GOT-IT (Guidelines on Target Assessment for Innovative Therapeutics) - Project

Target Assessment Guidelines

Why do we need Target Assessment Guidelines?
  • Translation of basic research findings into new therapeutics is a major challenge of biomedical research, and an important public health issue.
  • Currently there is a lack of a systematic, focused approach to assess newly identified targets and to identify the key factors, goals and milestones which are essential to pursue a drug development project.
  • The interaction and exchange of knowledge between Industry and Academia is often limited.
  • Important aspects that promote drug discovery are often unknown or not in the focus of early-stage drug development projects.
  • The published work on new targets is too often not reproducible and sufficient implementation of critical quality requirements is often missing.

What is the goal of the GOT-IT project?
  • Developing a fit-for-purpose, flexible set of recommendations on robust target validation and assessment suitable for different indications and research projects.
  • Presenting the complexity of the target assessment process and drawing attention to aspects that are likely to be neglected.
  • Helping to prioritize different aspects of target assessment for efficient use of available resources and for streamlining research activities.
  • Supporting the identification of value inflection points, milestones and Go/NoGo-decision points for each project and increasing confidence in a suitable target.
  • Providing support how to generate high-quality and robust data sets which facilitate decision-making.

How do we want to achieve this?

In the context of the GOT-IT recommendations, it is critical to acknowledge the specific needs and requirements of translational drug discovery projects with potentially commercial interests - in contrast to projects, which can be categorized as purely basic research.

Given that there is no single solution for all institutions, research areas and targets, guidelines for assessing a drug target must be flexible and fit-for-purpose (e.g. applicable within practical limits of time and money). For any selected target or specific research environment, target assessment is not an absolute ‘truth’ and its relative value is strongly dependent on the therapeutic area and today’s knowledge and state of technology. Consequently, best practice must be tailored to individual research and disease fields of interest. Thus, the GOT-IT concept is based on a modular system, the Critical Path, that allows for sufficient flexibility to address individual project goals and milestones, indication-specific needs, and availability of resources.

The Critical Path

  • Using the Critical Path concept ensures that guidelines are suitable for different indications and broad practical applications.
  • The Critical Path is assembled through different Assessment Blocks, covering relevant aspects of practical target validation and assessment.
  • The order in which Assessment Blocks are chosen and arranged is project- and indication-specific and the Critical Path entry point can vary depending on the nature of the discovery program.
  • Resource management: the Critical Path system outlines which milestones can be reached within the constraints of the available resources and also highlights areas where further funding is needed to implement additional critical Assessment Blocks.
  • The Critical Path defines the main framework and potential endpoints of a target assessment project, ensuring that scientists stay on the right track in translational drug discovery.
  • Assessment Blocks cover 5 different areas:
  • - Target-Disease Linkage,
  • - Target-related Safety aspects,
  • - Aspects related to non-human Targets,
  • - Technical Feasibility and
  • - Innovation Potential

Figure 1

Figure 1: Overview of the Critical Path concept for Target Assessment.

The Assessment Blocks

1. Assessment Block: Target-Disease Linkage

  • This Assessment Block focuses on generating evidence that modulating the target of interest leads to clinically relevant physiological effects.

2. Assessment Block: Target-related Safety

  • On-target or target-related toxicity refers to exaggerated and adverse effects, that result from manipulating the inherent biological function of the target of interest.
  • Early identification of potential target-related toxicities and increased understanding of the underlying molecular mechanisms can guide the development of safety biomarkers and help derive mitigation strategies to facilitate project progression.
  • The purpose of this Assessment Block is to identify potential unintended consequences of target modulation and to confirm and characterize unavoidable on-target toxicities in a timely manner.

3. Assessment Block: Non-human Targets

  • For anti-microbial research (and other therapeutic areas) drug discovery approaches have typically been divided into two classes: target-based drug discovery (TDD) and phenotypic drug discovery (PDD): The target-based strategy is based on the identification and validation of a molecular target before lead discovery starts. In contrast, phenotypic screening can be described as the process that identifies chemical matter that induce desired phenotypic changes (i.e. antibacterial activity) in cells or organisms. This PDD approach does not usually require prior knowledge about disease pathophysiology or the compound’s mode of action against a specific molecular target.
  • The retrospective identification (target deconvolution) and validation/assessment of the target underlying the observed phenotypic responses can, however, greatly facilitate subsequent target-specific enhancement of pharmacological properties. In addition, species-selectivity as well as target-based side effects and safety may need to be addressed, thereby potentially reducing later-stage attrition.

4. Assessment Block: Technical Feasibility

  • Requirements of an innovative and promising molecular target as the basis for a successful drug discovery program include aspects like ‘druggability’ and ‘assayability’, that may need to be taken into account early on in the process when designing the Critical Path.

5. Assessment Block: Degree of Innovation

  • In the context of the GOT-IT guidelines, Innovation is defined as a scientific breakthrough in basic research or discovery and its transforming into a marketable product that can be successfully launched into highly regulated markets. The key question is how to position validated targets favorable for the large-scale (external) investment required to develop new therapeutic products.
  • Thus, this Validation Block deals with strategic options for managing and protecting IP associated with validated targets, the competitor landscape, and medical as well as commercial needs - with the aim to generate valuable data for business and commercialization plans, attractive licensing propositions for commercial partners as well as for potential investors.

The Guiding Questions

  • A set of 40 Critical Path Questions (CPQs) helps to select relevant Assessment Blocks and provides meaningful guidance for positioning and prioritizing identified Assessment Blocks.
  • CPQs help to identify key gaps and road blocks for a translational target assessment project and identify areas (‘red flags’), which should be addressed rather at the early stages of a project.
  • Sets of Experimental Approach Questions (EAQs) will help to identify relevant key experiments, activities and tasks for each selected Assessment Block.
  • EAQs provide the opportunity to introduce project-specific elements. EAQs also address the need to design high-quality killer experiments which have the potential to de-validate a target and are the basis for Go/NoGo decisions depending on the results obtained.

Figure 2

Figure 2: Guiding Questions help to define the framework of the target assessment project and to select project-specific tasks for each Assessment Block chosen.

The Ranking Guide

  • The Ranking Guide will show the relative value of certain target assessment elements and will support scientists in increasing the scientific relevance of studies/experiments performed - in accordance to the resources available.
  • The Ranking Guide will help to assess the quality of evidence generated by any study/experiment performed.
  • Each category (e.g. model organism, system, readout) contributes to the overall strength of the evidence (for a target’s involvement in the pathophysiology of interest), which is elevated in the presence of diverse convergent evidence.
  • The Ranking Guide will help researchers to: 1) characterize the available evidence for a specific factor of interest; 2) prioritize steps for further research and 3) to identify potential risk factors.

Data Quality/Robustness Requirements

Several steps within the drug discovery value chain are well controlled by GxP-based quality control (e.g. GLP toxicology). However, these same standards cannot be applied to the non-regulated, preclinical areas of drug discovery and target assessment. Hence, there is a need for a specialized set of quality requirements that specifically focus on study design, unbiased conduct, statistical analysis and transparent reporting.

Data Quality Requirements form an essential part of the target assessment process and the GOT-IT project will support Academia-Industry interactions by aligning quality criteria in pre-clinical research. One of the core elements of the GOT-IT guidelines will be recommendations related to data robustness and reproducibility, ensuring unbiased and robust research outcomes.

Thus, it is critical to assess not only the scientific relevance of a certain study or experiment but also to analyse HOW these experiments have been designed and conducted - ensuring that high-quality and robust data sets are generated.

Internal validity

  • The internal validity of experimental studies can be increased by practical implementation of “confirmatory research” standards, including crucial processes like blinding and randomization, appropriate statistical power analyses, primary endpoint definitions, etc.

External validity

  • Multiple independent replicates as well as several orthogonal technologies provide higher confidence and converging evidence in therapeutic relevance of a target.

Quality of tools and reagents

  • A major requirement for validating experimental results is that researchers routinely question reagent purity, authenticate cell lines, validate antibodies and animal models, and include appropriate controls when assessing the design, execution, and the outcome of an experiment.


  • An experimental record should provide the amount of information and level of detail to permit peers to reconstruct, repeat the experiment or compare outcomes based on the information provided.
  • The description of an experiment should be clear and unambiguous.
  • It is critical to ensure that experimental records are attributable, legible, contemporaneous, original, accurate and complete.

Figure 3

Figure 3: Workflow of the target assessment process according to the GOT-IT recommendations.