(C) PLOS One
This story was originally published by PLOS One and is unaltered.
. . . . . . . . . .



Analysis of animal-to-human translation shows that only 5% of animal-tested therapeutic interventions obtain regulatory approval for human applications [1]

['Benjamin V. Ineichen', 'Centre For Reproducible Science', 'University Of Zurich', 'Zurich', 'Clinical Neuroscience Center', 'Eva Furrer', 'Servan L. Grüninger', 'Department Of Mathematics', 'Wolfgang E. Zürrer', 'Malcolm R. Macleod']

Date: 2024-06

Our umbrella systematic review evaluated (1) the proportion of therapies which translate from animal studies to human application, including timeframes; and (2) the consistency between animal and human study results. We observe a notable consistency between results from animal and human studies including a relatively large proportion of therapeutic interventions entering early clinical trials. However, only a minority of therapeutic intervention achieved regulatory approval.

Findings in the context of existing evidence

Translation across biomedical fields. Our review shows a high consistency between findings from animal and human studies, similar to studies outside of therapy translation [44]. In addition, a surprisingly high proportions of therapies entered early clinical development: half of the therapeutic interventions made the transition from animal studies to early human clinical studies (34% to 100% across different biomedical fields). Furthermore, 40% of these therapies progressed to the more rigorous RCT stage (29% to 62% for different biomedical fields). However, a strikingly low proportion—only 5%—of therapies achieved official approval (0% to 20% across the biomedical spectrum). How can we make sense of the fact that animal studies and early clinical trials seem to show promise, yet there is very limited official approval for these therapies? There are 2 possible explanations: One scenario is that the strict requirements of RCTs and regulatory approval are causing many potentially valuable treatments to be left behind. The other scenario is that both animal studies and early clinical trials may have limitations in their design, such as a lack of proper randomization and blinding, which affects their internal validity [45]. This could lead to unreliable findings in both domains, ultimately resulting in the exclusion of these therapies in more rigorous clinical trial settings like RCTs. This line of reasoning also includes the so called efficacy-effectiveness gap, i.e., the differences in outcomes between patients treated in ideal and controlled circumstances of clinical trials versus real-world scenarios [46,47]. We lean towards the second scenario for 2 reasons. First, as therapies progress to more rigorous study designs, their numbers do decrease as shown by our data, which contrasts to the mostly small and uncontrolled early clinical trials where these therapies were initially tested. Second, drawing from the field of clinical neurology, many therapies that have shown promise in animal studies and early trials reported as successful candidates herein, such as melatonin and mesenchymal stem cells for stroke, have not yet become standard clinical practice [48]. A similar pattern can be seen in other neurological diseases like Alzheimer’s disease and spinal cord injury, where there are several therapies with promising preclinical results but limited practical translation [49,50].

Potential hurdles for successful translation. Several factors contribute to the challenges in translating therapies from animal models to human application, as discussed by many of the included reviews. First, there is a notable discrepancy in the contexts of animal testing versus human application. For example, treatment strategies tested on young, healthy animals, such as those for stroke, may not directly apply to the more complex scenarios of elderly patients with multiple health conditions. Second, there is an overall poor quality of many animal studies. These studies often have inherent design flaws, lacking critical elements like blinding or randomization. This absence can bias the results and affect their applicability to the human case, i.e., their external validity. Third, there seems to be a disconnect between animal and human research [51]. This warrants a stronger focus on educating a new generation of translational scientists [52]. Fourth, when it comes to human studies, they can suffer from being underpowered or relying on outcome measures that do not capture the efficacy of a treatment [53]. For example, early phase clinical trials testing interventions for neurological diseases are commonly underpowered [54]. Similarly, clinical trials may use trial outcomes not genuinely reflecting real-world patient settings such as complex composite outcomes, commonly seen in trials of cardiovascular diseases [55] or assessing cognitive domains in dementia trials not relevant for patients [56]. Lastly, animal and human studies commonly address different questions: whereas animal studies tend to focus on mechanisms, human studies tend to focus on effectiveness of an intervention.

[END]
---
[1] Url: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002667

Published and (C) by PLOS One
Content appears here under this condition or license: Creative Commons - Attribution BY 4.0.

via Magical.Fish Gopher News Feeds:
gopher://magical.fish/1/feeds/news/plosone/