Look back in anger – what clinical studies tell us about preclinical work

Abstract

Summary 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.

Organic transistor platform with integrated microfluidics for in-line multi-parametric in vitro cell monitoring

“…In the near future, preclinical testing of new drugs using in vivo animal models is expected to be entirely substituted by less expensive, predictive multi-parametric in vitro cell culture models [1][2][3] . Currently, the most common in vitro models are still based on static cell culture models.…”

Urinary peptidomics provides a noninvasive humanized readout of diabetic nephropathy in mice

“…The translation of the extensive knowledge and plethora of potential targets 4 obtained in animal models of DN and other diseases to the clinic has been extremely limited 3,4 . This has been attributed to the fact that: i) human pathophysiology and drug susceptibility are often not adequately captured by animal models 5,6 , ii) readouts used in preclinical studies are usually different from the required endpoints in clinical trials 7 , or, iii) those readouts are based on a single molecule or phenotypic trait, not sufficient to assess pathology in detail and identify clinically valuable potential drug target ( Fig. 1A) 8,9 .…”

Building benchtop human models

“…However, the majority of medicines that start human trials fail to pass muster, often because of unexpected side effects or toxicity (1). Part of the problem is that scientists must test new medicines in isolated human cells, in animals, or in silico.…”