Translational medicine and the National Institutes of Health road map: Steep grades and tortuous curves

Abstract

“There does not exist a category of science to which one can give the name ‘applied science.’ There are science and the applications of science, bound together as the fruit of the tree which bears it.—Louis PasteurTranslational research has been described in terms ranging from the supportive “bench to bedside” to the detractive “discovery to commercialization.” Both believers and skeptics, however, would agree that it is a less traveled road because of steep inclines, speed bumps, potholes, and sharp curves that makes it hazardous for an investigator to devote a career to this research direction.1Goldstein J.L. Brown M.S. The clinical investigator bewitched, bothered, and bewildered—but still beloved.J Clin Invest. 1997; 99: 2803-2812Google Scholar Both public funding agencies, such as the National Institutes of Health, with its road map to reengineer the clinical research enterprise, and private foundations, such as the Howard Hughes Medical Institute, have made recent commitments to translational research.2Zerhouni E. The NIH roadmap.Science. 2003; 302 (72): 63-64Google Scholar, 3Birmingham K. What is translational research?.Nat Med. 2002; 8: 647Google Scholar This dedicated allocation of resources has occurred because of the rapid pace of discovery and heightened public expectations of new cures and treatments with increased investment of public and private monies.In efforts to refocus the Journal of Laboratory and Clinical Medicine toward this research area, the editors have requested that I provide a personal view of the complex path that our group has traveled over the last decade to bring one of our specific research programs to therapeutic evaluation.Physician scientists are driven to pursue a better understanding and perhaps a new therapeutic approach to an unmet medical need of a clinical disorder. For nephrology, acute renal failure secondary to acute tubular necrosis (ATN) continues to confound practicing nephrologists, with mortality rates in patients in the intensive care unit exceeding 70%, despite dialytic control of volume and electrolyte balance.4Humes H.D. Acute renal failure prevailing challenges and prospects for the future.Kidney Int. 1995; 48: S26-S32Google Scholar Several seminal observations of this clinical disorder have been widely acknowledged from both the bench and the clinic, which provided an opportunity to formulate a new therapeutic approach. The primary pathophysiology of this disorder is injury to renal tubule cells.5Thadhani R, Pascual M, Bonventre JV.N Engl J Med. 1996; 334: 1448-1460Google Scholar Clinical observations have demonstrated that patients with ATN experience a downward spiral leading to multiorgan failure with a dysregulated systemic inflammatory state. But unlike other acute solid-organ failures, the kidney has the ability to fully repair itself if given enough time, resulting in patient recovery. This reparative process depends on a subset of renal tubule progenitor/stem cells in the adult kidney to proliferate and differentiate to full nephronal functionality.6Humes H.D. Krauss J.C. Cieslinski D.A. Funke A.J. Tubulogenesis from isolated single cells of adult mammalian kidney clonal analysis with a recombinant retrovirus.Am J Physiol Renal Physiol. 1996; 271: F42-F49Google Scholar From these insights, a new therapeutic approach combining renal tubule cell therapy and conventional hemofiltration was developed to provide the metabolic functions of renal cells that are lost during the ATN process.7Humes H.D. Buffington D.A. MacKay S.M. Funke A.J. Weitzel W.F. Replacement of renal function in uremic animals with a tissue-engineered kidney.Nat Biotechnol. 1999; 17: 451-455Google Scholar This approach promised to provide more complete renal replacement therapy, including the clearance function achieved with hemodiafiltration and the synthetic and endocrine functions of cells. This approach could also test the unconventional hypothesis that renal tubule cells are important immunologic regulators under stress states.Although the technology is simple in concept, nearly a decade has been required to move this technology from bench to bedside in Food and Drug Administration (FDA)-approved Phase I and II clinical trials. The translation of this technology required a coordinated team of diverse talents, including cell and molecular biologists, tissue and bioengineers, and clinical investigators. The identification and evaluation of human tissue sources, extracorporeal pump systems, and device fabrication were required first in large animals before man. These technologic steps are detailed in our group’s scientific publications.8Humes H.D. MacKay S.M. Funke A.J. Buffington D.A. Tissue engineering of a bioartificial renal tubule assist device in vitro transport and metabolic characteristics.Kidney Int. 1999; 55: 2502-2514Google Scholar, 9Humes H.D. Fissell W.H. Weitzel W.F. et al.Metabolic replacement of renal function in uremic animals with a bioartificial kidney containing human cells.Am J Kidney Dis. 2002; 39: 1078-1087Google Scholar, 10Fissell W.H. Lou L. Abrishami S. Buffington D.A. Humes H.D. Bioartificial kidney ameliorates gram-negative bacteria-induced septic shock in uremic animals.J Am Soc Nephrol. 2003; 14: 454-461Google Scholar, 11Humes H.D. Buffington D.A. Lou L. et al.Cell therapy with a tissue-engineered kidney protects against the multi-organ consequences of septic shock.Crit Care Med. 2003; 31: 2421-2428Google Scholar, 12Humes H.D. Weitzel W.F. Bartlett R.H. et al.Initial clinical results of the bioartificial kidney containing human cells in ICU patients with acute renal failure.Kidney Int. 2004; 66: 1578-1588Google ScholarWhat is not detailed in the published literature was the complex set of commercialization steps required to move this technology to a therapeutic product. It would not be sufficient to prove the scientific thesis of our concept; it was also necessary for our team to do it in a way that would allow our technology to be successful in a commercially viable way to deliver the clinical benefit we hoped to demonstrate. For the purposes of this article, it is best to outline the key issues encountered along this rocky road. It needs to be acknowledged that huge sums of money are required to accomplish these clinical and commercial benefits and to obtain FDA approval to sell a product. This approval depends on pivotal controlled Phase III trials costing tens of millions of dollars. The total cost from discovery to commercial product has been estimated to require anywhere from $200 to $800 million.13Duyk G. Attrition and translation.Science. 2003; 302: 603-605Google Scholar This funding can only be obtained from venture capital or industrial sources. Accordingly, successful translational research requires a detailed commercialization strategy with multiple confounding and conflicting variables.Intellectual propertySuccessful medical diagnostic and therapeutic products require a broad and advantageous intellectual property (IP) position. This IP strategy forms the foundation of future funding decisions, because patent protection provides a monopoly position for the commercial product for the duration of the patent. Decisions on patent protection of new discoveries, however, must be made long before the development of a commercial product. Accordingly, universities with limited resources usually cannot apply for patent protection except in more conventional areas, such as gene products and small molecules, while supporting only U.S. applications, which cover less than half of most medical markets. Coverage of worldwide patent rights requires at least five times the cost of a U.S. patent and usually depends on funding from a licensing partner. From a career standpoint, patent applications and issued patents are rarely considered as important components of a faculty’s promotion process. IP concerns also have implications for the tension between the scientific transparency of academic communities versus the opacity of data developed in the for-profit sector.LicensingIf the IP and patent protection is compelling, the university, which owns the IP, is required to negotiate a licensing agreement to a for-profit entity for the right to commercialize the discovery into a saleable product.14Tang K. Vohora A. Freeman R. Taking research to market. Euromoney, London2004Google Scholar An initial decision between the investigator and the university is whether to license this technology to a large company or spinout a brand new start-up company. A number of issues must be resolved: royalty stream (what is appropriate?—1%, 2%, 5%, 10% of sales?) and annual licensing fees with or without milestone payments ($25,000 to $1 million). If it is a spinout company, what percent ownership of this biotech spinout should the university obtain as the incubator of the technology? The share of ownership by the university needs to be small enough to provide adequate incentive for the professional business management of the company and future investors. Without prior experience, a scientist has few resources on which to make rational and prudent decisions. As another recourse, identifying and trusting a business associate may not be easy. This business agreement may take a few weeks with an experienced technology transfer office at a university or more than 1 year with an inexperienced operation. All of these business discussions take time and careful thought, detracting from the educational and research pursuits of the faculty scientist.Conflict of interestConflicts of interest occur in every professional discipline. Two decades ago, a number of high-profile episodes of scientific misconduct demonstrated the need for checks and balances required by a research institution to manage the inherent pressures of a scientist to succeed with faculty advancement, successful funding of research grants, and professional accolades for creativity and discovery.15Korn D. Conflicts of interest in biomedical research.JAMA. 2000; 284: 2234-2237Google Scholar These inherent pressures tend to promote nonfinancial conflicts with a strong bias toward positive research results. Over the past two decades, research institutions have instituted deliberative policies and procedures, along with the scientific method, to manage these conflicts. More recently, tragic deaths in clinical research have made the issue of financial conflicts of interest even more pressing. The public perception is that faculty investigators and a university with financial interests in the results of a clinical study involving human subjects might compromise their credibility and safety of the research subjects. This concern has resulted in open disclosures of potential financial interests and carefully crafted institutional policies and procedures. Thus, the convergence of both nonfinancial and financial conflicts of interest places the translational researcher in an even more precarious position, because the reporting media seem to have an inherent bias to imply that financial interests in research may result in scientific misrepresentation and misconduct.These issues pose difficult questions to the institution and the individual faculty researcher. What role does the inventive translational scientist play in a clinical trial? Certainly, he/she should not be the Principal Investigator responsible for the recruitment of patients and oversight of the data but should be a coordinating investigator bringing the most detailed knowledge of the technology to the bedside for the safety of the patient in the initial Phase I or Phase I/II clinical trial. What role should the innovator play in Phase II/III clinical trials, as a member of the faculty or as a consultant to the company commercializing the technology? Should the university allow the clinical trial to proceed in its own medical center if it owns an equity interest in the commercial company? How should the translational scientist oversee doctoral students, postdoctoral fellows, and junior faculty involved in the project? How does the institution manage the potential use of these trainees for the pursuit of knowledge rather than the further commercialization of the technology? What research projects can the licensing company support in the inventor’s laboratory, such as basic research, preclinical animal studies, or product development? Recent public discussions about financial conflicts of interest in biomedical research present a precarious situation for both researcher and research institution. Public and governmental officials are demanding that universities and their faculty become engines of economic development in their states and the country, but often with an unwillingness to accept the potential conflicts of interest in conducting and evaluating the results of research as it relates to for-profit enterprises. The 1982 Bayh-Dole Act passed by Congress emphasized the importance of this commercialization process.16Kennedy D. Bayh-Dole almost 25.Science. 2005; 307: 1375Google Scholar It is an uncomfortable balance that is fraught with misinterpretation and misunderstandings.Food and Drug AdministrationThis venerable institution is the federal agency ultimately responsible for overseeing the safety and efficacy of new medical devices and therapeutics.17Hilts P.J. Protecting America’s health. University of North Carolina Press, Chapel Hill2004Google Scholar FDA approval is required for a new agent to be commercially sold in the United States. To ensure the safety of the development of a new therapeutic initiative, the FDA oversees the manufacture of the product to be tested and the conduct of the various phases of clinical testing. The documentation and facility requirements are formidable. For manufacturing, detailed requirements for standard operating procedures in good manufacturing practice facilities are mandated, with frequent air quality and sterility testing. Standards for device or product quality with detailed release criteria are required. Before proceeding to a clinical trial, an investigator must receive the permission of the FDA. An investigational new drug permit or an investigational device exemption certificate must be obtained from that agency. Applications normally consist of several hundred pages of data to support the safety of manufacture and study design. The application process can be truly formidable and can consume substantial resources and time. For the Phase I/II clinical studies, the translational researcher is often critically involved, because he or she is the knowledge expert without peer in this specific area and is best prepared to predict and evaluate any safety issues. Of note, an FDA-approved investigational new drug permit or investigational device exemption certificate is a substantial intellectual achievement (probably akin to a funded interdisciplinary program project) but has little academic currency to faculty promotion.Institutional oversightEven with FDA approval, clinical and other research involving human subjects may require local oversight. Institutional review boards (IRBs) have been established at medical centers to provide clinical study approval and oversight, but some centers and study sponsors use off-site boards. For truly innovative studies, the oversight board may lack the necessary expertise, perhaps because a knowledgeable member may have a personal, “conflicting” interest in the research and must therefore be excluded from the review process. Local oversight, however, is a two-way street with regard to expertise. The investigator, too, may hinder the review by not being process-savvy and gifted in presenting the necessary information to the IRB. Although an IRB-approved clinical study is an important research document, similar to an FDA-approved study, it currently has little academic value for faculty promotion. Nor, for that matter, is academic value placed on service on an IRB, so there is little incentive for an IRB member to share his or her time and knowledge with an investigator. In addition, some local IRBs meet only once per month, so approval of a clinical trial may require several months of deliberations and revisions. All the above problems may be compounded in the case of multicenter trials, because different issues are often raised at each of the various medical centers engaged in the clinical study. Thus, the road to institutional approval and oversight of a human research study is by no means a smooth expressway. It is strewn with an array of complex issues, and all parties bear responsibility in ensuring a satisfactory outcome.Translational research is not in the mainstream of the traditional academic pursuit and is not currently well understood by many academic medical centers, traditional faculty, and academic leaders. Institutional policies and procedures need to be reevaluated to promote a faculty member who has the intellect, courage, and tenacity to pursue this career path. Some suggestions can be considered and deliberated. Protection of intellectual property needs to have more appropriate resources. Filed and issued patents are important elements of new knowledge creation and should be acknowledged in faculty review and promotions. Technology transfer offices at universities need to involve and educate interested faculty in developing licensing agreements. Template agreements need to be developed on the basis of success stories. Conflict-of-interest committees need to balance institutional concerns while supporting faculty initiative. Mandating an idealized state of virtue by prohibiting even appearances of financial conflicts of interest guarantees failure in the development of any robust translational research program and its potential for immense societal benefit in innovative diagnostics and therapeutics. Institutions would be wise to evolve oversight processes that are more user-friendly to the translational researcher.With all these complexities, twists and turns, and uphill struggles, why would an energetic and creative researcher choose such an arduous career in academic translational medicine? To me, the choice is simple and is a distillation of the basic values of why one pursues an academic medical career. The pursuit of new knowledge is a most rewarding discipline. To apply that new knowledge to better understand a medical disease is a satisfying achievement. To translate that understanding to an innovative therapeutic or diagnostic approach that relieves pain and suffering is the ultimate professional accomplishment. “To have striven, to have made the effort, to have been true to certain ideals—this alone is worth the struggle.”—William Osler. “There does not exist a category of science to which one can give the name ‘applied science.’ There are science and the applications of science, bound together as the fruit of the tree which bears it. —Louis Pasteur Translational research has been described in terms ranging from the supportive “bench to bedside” to the detractive “discovery to commercialization.” Both believers and skeptics, however, would agree that it is a less traveled road because of steep inclines, speed bumps, potholes, and sharp curves that makes it hazardous for an investigator to devote a career to this research direction.1Goldstein J.L. Brown M.S. The clinical investigator bewitched, bothered, and bewildered—but still beloved.J Clin Invest. 1997; 99: 2803-2812Google Scholar Both public funding agencies, such as the National Institutes of Health, with its road map to reengineer the clinical research enterprise, and private foundations, such as the Howard Hughes Medical Institute, have made recent commitments to translational research.2Zerhouni E. The NIH roadmap.Science. 2003; 302 (72): 63-64Google Scholar, 3Birmingham K. What is translational research?.Nat Med. 2002; 8: 647Google Scholar This dedicated allocation of resources has occurred because of the rapid pace of discovery and heightened public expectations of new cures and treatments with increased investment of public and private monies. In efforts to refocus the Journal of Laboratory and Clinical Medicine toward this research area, the editors have requested that I provide a personal view of the complex path that our group has traveled over the last decade to bring one of our specific research programs to therapeutic evaluation. Physician scientists are driven to pursue a better understanding and perhaps a new therapeutic approach to an unmet medical need of a clinical disorder. For nephrology, acute renal failure secondary to acute tubular necrosis (ATN) continues to confound practicing nephrologists, with mortality rates in patients in the intensive care unit exceeding 70%, despite dialytic control of volume and electrolyte balance.4Humes H.D. Acute renal failure prevailing challenges and prospects for the future.Kidney Int. 1995; 48: S26-S32Google Scholar Several seminal observations of this clinical disorder have been widely acknowledged from both the bench and the clinic, which provided an opportunity to formulate a new therapeutic approach. The primary pathophysiology of this disorder is injury to renal tubule cells.5Thadhani R, Pascual M, Bonventre JV.N Engl J Med. 1996; 334: 1448-1460Google Scholar Clinical observations have demonstrated that patients with ATN experience a downward spiral leading to multiorgan failure with a dysregulated systemic inflammatory state. But unlike other acute solid-organ failures, the kidney has the ability to fully repair itself if given enough time, resulting in patient recovery. This reparative process depends on a subset of renal tubule progenitor/stem cells in the adult kidney to proliferate and differentiate to full nephronal functionality.6Humes H.D. Krauss J.C. Cieslinski D.A. Funke A.J. Tubulogenesis from isolated single cells of adult mammalian kidney clonal analysis with a recombinant retrovirus.Am J Physiol Renal Physiol. 1996; 271: F42-F49Google Scholar From these insights, a new therapeutic approach combining renal tubule cell therapy and conventional hemofiltration was developed to provide the metabolic functions of renal cells that are lost during the ATN process.7Humes H.D. Buffington D.A. MacKay S.M. Funke A.J. Weitzel W.F. Replacement of renal function in uremic animals with a tissue-engineered kidney.Nat Biotechnol. 1999; 17: 451-455Google Scholar This approach promised to provide more complete renal replacement therapy, including the clearance function achieved with hemodiafiltration and the synthetic and endocrine functions of cells. This approach could also test the unconventional hypothesis that renal tubule cells are important immunologic regulators under stress states. Although the technology is simple in concept, nearly a decade has been required to move this technology from bench to bedside in Food and Drug Administration (FDA)-approved Phase I and II clinical trials. The translation of this technology required a coordinated team of diverse talents, including cell and molecular biologists, tissue and bioengineers, and clinical investigators. The identification and evaluation of human tissue sources, extracorporeal pump systems, and device fabrication were required first in large animals before man. These technologic steps are detailed in our group’s scientific publications.8Humes H.D. MacKay S.M. Funke A.J. Buffington D.A. Tissue engineering of a bioartificial renal tubule assist device in vitro transport and metabolic characteristics.Kidney Int. 1999; 55: 2502-2514Google Scholar, 9Humes H.D. Fissell W.H. Weitzel W.F. et al.Metabolic replacement of renal function in uremic animals with a bioartificial kidney containing human cells.Am J Kidney Dis. 2002; 39: 1078-1087Google Scholar, 10Fissell W.H. Lou L. Abrishami S. Buffington D.A. Humes H.D. Bioartificial kidney ameliorates gram-negative bacteria-induced septic shock in uremic animals.J Am Soc Nephrol. 2003; 14: 454-461Google Scholar, 11Humes H.D. Buffington D.A. Lou L. et al.Cell therapy with a tissue-engineered kidney protects against the multi-organ consequences of septic shock.Crit Care Med. 2003; 31: 2421-2428Google Scholar, 12Humes H.D. Weitzel W.F. Bartlett R.H. et al.Initial clinical results of the bioartificial kidney containing human cells in ICU patients with acute renal failure.Kidney Int. 2004; 66: 1578-1588Google Scholar What is not detailed in the published literature was the complex set of commercialization steps required to move this technology to a therapeutic product. It would not be sufficient to prove the scientific thesis of our concept; it was also necessary for our team to do it in a way that would allow our technology to be successful in a commercially viable way to deliver the clinical benefit we hoped to demonstrate. For the purposes of this article, it is best to outline the key issues encountered along this rocky road. It needs to be acknowledged that huge sums of money are required to accomplish these clinical and commercial benefits and to obtain FDA approval to sell a product. This approval depends on pivotal controlled Phase III trials costing tens of millions of dollars. The total cost from discovery to commercial product has been estimated to require anywhere from $200 to $800 million.13Duyk G. Attrition and translation.Science. 2003; 302: 603-605Google Scholar This funding can only be obtained from venture capital or industrial sources. Accordingly, successful translational research requires a detailed commercialization strategy with multiple confounding and conflicting variables. Intellectual propertySuccessful medical diagnostic and therapeutic products require a broad and advantageous intellectual property (IP) position. This IP strategy forms the foundation of future funding decisions, because patent protection provides a monopoly position for the commercial product for the duration of the patent. Decisions on patent protection of new discoveries, however, must be made long before the development of a commercial product. Accordingly, universities with limited resources usually cannot apply for patent protection except in more conventional areas, such as gene products and small molecules, while supporting only U.S. applications, which cover less than half of most medical markets. Coverage of worldwide patent rights requires at least five times the cost of a U.S. patent and usually depends on funding from a licensing partner. From a career standpoint, patent applications and issued patents are rarely considered as important components of a faculty’s promotion process. IP concerns also have implications for the tension between the scientific transparency of academic communities versus the opacity of data developed in the for-profit sector. Successful medical diagnostic and therapeutic products require a broad and advantageous intellectual property (IP) position. This IP strategy forms the foundation of future funding decisions, because patent protection provides a monopoly position for the commercial product for the duration of the patent. Decisions on patent protection of new discoveries, however, must be made long before the development of a commercial product. Accordingly, universities with limited resources usually cannot apply for patent protection except in more conventional areas, such as gene products and small molecules, while supporting only U.S. applications, which cover less than half of most medical markets. Coverage of worldwide patent rights requires at least five times the cost of a U.S. patent and usually depends on funding from a licensing partner. From a career standpoint, patent applications and issued patents are rarely considered as important components of a faculty’s promotion process. IP concerns also have implications for the tension between the scientific transparency of academic communities versus the opacity of data developed in the for-profit sector. LicensingIf the IP and patent protection is compelling, the university, which owns the IP, is required to negotiate a licensing agreement to a for-profit entity for the right to commercialize the discovery into a saleable product.14Tang K. Vohora A. Freeman R. Taking research to market. Euromoney, London2004Google Scholar An initial decision between the investigator and the university is whether to license this technology to a large company or spinout a brand new start-up company. A number of issues must be resolved: royalty stream (what is appropriate?—1%, 2%, 5%, 10% of sales?) and annual licensing fees with or without milestone payments ($25,000 to $1 million). If it is a spinout company, what percent ownership of this biotech spinout should the university obtain as the incubator of the technology? The share of ownership by the university needs to be small enough to provide adequate incentive for the professional business management of the company and future investors. Without prior experience, a scientist has few resources on which to make rational and prudent decisions. As another recourse, identifying and trusting a business associate may not be easy. This business agreement may take a few weeks with an experienced technology transfer office at a university or more than 1 year with an inexperienced operation. All of these business discussions take time and careful thought, detracting from the educational and research pursuits of the faculty scientist. If the IP and patent protection is compelling, the university, which owns the IP, is required to negotiate a licensing agreement to a for-profit entity for the right to commercialize the discovery into a saleable product.14Tang K. Vohora A. Freeman R. Taking research to market. Euromoney, London2004Google Scholar An initial decision between the investigator and the university is whether to license this technology to a large company or spinout a brand new start-up company. A number of issues must be resolved: royalty stream (what is appropriate?—1%, 2%, 5%, 10% of sales?) and annual licensing fees with or without milestone payments ($25,000 to $1 million). If it is a spinout company, what percent ownership of this biotech spinout should the university obtain as the incubator of the technology? The share of ownership by the university needs to be small enough to provide adequate incentive for the professional business management of the company and future investors. Without prior experience, a scientist has few resources on which to make rational and prudent decisions. As another recourse, identifying and trusting a business associate may not be easy. This business agreement may take a few weeks with an experienced technology transfer office at a university or more than 1 year with an inexperienced operation. All of these business discussions take time and careful thought, detracting from the educational and research pursuits of the faculty scientist. Conflict of interestConflicts of interest occur in every professional discipline. Two decades ago, a number of high-profile episodes of scientific misconduct demonstrated the need for checks and balances required by a research institution to manage the inherent pressures of a scientist to succeed with faculty advancement, successful funding of research grants, and professional accolades for creativity and discovery.15Korn D. Conflicts of interest in biomedical research.JAMA. 2000; 284: 2234-2237Google Scholar These inherent pressures tend to promote nonfinancial conflicts with a strong bias toward positive research results. Over the past two decades, research institutions have instituted deliberative policies and procedures, along with the scientific method, to manage these conflicts. More recently, tragic deaths in clinical research have made the issue of financial conflicts of interest even more pressing. The public perception is that faculty investigators and a university with financial interests in the results of a clinical study involving human subjects might compromise their credibility and safety of the research subjects. This concern has resulted in open disclosures of potential financial interests and carefully crafted institutional policies and procedures. Thus, the convergence of both nonfinancial and financial conflicts of interest places the translational researcher in an even more precarious position, because the reporting media seem to have an inherent bias to imply that financial interests in research may result in scientific misrepresentation and misconduct.These issues pose difficult questions to the institution and the individual faculty researcher. What role does the inventive translational scientist play in a clinical trial? Certainly, he/she should not be the Principal Investigator responsible for the recruitment of patients and oversight of the data but should be a coordinating investigator bringing the most detailed knowledge of the technology to the bedside for the safety of the patient in the initial Phase I or Phase I/II clinical trial. What role should the innovator play in Phase II/III clinical trials, as a member of the faculty or as a consultant to the company commercializing the technology? Should the university allow the clinical trial to proceed in its own medical center if it owns an equity interest in the commercial company? How should the translational scientist oversee doctoral students, postdoctoral fellows, and junior faculty involved in the project? How does the institution manage the potential use of these trainees for the pursuit of knowledge rather than the further commercialization of the technology? What research projects can the licensing company support in the inventor’s laboratory, such as basic research, preclinical animal studies, or product development? Recent public discussions about financial conflicts of interest in biomedical research present a precarious situation for both researcher and research institution. Public and governmental officials are demanding that universities and their faculty become engines of economic development in their states and the country, but often with an unwillingness to accept the potential conflicts of interest in conducting and evaluating the results of research as it relates to for-profit enterprises. The 1982 Bayh-Dole Act passed by Congress emphasized the importance of this commercialization process.16Kennedy D. Bayh-Dole almost 25.Science. 2005; 307: 1375Google Scholar It is an uncomfortable balance that is fraught with misinterpretation and misunderstandings. Conflicts of interest occur in every professional discipline. Two decades ago, a number of high-profile episodes of scientific misconduct demonstrated the need for checks and balances required by a research institution to manage the inherent pressures of a scientist to succeed with faculty advancement, successful funding of research grants, and professional accolades for creativity and discovery.15Korn D. Conflicts of interest in biomedical research.JAMA. 2000; 284: 2234-2237Google Scholar These inherent pressures tend to promote nonfinancial conflicts with a strong bias toward positive research results. Over the past two decades, research institutions have instituted deliberative policies and procedures, along with the scientific method, to manage these conflicts. More recently, tragic deaths in clinical research have made the issue of financial conflicts of interest even more pressing. The public perception is that faculty investigators and a university with financial interests in the results of a clinical study involving human subjects might compromise their credibility and safety of the research subjects. This concern has resulted in open disclosures of potential financial interests and carefully crafted institutional policies and procedures. Thus, the convergence of both nonfinancial and financial conflicts of interest places the translational researcher in an even more precarious position, because the reporting media seem to have an inherent bias to imply that financial interests in research may result in scientific misrepresentation and misconduct. These issues pose difficult questions to the institution and the individual faculty researcher. What role does the inventive translational scientist play in a clinical trial? Certainly, he/she should not be the Principal Investigator responsible for the recruitment of patients and oversight of the data but should be a coordinating investigator bringing the most detailed knowledge of the technology to the bedside for the safety of the patient in the initial Phase I or Phase I/II clinical trial. What role should the innovator play in Phase II/III clinical trials, as a member of the faculty or as a consultant to the company commercializing the technology? Should the university allow the clinical trial to proceed in its own medical center if it owns an equity interest in the commercial company? How should the translational scientist oversee doctoral students, postdoctoral fellows, and junior faculty involved in the project? How does the institution manage the potential use of these trainees for the pursuit of knowledge rather than the further commercialization of the technology? What research projects can the licensing company support in the inventor’s laboratory, such as basic research, preclinical animal studies, or product development? Recent public discussions about financial conflicts of interest in biomedical research present a precarious situation for both researcher and research institution. Public and governmental officials are demanding that universities and their faculty become engines of economic development in their states and the country, but often with an unwillingness to accept the potential conflicts of interest in conducting and evaluating the results of research as it relates to for-profit enterprises. The 1982 Bayh-Dole Act passed by Congress emphasized the importance of this commercialization process.16Kennedy D. Bayh-Dole almost 25.Science. 2005; 307: 1375Google Scholar It is an uncomfortable balance that is fraught with misinterpretation and misunderstandings. Food and Drug AdministrationThis venerable institution is the federal agency ultimately responsible for overseeing the safety and efficacy of new medical devices and therapeutics.17Hilts P.J. Protecting America’s health. University of North Carolina Press, Chapel Hill2004Google Scholar FDA approval is required for a new agent to be commercially sold in the United States. To ensure the safety of the development of a new therapeutic initiative, the FDA oversees the manufacture of the product to be tested and the conduct of the various phases of clinical testing. The documentation and facility requirements are formidable. For manufacturing, detailed requirements for standard operating procedures in good manufacturing practice facilities are mandated, with frequent air quality and sterility testing. Standards for device or product quality with detailed release criteria are required. Before proceeding to a clinical trial, an investigator must receive the permission of the FDA. An investigational new drug permit or an investigational device exemption certificate must be obtained from that agency. Applications normally consist of several hundred pages of data to support the safety of manufacture and study design. The application process can be truly formidable and can consume substantial resources and time. For the Phase I/II clinical studies, the translational researcher is often critically involved, because he or she is the knowledge expert without peer in this specific area and is best prepared to predict and evaluate any safety issues. Of note, an FDA-approved investigational new drug permit or investigational device exemption certificate is a substantial intellectual achievement (probably akin to a funded interdisciplinary program project) but has little academic currency to faculty promotion. This venerable institution is the federal agency ultimately responsible for overseeing the safety and efficacy of new medical devices and therapeutics.17Hilts P.J. Protecting America’s health. University of North Carolina Press, Chapel Hill2004Google Scholar FDA approval is required for a new agent to be commercially sold in the United States. To ensure the safety of the development of a new therapeutic initiative, the FDA oversees the manufacture of the product to be tested and the conduct of the various phases of clinical testing. The documentation and facility requirements are formidable. For manufacturing, detailed requirements for standard operating procedures in good manufacturing practice facilities are mandated, with frequent air quality and sterility testing. Standards for device or product quality with detailed release criteria are required. Before proceeding to a clinical trial, an investigator must receive the permission of the FDA. An investigational new drug permit or an investigational device exemption certificate must be obtained from that agency. Applications normally consist of several hundred pages of data to support the safety of manufacture and study design. The application process can be truly formidable and can consume substantial resources and time. For the Phase I/II clinical studies, the translational researcher is often critically involved, because he or she is the knowledge expert without peer in this specific area and is best prepared to predict and evaluate any safety issues. Of note, an FDA-approved investigational new drug permit or investigational device exemption certificate is a substantial intellectual achievement (probably akin to a funded interdisciplinary program project) but has little academic currency to faculty promotion. Institutional oversightEven with FDA approval, clinical and other research involving human subjects may require local oversight. Institutional review boards (IRBs) have been established at medical centers to provide clinical study approval and oversight, but some centers and study sponsors use off-site boards. For truly innovative studies, the oversight board may lack the necessary expertise, perhaps because a knowledgeable member may have a personal, “conflicting” interest in the research and must therefore be excluded from the review process. Local oversight, however, is a two-way street with regard to expertise. The investigator, too, may hinder the review by not being process-savvy and gifted in presenting the necessary information to the IRB. Although an IRB-approved clinical study is an important research document, similar to an FDA-approved study, it currently has little academic value for faculty promotion. Nor, for that matter, is academic value placed on service on an IRB, so there is little incentive for an IRB member to share his or her time and knowledge with an investigator. In addition, some local IRBs meet only once per month, so approval of a clinical trial may require several months of deliberations and revisions. All the above problems may be compounded in the case of multicenter trials, because different issues are often raised at each of the various medical centers engaged in the clinical study. Thus, the road to institutional approval and oversight of a human research study is by no means a smooth expressway. It is strewn with an array of complex issues, and all parties bear responsibility in ensuring a satisfactory outcome.Translational research is not in the mainstream of the traditional academic pursuit and is not currently well understood by many academic medical centers, traditional faculty, and academic leaders. Institutional policies and procedures need to be reevaluated to promote a faculty member who has the intellect, courage, and tenacity to pursue this career path. Some suggestions can be considered and deliberated. Protection of intellectual property needs to have more appropriate resources. Filed and issued patents are important elements of new knowledge creation and should be acknowledged in faculty review and promotions. Technology transfer offices at universities need to involve and educate interested faculty in developing licensing agreements. Template agreements need to be developed on the basis of success stories. Conflict-of-interest committees need to balance institutional concerns while supporting faculty initiative. Mandating an idealized state of virtue by prohibiting even appearances of financial conflicts of interest guarantees failure in the development of any robust translational research program and its potential for immense societal benefit in innovative diagnostics and therapeutics. Institutions would be wise to evolve oversight processes that are more user-friendly to the translational researcher.With all these complexities, twists and turns, and uphill struggles, why would an energetic and creative researcher choose such an arduous career in academic translational medicine? To me, the choice is simple and is a distillation of the basic values of why one pursues an academic medical career. The pursuit of new knowledge is a most rewarding discipline. To apply that new knowledge to better understand a medical disease is a satisfying achievement. To translate that understanding to an innovative therapeutic or diagnostic approach that relieves pain and suffering is the ultimate professional accomplishment. “To have striven, to have made the effort, to have been true to certain ideals—this alone is worth the struggle.”—William Osler. Even with FDA approval, clinical and other research involving human subjects may require local oversight. Institutional review boards (IRBs) have been established at medical centers to provide clinical study approval and oversight, but some centers and study sponsors use off-site boards. For truly innovative studies, the oversight board may lack the necessary expertise, perhaps because a knowledgeable member may have a personal, “conflicting” interest in the research and must therefore be excluded from the review process. Local oversight, however, is a two-way street with regard to expertise. The investigator, too, may hinder the review by not being process-savvy and gifted in presenting the necessary information to the IRB. Although an IRB-approved clinical study is an important research document, similar to an FDA-approved study, it currently has little academic value for faculty promotion. Nor, for that matter, is academic value placed on service on an IRB, so there is little incentive for an IRB member to share his or her time and knowledge with an investigator. In addition, some local IRBs meet only once per month, so approval of a clinical trial may require several months of deliberations and revisions. All the above problems may be compounded in the case of multicenter trials, because different issues are often raised at each of the various medical centers engaged in the clinical study. Thus, the road to institutional approval and oversight of a human research study is by no means a smooth expressway. It is strewn with an array of complex issues, and all parties bear responsibility in ensuring a satisfactory outcome. Translational research is not in the mainstream of the traditional academic pursuit and is not currently well understood by many academic medical centers, traditional faculty, and academic leaders. Institutional policies and procedures need to be reevaluated to promote a faculty member who has the intellect, courage, and tenacity to pursue this career path. Some suggestions can be considered and deliberated. Protection of intellectual property needs to have more appropriate resources. Filed and issued patents are important elements of new knowledge creation and should be acknowledged in faculty review and promotions. Technology transfer offices at universities need to involve and educate interested faculty in developing licensing agreements. Template agreements need to be developed on the basis of success stories. Conflict-of-interest committees need to balance institutional concerns while supporting faculty initiative. Mandating an idealized state of virtue by prohibiting even appearances of financial conflicts of interest guarantees failure in the development of any robust translational research program and its potential for immense societal benefit in innovative diagnostics and therapeutics. Institutions would be wise to evolve oversight processes that are more user-friendly to the translational researcher. With all these complexities, twists and turns, and uphill struggles, why would an energetic and creative researcher choose such an arduous career in academic translational medicine? To me, the choice is simple and is a distillation of the basic values of why one pursues an academic medical career. The pursuit of new knowledge is a most rewarding discipline. To apply that new knowledge to better understand a medical disease is a satisfying achievement. To translate that understanding to an innovative therapeutic or diagnostic approach that relieves pain and suffering is the ultimate professional accomplishment. “To have striven, to have made the effort, to have been true to certain ideals—this alone is worth the struggle.”—William Osler.