An End-to-End Solution to Bridge The Valley of Death in In Vivo Drug Discovery
A blog article by Ashlie Reker Ph.D.
Translation of novel efficacious therapies to market exhibit alarmingly low rates of success. Recent aggregate data analysis placed the probability of success to be between 3.4% (investigative cancer therapy) and 33.4% (vaccines for infectious disease) (Wong & Siah, 2019), with the journey to acceptance or rejection taking a decade or more. In addition, from 2009-2018, the estimated mean investment into research and development to bring a new drug to market, accounting for failed trials, was $1.3B (Wouters, McKee, & Luyten,2020). Ultimately, the impact of lengthy, and often unsuccessful, therapeutic development ventures increases the burden of disease for vulnerable patient populations and demands improvement.
Bench-to-bedside describes the lifecycle through which an approved therapy reaches clinical application and is comprised of three essential phases: basic research (the bench), translational research, and clinical research (the bedside). Basic research, lauded as scientia gratia scientiae, aims to elucidate the underlying mechanisms of disease, and in so doing, identify lead targets to be explored for therapeutic development (Mohs & Greig, 2017). Both in vitro and in vivo techniques that assess behavior, genes, proteins, receptors and the -omics, to name a few, are used to confirm that sufficient homology exists between the animal model and the human presentation of disease. By and large, these foundations of drug discovery live within the realm of academia (Flier, J.S, 2019; Silber, B.M, 2010). Clinical research, or clinical trials, evaluate the safety and efficacy of the new therapeutic in humans. This phase of drug development is often the lengthiest and most costly, consisting of four phases of rigid criteria (see NIH/NIA article for an overview of clinical trials). The keystone to moving from the bench to the bedside, and ultimately marketed product, is translational science – The Valley of Death of drug development.
Valley of the Shadow of Death by Roger Fenton, April 23, 1855
In therapeutic development, translational research is the multidisciplinary process by which experimental interventions identified and refined in the laboratories of basic science are implemented in successively more complex research models in order to gain approval for human trial. The objective of this arm of development is to apply the same techniques of basic research, as above, to determine if the treatment meets pre-determined criteria of efficacy and conduct extensive pharmacokinetic and pharmacodynamic studies assess the safety profile of the new intervention. Given that poor efficacy and safety profile are major causes of drug development failure at clinical testing (Seyhan, A. A., 2019), it becomes clear why well designed and executed in vivo translational research is necessary. This process seems straightforward – so why the valley of death?
Often times, the 3 major arms of development function in relative isolation, but in reality, science is iterative and agile, requiring cross-disciplinary cooperation for timely success. This is especially true for the limited, yet crucial, academia-industry relationships (Flier, J. S., 2019; Takebe, T. et al., 2018). For example, if an intervention is successful in one species, but not the next higher order model, experts from basic science offer a wealth of knowledge, which, when discussed with experts in translational research, can enhance the lead target, and result in renewed R&D funding.
Significant hindrances to facilitating these successful relationships lie in reproducibility, transparency, and collaboration (Seyhan, A. A., 2019). In an effort to address these shortcomings, The Dutch Translational research IT (TraIT) initiative focused on improving organization, logistics and data management to upgrade extract-transform-load, to more efficiently collect, transform and store data into a data warehouse for international multi-center use (Boiten, J-W et al., 2020). Harnessing the advancements of information technologies can revolutionize the process of drug discovery – reducing cost, time spent on false leads, and helping patients sooner.
Dotmatics and Climb 2.0 from RockStep Solutions together provide an end-to-end solution to bridge The Valley of Death in in vivo research. Hosted on the secure Microsoft Azure cloud, Climb 2.0 offers the ability to securely collaborate in real-time on experimental design, study execution, data collection, drug safety metrics, and sample creation. Climb also has comprehensive animal husbandry and administration capabilities supporting fast veterinary response and IACUC reports. Dotmatics is an internationally established application that provides, inventory management, biologics registration, chemistry design, and data analysis and visualization. Furthermore, with their ELN capabilities, you have a secure repository where any and all research information can be stored and accessed by specified relevant stakeholders or made publicly available. Single sign on and sync features offer a seamless and secure solution for your in vivo research needs.
Boiten, J-W, Azevedo, R., van Bochove, K., Cavelaars, M., Dekker, A., Fijneman, R. J. A, Lansberg, P., van der Linden, W., Mons, B., Stathonikos, N., Verheul, H. M.W., Beliën, J. A.M., Meijer, G. A. (202). bioRxiv. doi: https://doi.org/10.1101/2020.05.18.052563
Flier, J.S. (2019). Academia and industry: allocating credit for discovery and development of new therapies. The Journal of Clinical Investigation, 129 (6), 2172-2174. https://doi.org/10.1172/JCI129122
Mohs, R.C. & Greig, N.H. (2017). Drug discovery and development: Role of basic biological research. Alzheimer’s & Dementia: Translational Research & Clinical Interventions, 3, 651-657. https://doi.org/10.1016/j.trci.2017.10.005
Seyhan, A. A. (2019). Lost in translation: the valley of death across preclinical and clinical divide – identification of problems and overcoming obstacles. Translational Medicine Communications, 4 (18). https://doi.org/10.1186/s41231-019-0050-7
Silber, B. M. (2010). Driving Drug Discovery: The Fundamental Role of Academic Labs. Science Translational Medicine, 2 (30). www.ScienceTranslationalMedicine.org
Takebe, T., Imai, R., Ono, S. (2018). The Current Status of Drug Discovery and Development as Originated in United States Academia: The Influence of Industrial and Academic Collaboration on Drug Discovery and Development. Clinical and Translational Science, 11, 597-606. https://doi.org/10.1111/cts.12577
Wong, C.H. & Siah, K.W. (2019). Estimation of clinical trial success rates and related parameters. Biostatistics, 20 (2), 273-286.
Wouters, O.J., McKee, M., Luyten, J. (2020). Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018. JAMA, 323 (9), 844-853. https://doi:10.1001/jama.2020.1166