Optimizing early Go/No Go decisions in CNS drug development
1National Institute of Mental Health, Bethesda, MD.
Abstract:
Go/No Go decisions concerning development of any single compound determine investment in increasingly costly studies from Phases I-III. Such decisions are problematic for CNS drug development where the variety of molecular targets in the brain have stimulated decades of studies without major therapeutic advances. Many costly studies do not even yield interpretable results as to whether the mechanism being pursued has therapeutic potential. Therefore, both industry and the public sector have implemented a decision making strategy based on whether a compound can test a molecular hypothesis of drug action. One requires, at a minimum, compelling evidence in humans that a compound both interacts with its presumed molecular targets in brain and ideally documents a CNS functional consequence of the interaction prior to efficacy studies. This strategy will much more quickly rule out ineffective mechanisms although it does not address the problem of poorly predictive models of novel CNS drug efficacy.
Insights
Deciding whether to advance new central nervous system (CNS) drugs is challenging. A new strategy requires human data showing target engagement and functional effects before expensive efficacy studies.
Area of Science:
- Neuroscience
- Pharmacology
- Drug Development
Background:
- Central nervous system (CNS) drug development faces significant challenges due to numerous molecular targets and limited therapeutic advances.
- Costly clinical trials often fail to provide interpretable results on the therapeutic potential of pursued mechanisms.
- Current decision-making processes for CNS compounds are problematic, leading to substantial investment without clear validation.
Discussion:
- A new strategy mandates compelling human evidence of target engagement and CNS functional consequences before efficacy studies.
- This approach aims to validate molecular hypotheses of drug action early in development.
- Focusing on target engagement and functional outcomes can accelerate the identification of promising CNS drug candidates.
Key Insights:
- Early human data on target engagement and functional effects are crucial for CNS drug development.
- Testing molecular hypotheses in humans prior to extensive trials can improve decision-making.
- This strategy enhances the efficiency of ruling out ineffective therapeutic mechanisms.
Outlook:
- This refined decision-making process can improve the success rate of CNS drug development.
- Further research is needed to address the limitations of predictive models for novel CNS drug efficacy.
- Continued validation of molecular targets and mechanisms in humans is essential for future therapeutic breakthroughs.
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