From “bench to bedside”, the mission of translational science is to bring predictivity and efficacy to the development and dissemination of intervention that improve human health (Austin CP, 2021). Translational science translates basic science discoveries into therapeutic applications. This is a progression from discovery research to pre-clinical studies defining targets, describing mechanisms of action and release criteria, to early stage human studies with primary endpoint(s) on safety, to more advanced and controlled clinical trials assessing efficacy on a large number of patients toward marketing authorisation applications. Exploratory studies performed during clinical trials accumulate data from drug product analysis and patient samples. Based on this data set, translational research allows the rational design of next generation products and therapies. For example, a gene therapy for sickle cell which is due to a mutation of the beta globin gene was based on the addition of the normal version of this gene (lentivital vector coding for beta globin). Another approach, was based on a deep understanding of the hemoglobin switching mechanism and on the reactivation of fetal hemobin (lentiviral vector coding for a shRNA against BCL11a). Other drug development approaches are based on random screening of compounds or on empiricism. Some well known drugs like morphine for pain or aspirin for inflammation were developed without fully understanding the cause of the disease and the mechanism of action of the treatment. In gene and cell therapies, many challenges can prevent scientific breakthroughs to be translated into patient care: biological mechanisms underlying a potential clinical application have to be understood and converted into a therapeutic strategy not too complex to implement, pre-clinical models can be complicated to setup and may poorly mimic human physiology, manufacturing large scale batches of clinical grade products requires to control all the parameters that are critical to reach the targeted dose and to obtain the desired quality attributes of the product, a business model should be developed to cover the costs, to make the new therapeutic product accessible to patients and to allow investments.
Stakeholders
Translational science happens all along the product chain, it involves multiple stakeholders.
Academic laboratories are often carrying out basic science and fundamental research in silico with mathematical models, in vitro on macromolecules, viruses or cells, in vivo through animal studies to define targets, describe mechanisms, and propose development candidates.
A research and development team from academia or industry will bring the development candidate from the bench to the bedside through Clinical Trial Application (CTA) or Investigational New Drug application (IND) enabling studies. Biodistribution and toxicity studies are standardized and usually performed in Good Laboratory Practice (GLP) compliant Contract Research Organizations (CROs).
The Chemistry Manufacturing and Control (CMC) group will setup a manufacturing process according to Good Manufacturing Practice (GMP) principles to generate clinical grade products at scale for clinical trials. In addition to quality controls to release the drug product, exploratory studies help developing the knowledge about the product and allow the search for correlations between product characteristics and clinical results. Manufacturing and controls are often entrusted to Contract Development and Manufacturing Organizations (CDMOs).
A clinical department will design the clinical study protocol, write the investigator’s brochure, the subject information and informed consent form, the clinical study reports and the case report form.
In industry, the regulatory affairs department handles interactions with regulatory bodies and checks the consents are in place to take and analyse samples from patients or healthy donors.
Generally from an industry, the quality department takes care of the documents, especially data records on the drug products and clinical samples.
In that context, specific bodies have been developed in the European Union and in the USA to foster translational science.
The European Advanced Translational Research Infrastructure in Medicine (EATRIS) is a non-profit European Research Infrastructure Consortium (ERIC) bringing together resources and services for research communities to accelerate the translation of biomedical and to translate scientific discoveries into benefits for patients. EATRIS has been founded in 2007 and became the first biomedical science infrastructure to receive European Research Infrastructure Consortium status, established by the European Commission, in 2013.
In the USA, the National Center for Advancing Translational Science (NCATS) was founded in 2012 and established to transform the translational process so that new treatments and cures for disease can be delivered to patients faster. It is one of the 27 Institutes and Centers at the National Institutes of Health (NIH).
Definitions
Translational science describes a continuum of scientific activities from basic research to pre-clinical development, clinical trials, up to approved therapies. Through translational science, basic research results are translated into therapeutic applications. Accelerating and optimising this translation is the aim of translational scientists. Scientific discoveries can be translated into therapies following the drug development path and data collected from drug products and clinical trials can be translated into next generation therapeutic modalities with optimized safety and efficacy profiles. See figure 1.
Figure 1: Translational science
Translating discoveries in therapies and first-generation product in next generation therapeutic modality.
Challenges
Biological mechanisms underlying a potential clinical application have to be understood to envisage a rational design and of future treatment and to set up a therapeutic strategy that is not too complex to develop, to industrialise and to bring to bedside.
There is a need for pre-clinical models that are more predictive of clinical safety and efficacy.
A business model should be developed to figure out if the financial return if sufficient.
Data interoperability and transparency have to be maintained.
New therapeutic modalities have to be developed and implemented to reach currently inaccessible disease areas (e.g. gene therapies for severe genetic disorders).
Before reaching the clinic, expensive pre-clinical research is necessary for proof-of-concept and proof-of-value.
Manufacturing large scale batches of clinical grade products can be a bottleneck to performing the first in human study but also to enter the market with a robust process able to deliver at reasonable cost the product for all patients who need it. It is key to control all the parameters that are critical to reach the targeted dose and to obtain the desired quality attributes of the product.
The 4D (Drug Discovery, Development and Deployment) Biologics Map depicts the interconnected nature of key steps in the drug development lifecycle for biologics (Drug Discovery, Development and Deployment Maps). The map summarizes activities, opportunities and challenges in translational science. See figure 2.
Figure 2: Opportunities and challenges in translational sciences
Reproduced from: John A. Wagner et al., "Discovery, Development and Deployment Map (4DM): Biologics," Clin. Transl. Sci. 11, no.2 (2018): 116–174, https://doi.org/10.1111/cts.12531. Licensed under CC BY-SA 4.0.
Operational challenges for translational science and medicine are depicted in the publication by Joseph S. Fernandez-Moure, “Lost in translation : the gap in scientific advancements and clinical application” (Frontiers in Bioengineering and Biotechnology, 2016): Translational science is an iterative, dynamic, and layered process with several tasks to be accomplished. These layers include:
T0: identification of clinical problem followed by pre-clinical and optimisation studies to define material candidates for compound synthesis or cellular mechanisms for intervention;
T1: initial Phase I studies in humans that aim to demonstrate proof of concept and safety;
T2: Phase II and III clinical trials that allowed for incremental and sequential evaluations and approvals prior to implementation;
T3: post-marketing surveillance trials, conducted after the device has been in the market, are used to determine long term efficacy, impact on quality of life, and comparison to other similar devices; and
The “Valley of Death” concept: between basic science and clinical applications many challenges need to be overcome. To cross the “Valley of Death”, several key requirements must be in place to move these discoveries into new treatments, diagnostics or preventions: technical expertise, clinical relevance, funding (Illustration of the valley of death in biomedical research). Even with the fascinating observations and creative science, most of the basic scientific discoveries fail to get into the therapeutic development process and often get lost in translation because they are irrelevant to human disease or lack funding, incentives, and technical expertise to advance any further (Seyhan A, 2019). See figure 3.
Figure 3: Illustration of the valley of death in biomedical research
Reproduced from: Attila A. Seyhan, "Lost in translation: The valley of death across pre-clinical and clinical divide – identification of problems and overcoming obstacles," Transl Med Commun 4, no.18 (2019). https://doi.org/10.1186/s41231-019-0050-7. Licensed under CC BY 4.0.
Opportunities and incentives
Translational science aims to use the knowledge accumulated through pre-clinical studies and clinical trials to improve therapeutic efficacy and describe more precisely the product attributes.
Publications like “Lost in translation: Barriers to incentives for translational research in medical sciences” describe ways to prioritise and accelerate translational science in biomedical sciences and rapidly turning new knowledge into first-in-human studies (Srivastava R et al., 2014). Engagement of patients and communities in translational science seems very beneficial to the development new therapies but the field currently lacks robust strategies to shorten the time and to improve the efficiency of translational activities. The National Center for Advancing Translational Sciences (NCATS) set up a Toolkit for Patient-Focused Therapy Development. Tools include how to establish a patient registry, how to drive patient-focused discovery and pre-clinical research and development, how to conduct post-market surveillance.
EATRIS (The European advanced translational research infrastructure in medicine) is an initiative to create a European, globally competitive infrastructure for biomedical translational research. Translation of basic research discoveries into clinical application has turned out to be a major challenge for the European Research Area (ERA). Sharing experience and building powerful translational infrastructures will lead to better healthcare provision and provide a bridge between countries of different translational capacity, making Europe more competitive.
Reproduced from: Romaldas Maciulaitis et al.,"Clinical Development of Advanced Therapy Medicinal Products in Europe: Evidence That Regulators Must Be Proactive," Mol. Ther. 20, no.3 (2012): 479–482, https://doi.org/10.1038/mt.2012.13. Licensed under CC BY-NC-ND 4.0.
USA
The Office of Translational Sciences (OTS) is composed of five offices with 22 divisions. The OTS Immediate Office supports translational medicine efforts for the Center for Drug Evaluation and Research (CDER) and leads the areas of technology transfer, data mining, health information technology, science and research oversight, and knowledge management.
Indeed, EU legislation, currently under revision, so far only covers the use of human samples in clinical applications:
Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells, OJ L 102, 7.4.2004, p. 48-58, CELEX number: 32004L0023
Original text (available in the 24 official languages of the EU)
Document summary (available in the 24 official languages of the EU)
Commission Directive 2006/17/EC of 8 February 2006 implementing Directive 2004/23/EC of the European Parliament and of the Council as regards certain technical requirements for the donation, procurement and testing of human tissues and cells (Text with EEA relevance), OJ L 38, 9.2.2006, p. 40-52, CELEX number: 32006L0017
Original text (available in the 24 official languages of the EU)
Commission Directive 2006/86/EC of 24 October 2006 implementing Directive 2004/23/EC of the European Parliament and of the Council as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells (Text with EEA relevance), OJ L 294, 25.10.2006, p. 32-50, CELEX number: 32006L0086
Original text (available in the 24 official languages of the EU)
2010/453/EU: Commission Decision of 3 August 2010 establishing guidelines concerning the conditions of inspections and control measures, and on the training and qualification of officials, in the field of human tissues and cells provided for in Directive 2004/23/EC of the European Parliament and of the Council (notified under document C(2010) 5278) Text with EEA relevance, OJ L 213, 13.8.2010, p. 48-50, CELEX number: 32010D0453
Original text(available in the 24 official languages of the EU)
Commission Directive 2012/39/EU of 26 November 2012 amending Directive 2006/17/EC as regards certain technical requirements for the testing of human tissues and cells (Text with EEA relevance), OJ L 327, 27.11.2012, p. 24–25, CELEX number: 32012L0039
Original text(available in the 24 official languages of the EU)
Commission Directive (EU) 2015/565 of 8 April 2015 amending Directive 2006/86/EC as regards certain technical requirements for the coding of human tissues and cells (Text with EEA relevance), OJ L 93, 9.4.2015, p. 43-55, CELEX number: 32015L0565
Original text(available in the 24 official languages of the EU)
Commission Directive (EU) 2015/566 of 8 April 2015 implementing Directive 2004/23/EC as regards the procedures for verifying the equivalent standards of quality and safety of imported tissues and cells (Text with EEA relevance), OJ L 93, 9.4.2015, p. 56-68, CELEX number: 32015L0566
Original text(available in the 24 official languages of the EU)
The European research infrastructure for biobanking (BBMRI-ERIC), brings together all the main players from the biobanking field (researchers, biobanks, industry, and patients) to boost biomedical research, offers quality management services, support with ethical, legal and societal issues, and a number of online tools and software solutions. In that context, it provides support to the translation of clinical research into new treatments.
European Union Guidance
Recommendations of the European advanced translational research infrastructure in medicine (EATRIS).
Olivier Negre, Member of The General Committee Management Group at EuroGCT, Board Member of the French Society of Cell and Gene Therapy, Paris, France; Co-President of the Gene and Cell Therapy Institute, Expert in Cell and Gene Therapy at Biotherapy Partners, Paris, France.
