Planning a target assessment project
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Planning a target assessment project
What are Target Validation and Target Assessment?
Target validation can be understood in numerous ways depending on the context, but usually describes the experimental confirmation that a target molecule is demonstrably disease relevant and plays a causal role in disease initiation or prolongation.
For applied and commercial biomedical projects, additional aspects become critical, like the target-related safety profile, the molecular druggability, biomarker research, assayability, legal and intellectual property (IP) state as well as the unmet medical need, and the commercial potential. These considerations altogether are defined as target assessment in the context of the GOT-IT recommendations.
Why do I need to perform target assessment?
The average likelihood of approval from Phase I across all therapeutic areas is reported to be less than 10%. [1] In many cases, clinical failures can be linked to insufficient validation of the selected target. [2] Robust target assessment is crucial to drug discovery and target assessment deserves strong emphasis in order to facilitate the development of new therapies. Doing this adequately increases chances for successful co-operation with industry or receiving additional funding.
[1] Hay M, et al., Rosenthal J.
Clinical development success rates for investigational drugs.
Nature Biotechnology (2014)
Drug discovery and development
PMID: 24406927
[2] Bunnage ME.
Getting pharmaceutical R&D back on target.
Nature Chemical Biology (2011)
Target identification and validation & Drug discovery and development
PMID: 21587251
Who can help me perform proper target assessment?
The GOT-IT (Guidelines on Target Assessment for Innovative Therapeutics) team developed a fit-for-purpose, flexible set of guidelines on robust target assessment suitable for implementation in an academic setting.
Please see the information table for further information.
What are Target Validation and Target Assessment?
Target validation can be understood in numerous ways depending on the context, but usually describes the experimental confirmation that a target molecule is demonstrably disease relevant and plays a causal role in disease initiation or prolongation.
For applied and commercial biomedical projects, additional aspects become critical, like the target-related safety profile, the molecular druggability, biomarker research, assayability, legal and intellectual property (IP) state as well as the unmet medical need, and the commercial potential. These considerations altogether are defined as target assessment in the context of the GOT-IT recommendations.
Why do I need to perform target assessment?
The average likelihood of approval from Phase I across all therapeutic areas is reported to be less than 10%. [1] In many cases, clinical failures can be linked to insufficient validation of the selected target. [2] Robust target assessment is crucial to drug discovery and target assessment deserves strong emphasis in order to facilitate the development of new therapies. Doing this adequately increases chances for successful co-operation with industry or receiving additional funding.
[1] Hay M, et al., Rosenthal J.
Clinical development success rates for investigational drugs.
Nature Biotechnology (2014)
Drug discovery and development
PMID: 24406927
[2] Bunnage ME.
Getting pharmaceutical R&D back on target.
Nature Chemical Biology (2011)
Target identification and validation & Drug discovery and development
PMID: 21587251
Who can help me perform proper target assessment?
The GOT-IT (Guidelines on Target Assessment for Innovative Therapeutics) team developed a fit-for-purpose, flexible set of guidelines on robust target assessment suitable for implementation in an academic setting.
Please see the information table for further information.
Planning a target assessment project
How do I use the GOT-IT guidelines?
The GOT-IT guidelines assist you in planning a target assessment project by developing a project-specific Critical Path. The Critical Path is assembled using different Validation Blocks that can be identified and prioritized by answering Critical Path Questions. For more information click here.
In addition, GOT-IT also provides relevant information for target assessment in the TARGET ASSESSMENT RESOURCE CENTRE.
What is my project goal/destination?
Several destinations can be reached within a target assessment project. While all theoretically possible stages in such a project may not be required, specifying your final goal will help define which of the recommended steps are needed (and how to answer the sets of Critical Path Questions).
Cool! Where do I find potential examples for TaV journey goals and destinations?
You can select any of the destinations of the tracks. Along your journey, information and examples are offered, depending on which destination you select.
Have a safe journey and proceed to the ticket inspector.
Why is target assessment so challenging?
The target assessment process consists of many different stages, such as establishing a) the link between target and disease b) druggability of the target c) safety issues of the target d) sufficient level of project innovation. Frequently, problems arise during the course of the project and you may have to take detours to stay on track. For examples and case studies, please proceed to the ticket counter to book a target assessment journey.
How do I use the GOT-IT guidelines?
The GOT-IT guidelines assist you in planning a target assessment project by developing a project-specific Critical Path. The Critical Path is assembled using different Validation Blocks that can be identified and prioritized by answering Critical Path Questions. For more information click here.
In addition, GOT-IT also provides relevant information for target assessment in the TARGET ASSESSMENT RESOURCE CENTRE.
What is my project goal/destination?
Several destinations can be reached within a target assessment project. While all theoretically possible stages in such a project may not be required, specifying your final goal will help define which of the recommended steps are needed (and how to answer the sets of Critical Path Questions).
Cool! Where do I find potential examples for TaV journey goals and destinations?
You can select any of the destinations of the tracks. Along your journey, information and examples are offered, depending on which destination you select.
Have a safe journey and proceed to the ticket inspector.
Why is target assessment so challenging?
The target assessment process consists of many different stages, such as establishing a) the link between target and disease b) druggability of the target c) safety issues of the target d) sufficient level of project innovation. Frequently, problems arise during the course of the project and you may have to take detours to stay on track. For examples and case studies, please proceed to the ticket counter to book a target assessment journey.
Planning a target assessment project
I should like to book a target assessment journey.
Where would you like to travel and on which track? Do you know the goal(s)/destinations you would like to reach?
How do I know which path I have to choose?
You need a clear definition of indication and project goals before preclinical studies are planned. This ensures that all project-specific characteristics and conditions are taken into account, depending on your needs and requirements.
Try defining a Target Product Profile (TPP) to define the characteristics of the product you want to develop.
Use the Critical Path Generator to develop a path.
I should like to book a target assessment journey.
Where would you like to travel and on which track? Do you know the goal(s)/destinations you would like to reach?
How do I know which path I have to choose?
You need a clear definition of indication and project goals before preclinical studies are planned. This ensures that all project-specific characteristics and conditions are taken into account, depending on your needs and requirements.
Try defining a Target Product Profile (TPP) to define the characteristics of the product you want to develop.
Use the Critical Path Generator to develop a path.
Planning a target assessment project
I should like to start my target assessment journey now.
Very well. Have you considered that target assessment includes Go/NoGo decision points? Decision-enabling studies need to be based on robust and high-quality data sets. Thus, it is essential to implement data quality requirements (e.g. ‘confirmatory research’ standards).
Also take formal and legal issues into account: e.g., a patent cannot be obtained if an invention was previously known or used by others, or published anywhere in the world, including poster presentations and grant abstracts/ applications (if published).
What do I need to do to produce robust data?
You need a set of quality requirements specifically focusing on study design, unbiased conduct, statistical analysis and transparent reporting that will support academic-industry interactions by aligning quality criteria in pre-clinical research.
Guidance related to data quality is part of the GOT-IT GUIDELINES, including crucial processes like blinding and randomization, appropriate statistical power analyses, primary endpoint definitions, etc. Often, multiple independent replicates as well as several orthogonal technologies are needed to provide greater confidence and converging evidence for the therapeutic relevance of a target.
Is there anything else I need to consider?
You need to routinely question reagent purity, authenticate cell lines, validate antibodies and animal models, and include appropriate controls when assessing the design, execution, and the results of an experiment. [1] Experimental records should provide the amount of information and level of detail to permit peers to reconstruct and/or repeat the experiment based on the information provided and compare outcomes. [2] Specific guidance for documentation and the traceability of research data is provided in the GOT-IT GUIDELINES. If you comply with the quality requirements, your journey should be less bumpy!
[1] Williams M.
Reagent Validation to Facilitate Experimental Reproducibility.
Curr Protocols in Pharmacology (2018)
Quality in research, robustness of data
PMID: 29927084
[2] Wilkinson MD, et al., Mons B.
The FAIR Guiding Principles for scientific data management and stewardship.
Scientific Data (2016)
Quality in research, robustness of data
PMID: 26978244
Thank you. Could you give me an example?
Animal studies are susceptible to study quality biases, which may lead to overstatement of drug efficacy. Studies on animal models of stroke, which did not report/implement critical quality requirements (i.e. randomization, concealment of treatment allocation, and blinded outcome assessment) gave substantially higher effect sizes (i.e. reduction in infarct volume) than did higher-quality studies. The failure of the SAINT II clinical trial highlights the need for substantial improvements in the design, conduct, and reporting of animal studies. [1]
...oh dear...
...Another example: published effect responses (i.e. change in survival) in ALS (Amyotrophic Lateral Sclerosis) mouse models were much larger than those obtained by the ALS Therapy Development Institute when the studies were repeated under rigorous conditions and after implementing critical quality standards. These were: randomizing litter mates, balancing for gender, defining exclusion criteria, assessing animals' physical and biochemical traits in terms of human disease; characterizing when disease symptoms and death occur and being alert to unexpected variation; and creating a mathematical model to aid experimental design, including how many mice must be included in a study to minimize experimental noise. [1]
I should like to start my target assessment journey now.
Very well. Have you considered that target assessment includes Go/NoGo decision points? Decision-enabling studies need to be based on robust and high-quality data sets. Thus, it is essential to implement data quality requirements (e.g. ‘confirmatory research’ standards).
Also take formal and legal issues into account: e.g., a patent cannot be obtained if an invention was previously known or used by others, or published anywhere in the world, including poster presentations and grant abstracts/ applications (if published).
What do I need to do to produce robust data?
You need a set of quality requirements specifically focusing on study design, unbiased conduct, statistical analysis and transparent reporting that will support academic-industry interactions by aligning quality criteria in pre-clinical research.
Guidance related to data quality is part of the GOT-IT GUIDELINES, including crucial processes like blinding and randomization, appropriate statistical power analyses, primary endpoint definitions, etc. Often, multiple independent replicates as well as several orthogonal technologies are needed to provide greater confidence and converging evidence for the therapeutic relevance of a target.
Is there anything else I need to consider?
You need to routinely question reagent purity, authenticate cell lines, validate antibodies and animal models, and include appropriate controls when assessing the design, execution, and the results of an experiment. [1] Experimental records should provide the amount of information and level of detail to permit peers to reconstruct and/or repeat the experiment based on the information provided and compare outcomes. [2] Specific guidance for documentation and the traceability of research data is provided in the GOT-IT GUIDELINES. If you comply with the quality requirements, your journey should be less bumpy!
[1] Williams M.
Reagent Validation to Facilitate Experimental Reproducibility.
Curr Protocols in Pharmacology (2018)
Quality in research, robustness of data
PMID: 29927084
[2] Wilkinson MD, et al., Mons B.
The FAIR Guiding Principles for scientific data management and stewardship.
Scientific Data (2016)
Quality in research, robustness of data
PMID: 26978244
Thank you. Could you give me an example?
Animal studies are susceptible to study quality biases, which may lead to overstatement of drug efficacy. Studies on animal models of stroke, which did not report/implement critical quality requirements (i.e. randomization, concealment of treatment allocation, and blinded outcome assessment) gave substantially higher effect sizes (i.e. reduction in infarct volume) than did higher-quality studies. The failure of the SAINT II clinical trial highlights the need for substantial improvements in the design, conduct, and reporting of animal studies. [1]
...oh dear...
...Another example: published effect responses (i.e. change in survival) in ALS (Amyotrophic Lateral Sclerosis) mouse models were much larger than those obtained by the ALS Therapy Development Institute when the studies were repeated under rigorous conditions and after implementing critical quality standards. These were: randomizing litter mates, balancing for gender, defining exclusion criteria, assessing animals' physical and biochemical traits in terms of human disease; characterizing when disease symptoms and death occur and being alert to unexpected variation; and creating a mathematical model to aid experimental design, including how many mice must be included in a study to minimize experimental noise. [1]
Planning a target assessment project
The Critical Path Concept:
The Critical Path is assembled using different Assessment Blocks (ABs), which define and categorize different activities to assess and validate a new drug target:
- Entering translational projects with a strategic plan clearly outlining milestones and Go/NoGo decision points helps to reduce operational risks and facilitate resource management. The Target Assessment Project Plan (TAPP) defines the overall goals of a target assessment project and outlines the strategy needed to achieve the goals specified.
- The identification and arrangement of project-relevant ABs is facilitated by answering a set of Critical Path Questions (CPQs) at the beginning of a project. Here, the goal is to prioritize AB-related activities once a target is identified and to allocate existing resources. CPQs also help to identify key gaps and roadblocks for a translational project and identify areas (‘red flags’), which should be addressed preferentially at the early stages of a project.
- The next step is to define specific activities for each selected Assessment Block. Sets of Experimental Approach Questions are designed to identify key experiments to increase confidence in the target of interest and provide the opportunity to introduce project-specific tasks.
- The EAQs also address the need to design high-quality killer experiments which have the potential to invalidate a target and are the basis for Go/NoGo decisions depending on the results obtained. When assessing the Quality of Evidence at each decision-point, it is critical to consider both data quality requirements as well as the relevance of experiments conducted.
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