modeling and simulation platforms used to characterize, optimize, and develop the potential therapy. In summary, a compact definition of forward translation is the application or translation of laboratory research to clinical experiments or patients. Forward translation subsumes many of the traditional activities of drug discovery and development.
The exclusively bench‐to‐bedside approach is limiting. The most obvious limitations are in target discovery and the frequent route reversals necessary for drug discovery and development. Targets do not emerge from a vacuum, and that is where a patient‐centered reverse translation approach is particularly critical. Figure1 shows that reverse translation starts with deep characterization of the patient, perhaps by identifying unique phenotypes or genotypes of disease. Next, this deep understanding of the patient and disease informs the mechanism, which in turn drives deeper understanding and better selection of targets. Reverse translation activities aim to explain disease and patient biology through an integrative, cross‐functional approach linking “omic” data derived from a deep characterization of patients with their health phenotype data. The goal is to generate actionable hypotheses about disease mechanisms and drug response supporting validation of existing targets, identifying new targets and disease mechanisms/indications, and driving precision medicine strategies. Data for reverse translation can be derived from exploratory characterization of patients in clinical trials, noninterventional human studies, or through access to well‐characterized patient databases/tissue repositories, including public–profit consortia efforts. Thus, a key goal of reverse translation is to choose targets that are derived from human patient data, and are predicted to deliver striking functional outcomes. But that is not the only activity of reverse translation. Forward translation does not formally account for the critical reverse steps, such as learnings from patients that are reflected back to drug discovery and development tools (e.g., biomarkers, animals models, or modeling and simulation approaches, including quantitative disease models) or to refinements of a therapeutic (e.g., pharmacokinetically unacceptable profiles leading to different desired molecular or metabolic properties). In summary, a compact definition of reverse translation is the application or translation of clinical, patient‐centered data to laboratory research.
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