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Look back in anger - what clinical studies tell us about preclinical work
1Johns Hopkins University, Bloomberg School of Public Health, CAAT, Baltimore, MD 21205, USA. thartung@jhsph.edu
Unlabelled:
Misled by animal studies and basic research? Whenever we take a closer look at the outcome of clinical trials in a field such as, most recently, stroke or septic shock, we see how limited the value of our preclinical models was. For all indications, 95% of drugs that enter clinical trials do not make it to the market, despite all promise of the (animal) models used to develop them. Drug development has started already to decrease its reliance on animal models: In Europe, for example, despite increasing R&D expenditure, animal use by pharmaceutical companies dropped by more than 25% from 2005 to 2008. In vitro studies are likewise limited: questionable cell authenticity, over-passaging, mycoplasma infections, and lack of differentiation as well as non-homeostatic and non-physiologic culture conditions endanger the relevance of these models. The standards of statistics and reporting often are poor, further impairing reliability. Alarming studies from industry show miserable reproducibility of landmark studies. This paper discusses factors contributing to the lack of reproducibility and relevance of pre-clinical research.
The Conclusion:
Publish less but of better quality and do not rely on the face value of animal studies.
Insights
Preclinical research, including animal and in vitro studies, often fails to predict clinical trial outcomes due to poor reproducibility and relevance. Improving study quality and reducing reliance on animal models is crucial for effective drug development.
Area of Science:
- Biomedical research
- Drug discovery and development
Background:
- Preclinical models (animal studies, in vitro assays) frequently overestimate drug efficacy.
- High failure rates (95%) in clinical trials highlight the limitations of current preclinical research.
- Declining animal use in pharmaceutical research (e.g., >25% drop in Europe 2005-2008) signals a shift away from traditional models.
Purpose of the Study:
- To critically evaluate the reproducibility and relevance of preclinical research models.
- To identify factors contributing to the poor predictive value of animal and in vitro studies for clinical outcomes.
- To advocate for improved research quality and reduced reliance on potentially misleading preclinical data.
Main Methods:
- Review of clinical trial outcomes versus preclinical model predictions.
- Analysis of limitations in in vitro study methodologies (e.g., cell authenticity, culture conditions).
- Discussion of statistical and reporting standards affecting research reliability.
Main Results:
- Preclinical models demonstrate limited value in predicting clinical trial success for various indications.
- In vitro studies suffer from issues like poor cell authenticity, over-passaging, and non-physiologic conditions.
- Inconsistent statistical practices and reporting standards further compromise the reliability of preclinical findings.
Conclusions:
- The current reliance on preclinical research, particularly animal studies, is questionable due to low reproducibility and relevance.
- Enhancing the quality of research and reducing dependence on face-value interpretations of animal studies are essential.
- A shift towards higher-quality, more reliable research methods is needed for successful drug development.
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