The advancement of translational medicine—from regional challenges to global solutions

Salvatore Albani & Berent Prakken

Translating the progress in molecular medicine into new therapies has met with limited success; the route from idea to drug has many hurdles and is a very fragmented process. This fragmentation is evident at all levels—academia, industry and governments—and across geographic boundaries. Moreover, the complexity of the translational process makes it very difficult for a single individual to be an expert in each of its steps. To move beyond the current stagnation, we need change at the individual and institutional levels. At the individual level, we need a new professional figure with the specific skills that are needed to navigate the whole itinerary of translational medicine to overcome fragmentation. At the institutional level, the creation of translational medicine research interfaces—support structures to bring together the different competences relevant to translational medicine that already exist within universities—would be a step forward toward speeding up the translational process.

Translational medicine encompasses the continuum of activities that extend from the conception of an idea to advanced clinical testing and, ultimately, to the development of a new medical technology or drug. This itinerary includes many components that require very different skills (Table 1). Such skills are often compartmentalized within three separate domains—academia, government and industry. Each of these domains has its own set of challenges (Table 2).

 

Table 1 Comprehensive list of tools needed in translational medicine

Field Tools and skills needed
Biomedical research Comprehensive knowledge of the field, ability to perform solid bench work and knowledge of appropriate study design
Intellectual property Access to experts for development and protection, basic understanding of the process, strategies and importance of intellectual property, and knowledge of patents
Funding Knowledge of funding sources, ability to negotiate and ability to develop contacts in government and industry
Regulatory agencies Knowledge of various regulatory bodies (national, international and supranational), ability to navigate through the system and awareness of forms, processes.
Ethical issues Knowledge of patient and animal rights, understanding of university and regulatory body rules for protocol development and support, and knowledge of risk-benefit analysis
Communication skills Ability to talk to various audiences, prepare manuscripts and other documents, and interact between departments
Preclinical testing Knowledge of regulatory requirements before clinical testing, ability to evaluate the viability of standard operating procedures and ability to strategically plan to optimize resources
Design of preclinical and clinical trials Knowledge of the process, challenges and concerns, ability to effectively plan, possession of critical thinking skills to overcome challenges, ability to develop a protocol and ability to forge collaborations
Fundamental skill sets
(applies to all fields)
Networking, team-building and communication skills and strategic thinkingand creative problem solving

 

 

Current state of play

Academia. Biomedical research in academia has been very successful in generating an immense amount of information, leading to a true revolution in molecular medicine1,2. However, at least two different dimensions coexist within academia. One, based on high-output, systems-biology approaches, grows exponentially, generating vast volumes of data that are categorized but never fully evaluated. A second dimension comprises hypothesis-driven research that asks questions about human pathophysiology, relies on low-throughput technologies and moves at a much slower pace. The interfacing of both dimensions often leads to considerable friction3—the generation of large, vertical databases requires an understanding of complex transverse relationships that single-dimensional landscapes cannot accommodate1–3.

 

Industry. Historically, the pharmaceutical industry has relied on well-tested but often obsolete standard operating proce-dures4. As a result, industry is reticent to rapid change and not prone to taking risks. One example is the reliance on a sequential product development model that goes from animal model to human—one of the corner-stones of product development. However, it is becoming increasingly clear that animal models often fail to capture all the aspects relevant to the transition from lead validation to clinical development. Moreover, the research and development costs to create new drug leads have bloated at a time when share values and cash reserves are dwindling5,6; the reduced capacity to develop new therapies has increased the cost of developing a new drug to over $1 billion7. This increased cost is a crucial factor in the alarming rise in costs of health care for society as a whole.

The pharmaceutical industry has also often relied on promising ideas that spawn from academia and that are developed to the first stage of validation by small enterprises. Contrary to big pharmaceutical conglomerates, these entities are risk prone, and a tangible product to be found on pharmacy shelves is not necessarily their final goal. Instead, the objective of small biotechnology companies is often to achieve proof of concept of the safety and initial clinical efficacy of a given potential therapy before licensing it to a large pharmaceutical firm.

Only a small fraction of biotechnology companies succeed. Those that do, however, provide initial investors, typically venture-capital groups, financial returns that amply justify the risk8. This relatively young biotechnology industry is also in trouble. Not only have con-tractions in the venture-capital market made it very difficult for start-up entrepreneurs to find the capital they need9, but also a change within the field has occurred—the requirements for venture funding have become tougher; proof of concept and safety data are often required before any meaningful financial resources are made available. Yet, to go from an idea to initial testing in humans, resources are needed for scientifically tedious but essential steps in the translational road, such as synthesizing active pharmaceutical ingredients, toxicological work, securing intellectual property and many others. These processes are frequently too unfamiliar and too expensive for the individual scientist to tackle. In most cases, academia does not have the financial resources to sustain the process10. So the fundamental part small biotechnology companies have played in translational research is also in danger11.

 

Government. National governments are confronted with increasing demands for regulation that stem from supranational governing bodies (such as the European Union), regulatory agencies, politics, legal and ethical experts, and special-interest groups. Yet the paradigms that govern decision-making and regulation are often no longer adequate for the development of new therapies. This problem is particularly evident for the development of combination therapies or biomarkers5,12.

Conventional forms of preclinical testing such as pharmacology and toxicology cannot predict the potential risk of a new biological agent13. Recent events during which the thorough application of standard procedures in product development could not prevent catastrophic effects on patients and healthy volunteers are still vivid in our collective memory14,15.

Importantly, the inadequacy of our procedures fosters overregulation, which results in delays in the development of potentially useful therapies. This, in turn, translates into financial damage to industry and society alike. The increased difficulty to translate findings into therapies increases the development costs of the pharmaceutical industry, which brings about an escalation of medical costs that is paid for by society. These rising costs contribute to the unfortunate fact that, even in some developed countries, many people do not have adequate health coverage16,17.

 

Table 2 Challenges to translational medicine at all levels

Compartment Process Problem
Academia Biomedical research Drive for specialization and insufficient integration of high and low throughput
Intellectual property, publications and funding Competition
Animal models Often a marked difference between animal and human physiology
Human studies Inherent variability among individuals, limited access to patients and samples, and ethical and legal constrictions
Industry Interaction with academia Fewer and increasingly complex leads, difficulty in choosing which leads are worth pursuing, and lack of resources for manufacturing and toxicity studies
State of small biotechnology companies High volatility and increasingly stringent requirements
of product maturity for venture capital support
Endogenous culture Risk aversion and obsolete standard operating procedures
Government Increased demand for regulation Increased costs of health care
Economic recession Decreased national and international funds for research

 

 

A way forward

Any solution to these problems needs to start with the realization that a proportion of our current systems and regulations are inadequate for dealing with the challenges of translational medicine in the twenty-first century. There is no quick fix; major changes need to take place at all levels.

 

Change from within. Universities are the places where the disconnection within the translational medicine itinerary is most evident. Academia is also the place where those gaps can be bridged in a straightforward manner, and important local initiatives to catalyze translational research have spawned in the US from the ashes of the now discontinued General Clinical Research Center structures. The Institute for Translational Medicine and Therapeutics at the University of Pennsylvania, the Clinical and Translational Science Institute in Pittsburgh and the Clinical and Translational Science Awards initiatives nationwide are examples of the convergence of resources and focus toward areas of perceived need18,19. Nevertheless, a university’s inability to develop its own intellectual property and take it into clinical testing continues to be one of the main problems within academia. Yet, in most cases, universities have the entire range of expertise that is needed to ensure identification, validation and development of a new idea.

A feasible, cost-effective way to transcend the limitations of academia could be the creation of Translational Medicine Research Interfaces (TMRIs)—nonredundant, transparent sup-port frames that bring together the relevant units within a university (clinical departments, research centers, legal teams) into a ‘virtual translational institute’ (Fig. 1). The job of TMRIs would be to facilitate, identify and develop medical advances from conception to clinical testing, with an emphasis on multi-disciplinary approaches. They could capitalize on the strengths existing within and around a given academic center and might develop from already existing initiatives, such as Clinical and Translational Science Awards. The gamut of competencies would not only include basic and clinical sciences, but also legal, business and regulatory know-how. An authoritative pool of individuals with expertise in the various aspects of translational research would form the steering committee for the TMRI. Out of the core, experts on a given discipline could be identified on a case-by-case basis to evaluate specific projects and design a plan for their development.

More specifically, TMRIs could support the design and execution of multidisciplinary research projects and facilitate the translational medicine itinerary by serving the following functions: (i) target identification and validation in vitro, in vivo and in human samples; (ii) intellectual property development and protection with a focus on crafting patents to maximize returns and aiming to reach early clinical stage, on creating value by exploring licensing opportunities, or both; (iii) business development analysis with the objective of designing an appropriate strategy to maximize the chances of success of the project and the possible returns to the university and the inventor; (iv) preclinical development plan to prepare a product for an Investigational New Drug application, as required by the US Food and Drug Administration, and clinical trial design and execution up to phase 1 or 2; and (v) funding requirements and source scouting.

TMRIs could increase the success rate for drug development and ease the transition from lead to product while keeping the university engaged in the process. Eventually, a virtuous loop would be generated where resources would be made available for new projects, intellectual property could be appropriately identified and developed, and investors would be more comfortable about funding projects. Of note, the resources to initiate the process would be modest, as TMRIs are, in essence, a rational aggregation of already existing units that would maintain their independence.

 

figure

Figure 1 Diagrammatic view of a Translational Medicine Research Interface (TMRI). The green boxes depict the structures that are needed to move an idea from its conceptual stage to early clinical development. In the long term, the TMRI would establish a funding loop to support the exploration and development of additional leads. The purple boxes show the key areas that a researcher must traverse in the translational medicine itinerary and in which support structures might be developed to improve the chances of success.

 

Interfacing more effectively. Industry could also profit from TMRIs, as they would help craft a more effective and direct interface with scientists and researchers. To facilitate this from the industrial side, the development of new structures is crucial. Currently, this occurs in the form of incubators—a conglomeration of start-up companies that share common infrastructural support. As discoveries often originate in academia, these incubators need to act as an interface between academia and the pharmaceutical industry20. Industry can contribute by providing funding and accelerating further development of leads that have shown promise in early-stage clinical testing. Such an interface can facilitate dialog and cooperation.

Facilitating access is another key aspect of interfacing. Biotechnology incubators or other types of technology hubs provide the critical mass to attract players with diverse and complementary roles, providing credibility to the project and making development processes more effective. Technology communities, ranging from institutionalized incubators to metropolitan areas with a high density of biomedical institutions, are also places where ideas are scouted and blueprints for development are forged.

 

Leading with vision. The traditional model of government support of individual projects does not meet the cost, diversity and breadth of translational medicine, and the funding structure needs to be reshaped on the basis of understanding this limitation of the traditional funding model21. It is encouraging to see that governments and supranational entities are developing an increasing number of multidisciplinary and multidimensional funding initiatives, such as the National Institutes of Health Small Business Innovation Research (SBIR) program in the US and the Seventh European Framework in the European Union. These initiatives are specifically aimed at nurturing the growth of promising technologies along a translational itinerary. There are also many, often regionally delimited, specific programs that fund collaborations between academia and start-up companies.

Another major aspect where government is in need of creative solutions is in regulation. An open dialog should be initiated to redefine regulations while protecting the rights of patients. Historically, this discussion has been dominated by politicians, ethicists and lawyers22. Although their contributions are essential, patients, scientists and healthcare providers must also have a central role in a renewed dialog. The Critical Path Institute is worth mentioning in this context as an independent, nonprofit organization uniquely dedicated to implementing the Food and Drug Administration’s Critical Path Initiative by creating collaborations among regulators and the regulated23.

Several patient groups are now professionally organized and capable of participating in such a discussion. The invaluable input of patient groups is illustrated by their contribution to the rapid development of antiviral therapies for HIV24.

New procedures for assessing safety should be identified by using a consensus-based approach that involves all stakeholders with the appropriate know-how. This includes the inventors, who are, ironically, often left out of the process.

 

From regional to global. Traditionally, the development of new therapies transcends local boundaries when the product is close to or ready for commercial distribution. In most cases, the process is, at that point, firmly in the hands of the pharmaceutical industry, which is well-positioned to act on a global scale. However, the globalization of translational medicine is increasingly occurring at an earlier stage of development. For instance, lead identification is often the outcome of work from international consortia25,26. Funding of biotechnology initiatives is routinely underwritten by international venture-capital groups. The synthesis of active pharmaceutical ingredients and the required toxicological work is often outsourced to countries where these processes are cheaper. Most importantly, clinical development is increasingly reliant on countries where the costs of clinical trials are lower, raising concerns about the quality and ethical standards of practices that require a considerable level of standardization and oversight. But, despite this globalization, regulatory procedures, intellectual property laws and financial models of health care, to name a few aspects, remain entrenched within national boundaries. International networks and initiatives are needed to meet these challenges. Networks should provide individual researchers and their institutions with the opportunity to integrate their own research seamlessly in the context of a development plan from concept to product. Ideally, an international network would be composed not only of scientists, but also of professionals from other fields. Scientists from other areas could share ideas, technology and human and material resources. A core of experts from diverse fields (financial, legal, regulatory and others) could provide the knowledge for evaluating projects and creating viable plans for their development. In a sense, these international networks would reproduce on a global scale the structure and objectives of a local TMRI.

 

Creating a new professional figure. It is clear that an individual who tries to complete the full itinerary of translational medicine requires an overwhelming breadth and depth of expertise (Table 1). To assimilate this knowledge base in one person is difficult, but this individual does not need to be an expert in all fields if he or she has the tools to navigate easily through the different domains of translational medicine. Unfortunately, no formal training exists that could create a professional capable of acting as an interface among the various components of the itinerary. This deficiency is particularly pressing on the international stage, where awareness of regional peculiarities should be combined with a global vision.

Programs are needed to prepare future leaders in translational medicine who will facilitate the traffic from lead identification to clinical testing. The educational content of such programs needs to provide more than the essential knowledge on the itinerary of translational medicine. It also should promote skills of critical analysis, needed for out-of-the-box thinking, communication skills as a tool to bring about changes and an attitude of collaboration and teamwork. Because academia, industry and government cannot solve the problems of translational research in a compartmental vacuum, it is crucial that individuals learn how to cross traditional boundaries competently. This will foster innovative collaboration and help train a new generation of professionals prepared for a wide range of careers focusing on improving human health with a multidimensional approach.

 

Conclusion

The challenges of translational medicine are of such a magnitude and, especially in times of economic crisis, have such formidable repercussions for society that we need innovative ideas to tackle them. As the problems are multidimensional and interconnected, so must be the solutions. Decision makers at all levels need to be open to a change in their philosophy to incorporate the rules of a fast-evolving landscape. Solutions should include new structures, rules and procedures from all parties involved. There is an urgent need to train individuals with a new professional competence—a full understanding of the complexity and challenges of translational medicine in an international setting—who can act as catalysts of the process. Altogether, the solution amounts to a paradigm shift involving all the major stakeholders in a multidimensional context.

 

ACKNOWLEDGMENTS

We thank J. Colomb for her contribution to developing the manuscript. We also thank E. Albani, J. Colomb, L. Guidotti, D. Hafler, J. Hafler, M. von Herrath, K. Joiner, E. Muter, M.-G. Roncarolo, N. Rosenblum, V. Seyfert-Margolis and T. Staeva, charter members of the Eureka Institute for Translational Medicine. The Eureka Institute is committed to preparing future leaders in translational medicine along the lines discussed in this article. We also thank M. Lotz and P. Coffer for critically reading the manuscript.

 

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