The National Heart, Lung, and Blood Institute (NHLBI) convened an expert Working Group meeting on July 6, 2010 in Bethesda, Maryland to advise the Institute on the research opportunities in, and the support needed to facilitate, translational research in vascular diseases.
Disorders related to vascular disease are myriad and represent major causes of death and disability the world over, from the lowest income nations to the highest income nations. Just as no nation is unaffected, no organ system is free of risk related to disease in the extensive vasculature of arteries, veins, microvessels, and lymphatics found in the human body. Currently there is a large unmet medical need for effective therapies for vascular diseases, and this need is sure to rise as risk factors (e.g., diabetes, dyslipidemia, obesity, hypertension) become increasingly prevalent in our population. The process of developing effective therapeutic interventions is complex and requires a wide range of expertise and facilities, as well as significant investments of time and money. Traditionally, many of the basic science discoveries that led to successful therapies originated in academia, but their further successful development and commercialization required the human resources and financial capital of the pharmaceutical industry. However, in recent years there has been an operational paradigm shift in industry, leading many major pharmaceutical companies away from the development of new therapies for cardiovascular diseases. Some reasons for this shift include: loss of patent protection for key products in their respective portfolios; large, expensive, and lengthy clinical trials needed to meet specific cardiovascular endpoints; safety concerns; and other therapeutic areas seen as more promising and attractive.
The NIH is a major funding source for academic biomedical research in the United States, but there is a huge gap in funding for activities between basic science discoveries and new approved medical therapies. While academia is still a hotbed of discovery and innovation, it is not yet a powerhouse in translating those findings into widespread clinical utility. In this changing research and development landscape, the NIH, academia, and industry recognize that their roles in the development of therapies have changed and can intertwine along the translational pathway. For this Working Group meeting, two speakers from industry and fourteen academic researchers were invited to discuss the challenges and opportunities in translational research in vascular diseases and to advise NHLBI on what elements would be particularly helpful in facilitating research to advance basic science discoveries into the clinic.
At the beginning of the meeting, invited speaker Dr. Kuldeep Neote gave a presentation on ?How Industry or Venture Capital Groups Assess Candidates for Licensure/Support." The second invited speaker, Dr. Brenda Bondesen, presented ?Project Management in Academia-Challenges and Opportunities." There was a group discussion following each speaker?s presentation, and then the Working Group focused their discussion on the questions posed to the Working Group members prior to the meeting, as well as on those raised at the meeting to elicit specific recommendations. These questions were:
- With respect to vascular diseases, what discoveries in your area of expertise are poised for translation?
- Are you aware of discoveries that are promising or poised for translation but are languishing due to a lack of resources or other barriers to translation?
- What are the identifiable barriers to translation?
- What resources are needed to overcome these barriers?
- What vascular diseases/areas of research are in need of stimulation or resource infrastructure development?
- Is the academic community prepared and staffed for a multi-disciplinary translational approach to product development?
- What are some appropriate metrics for a translational program in vascular diseases?
- What elements should be fundamental to the design of a translational research program in vascular diseases?
Salient points of the Working Group discussions can be summarized in three areas: 1.) perceived barriers at the institutional level, 2.) areas of opportunity, and 3.) suggestions for the structure of a new translational research program in vascular diseases.
Barriers to Translational Research in Academia
- Intellectual property (IP) issues are possibly the biggest issue stifling the progress of translational research in academia.
- There is a dearth of academic researchers with experience in translational therapeutics, which is fundamental to successful product development.
Additionally, this requires extensive organization, coordination, and knowledge of the business and regulatory aspects of biomedical research.
- The cost of obtaining preclinical pharmacology and toxicology testing is a barrier to translational research as these tests are required to advance product development but do not lend themselves well to NIH grants.
- Medicinal chemistry support, GMP production of small quantities of drugs for early human studies, and pharmacokinetic testing/modeling are not widely available to academic researchers.
- Advice on regulatory matters, particularly pre-IND considerations and the preparation and submission of an IND, is either not readily available or researchers are not aware of its availability.
Areas of Opportunity for Vascular Research
Some areas of research opportunity identified by the Working Group include: venous disease; aortic aneurysms; peripheral arterial disease; lymphatic disease; novel therapeutic opportunities in angiogenesis; vascular remodeling; integration of quantitative imaging techniques with other approaches to prediction and assessment of vascular disease burden; assessments of approved and unapproved agents from other therapeutic areas for applicability to vascular disease; development and validation of surrogate endpoints of vascular disease to facilitate clinical translation; and the field of applied genomics and metabolomics for determining susceptibility to and classification of vascular disease states and response to treatment.
Suggestions for the structure of a New Translational Research Program
- The range of vascular science allowed in this program should be broad, but research proposals should describe an integrated, interdisciplinary approach and the budget should be justified by the science proposed.
- The funding opportunity should be flexible as applications may be quite heterogeneous with respect to vascular disease, modality (e.g., diagnostic, therapeutic, or surrogate endpoint) technology or approach tested, and stage of development. The proposed research should address an unmet medical need.
- The researchers should be allowed to buy outside services such as chemistry support, pharmacokinetic testing/modeling, pharmacology and toxicology testing, and project management support, including assistance with regulatory affairs. Additionally, opportunities for the researchers to acquire relevant training should be incorporated into the program.
- Data disclosure should be staged and IP plans described in the application, but the actual handling of these issues must be addressed by the Principal Investigator(s) and thir Institution, adhering to any applicable NIH rules.
- Though the researchers should be encouraged to file for patents, performance metrics should not be tied to this as the patent application process is lengthy and IP issues are complex.
- Consideration should be given to a two-stage application process that could allow researchers to identify potential collaborators. Applicants should be encouraged, but not required, to collaborate with relevant partners such as industry, the FDA, and other institutions at home or abroad. Applicants who already have collaborating partners in place should be allowed to apply at the outset of the program.
- The program should have an External Advisory Committee and a Program Coordinating Center that offers professional Project Management assistance to the awarded research centers.
- Each applicant should have an in-house strategy of project management with professional guidance from Project Management Professionals based in the Program Coordinating Center.
- Consideration should be given to having individuals with industry and venture capital experience serve on the External Advisory Committee.
Division of Cardiovascular Sciences
Cheryl L. McDonald, M.D.
Working Group Composition:
Garret A. FitzGerald, M.D., University of Pennsylvania
Brenda Bondesen, Ph.D., PMP, Merial, Ltd.
Elliot Chaikof, M.D., Ph.D, Emory University
Mark Creager, M.D., Brigham and Women?s Hospital
Michael S. Conte, M.D., University of California at San Francisco
Sam Dudley, M.D., Ph.D., University of Illinois in Chicago
Geoffrey S. Ginsburg, M.D., Ph.D., Duke University Medical Center
Jennifer A. Heller, M.D., Johns Hopkins University
Timothy Hla, Ph.D., Weill Medical College of Cornell University
Dara L. Kraitchman, VMD, Ph.D., Johns Hopkins University
Christopher M. Kramer, M.D., University of Virginia
Doug W. Losordo, M.D., Northwestern University
Kuldeep Neote, PhD, Eli Lilly and Company
Stanley Rockson, M.D., Stanford University
Geert Schmid-Schönbein, Ph.D., University of California at San Diego
William C. Sessa, Ph.D., Yale University School of Medicine
Narasimhan Danthi, Ph.D.
Zorina Galis, Ph.D.*
Yunling Gao, Ph.D.
Cheryl L. McDonald, M.D.
Marissa A. Miller, DVM, MPH
Valerie C. Robinson, MBA
H. Eser Tolunay, Ph.D.
Katherine Wood, Ph.D.
*Intergovernmental Personnel Agreement Guest Researcher
Last Updated: September 2010