Dr Alo, DO, FACC@MohammedAlo
Analysis of animal-to-human translation shows that only 5% of animal-tested therapeutic interventions obtain regulatory approval for human applications.
Introduction:-
1️⃣ Animal studies remain foundational in basic research, accounting for a substantial share of global biomedical research investment. These experiments have provided insight on aspects of human diseases and have paved the way for therapeutic innovations.
2️⃣ In recent years, concerns have grown about the low translatability of findings from animal experiments to humans, a concern that certain drugs with beneficial findings in animal experiments did not show similar effects in humans.
3️⃣ The concerns of low translatability of animal research are particularly relevant to the debate on the ethical use of animals in research because clinical translation is one of the primary justifications for such research. Discussions around the usefulness of animal experiments persist, but much of the current debate relies on anecdotal findings from discrete research areas.
Results:-
A surprisingly high proportions of therapies entered early clinical development: half(50%) 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).
Translation across biomedical fields:-
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.
1️⃣ One scenario is that the strict requirements of RCTs and regulatory approval are causing many potentially valuable treatments to be left behind.
2️⃣ 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. 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.
3️⃣ 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.
4️⃣ 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.
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.
1️⃣ 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.
2️⃣ 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.
3️⃣ Third, there seems to be a disconnect between animal and human research. This warrants a stronger focus on educating a new generation of translational scientists.
4️⃣ 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. For example, early phase clinical trials testing interventions for neurological diseases are commonly underpowered.
5️⃣ 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.
How can we improve translation?
While finding a straightforward solution is challenging, we emphasize 2 crucial elements to enhance the transition from preclinical studies to clinical applications: the robustness and generalizability of data.
1️⃣ ALS research illustrates data robustness issues, with treatments effective in animal models often failing in human studies.
2️⃣ On the other hand, the variability in experimental protocols and tools affects how generalizable the results are: drugs effective across diverse laboratory settings tend to promise better outcomes in human studies.
3️⃣ In addition, outcomes from animal and early clinical studies must align with actual clinical needs. Incorporating these measures could not only streamline drug development but also positively impact animal welfare by reducing research waste.
4️⃣ Could low translation be an innate characteristic of translational animal research? Instead of disposing animal research due to low translation, a more telling comparison might be drawing parallels between translational rates in animal research and sectors like medical device approvals, where development largely bypasses animal use. It might emerge that translation proportions could be similarly modest in these animal-free sectors.
Conclusion:-
Although the consistency between animal and early clinical studies was high, only a minority of therapeutic interventions achieved regulatory approval.
