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Genetic factors associated with reasons for clinical trial stoppage

Olesya Razuvayevskaya1,2, Irene Lopez1,2, Ian Dunham1,2,3

  • 1Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire, UK.

Nature Genetics
|July 29, 2024
PubMed

Insights

Human genetics evidence significantly boosts drug trial success. Lack of genetic support leads to trial failure due to poor efficacy or safety concerns, highlighting genetics

Area of Science:

  • Pharmacology and Translational Medicine
  • Genetics and Genomics in Drug Discovery

Background:

  • High attrition rates plague drug discovery, with many clinical trials failing before approval.
  • Prior research indicates that human genetic evidence supporting a therapeutic hypothesis improves clinical trial progression rates.

Purpose of the Study:

  • To analyze the reasons for clinical trial discontinuation using natural language processing.
  • To evaluate the association between trial failure reasons, therapeutic hypothesis strength (particularly human genetic evidence), and drug target properties.

Main Methods:

  • Applied natural language processing (NLP) to categorize free-text reasons for 28,561 terminated clinical trials.
  • Assessed categorized reasons against human genetic evidence supporting the therapeutic hypothesis and target gene characteristics.

Main Results:

  • Trials lacking robust human genetic evidence (from populations or genetically modified models) were more likely to fail due to lack of efficacy.
  • Trials targeting genes with high evolutionary constraint in human populations and broad tissue expression were more prone to safety-related terminations.

Conclusions:

  • Human genetic validation is crucial for de-risking drug discovery programs.
  • Integrating genetic evidence early can predict and mitigate risks of trial failure related to efficacy and safety.

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