The clinical and translational sciences seemed to have suddenly arrived on Washington's political agenda. This past spring, Dr. Francis Collins, Director of the National Institutes of Health (NIH), proposed creation and funding of the National Center for Advancing Translational Sciences (NCATS). The center has lofty goals: “to reengineer the process of developing diagnostics, devices and therapeutics” and to accelerate the translation of laboratory findings to the clinical arena across a wide range of human conditions.1 It has; however, been criticized by both Democratic and Republican legislators, forcing Dr. Collins to defend his reorganization plans in the press and on Capitol Hill.2 In October 2011, President Obama also took up the banner of translational medicine.3 He directed all Federal research agencies to enhance their formation of research partnerships with small businesses, universities, and local communities, create new programs designed to support regional innovation clusters, support public–private partnerships, and to share Federal laboratory facilities with new biotechnology companies. The President also called on the NIH to facilitate the ability of biotechnology startups to license patents from the NIH, asked the US Patent and Trademark Office to assist small businesses with their intellectual property and created a program at the National Institute of Standards and Technology to better support entrepreneurs and connect them with funding opportunities. At a time when the country is stuck in a recession, the President's goals were transparent—he pointed out that the movement of scientific breakthroughs into the market place could lead to the development of new industries and new jobs.
For those of us who pursue translational research, the creation of NCATS by the NIH and President Obama's directives to Federal agencies to support and facilitate academic–industry partnerships is laudable and encouraging. Nonetheless, we must carefully look at these initiatives to assess whether they will truly enhance our ability to transition discoveries from the bench to the bedside and improve the health of Americans or whether they represent election year political posturing. I worry that neither NCATS nor the new Federal mandates will appreciably affect drug discovery in the United States unless additional actions are taken that will mitigate some of the key roadblocks in the drug discovery pipeline: a short patent runway for many drugs and devices; decreasing venture capital financing; and the high cost of drug development to name a few.
The average new drug takes 12–15 years to develop— exhausting much if not all of its patent life and costing close to a billion dollars. For drugs that have reached the end of their patent life, the Hatch–Waxman Act provides a period of exclusivity of only 5 years. In the present economic climate in the United States, the brief period of exclusivity afforded by Hatch–Waxman has deterred many venture capital firms and pharmaceutical companies from pursuing the development of drugs whose patents have expired or are expected to expire during their clinical testing. A good example is the drug lidorestat, a potent inhibitor of aldose reductase. In the absence of insulin, aldose reductase metabolizes glucose into the toxic byproducts sorbitol and fructose. Lidorestat inhibited aldose reductase activity and prevented the complications of diabetes in animal models. Initial clinical studies focused on the role of preventing diabetic neuropathy in patients with diabetes. Unfortunately, these studies were time consuming, expensive, and ill conceived because there were no objective end points to follow in a large and heterogeneous patient population. Although other diabetic complications—in particular diabetic cardiomyopathy—were found to provide more attainable clinical end points for purposes of clinical evaluation, development of the drug was stopped when the initial patent life terminated. Venture capital financing was unattainable because the 5-year window of exclusivity provided by the Hatch–Waxman Act was perceived as being too short to recoup the costs of what were expected to be expensive and time-consuming clinical trials. Interestingly, in Europe, drugs whose patents have expired can gain 10 years of additional exclusivity on the basis of the results of clinical trials.
Dr. Collins envisions NCATS's mission as catalyzing the development of new technologies and innovative methods that will enhance the ability of both the public and private sectors to develop and test tomorrow's therapeutics. With just a billion dollars per year in new funding allocated to NCATS, the commercialization of these new technologies will require substantive private support. In fact, President Obama pointed out in his own directive to the Federal agencies the need to work closely with private industry. However, neither Dr. Collin's comments nor those of the President take into account the fact that the US venture capital industry has become increasingly less venturesome and it has become far more difficult for new companies to acquire the support required to develop investigational drugs or devices. For example, in 2000 venture capital funds capitalized 358 new biotechnology companies with a total investment of $4.0 billion. Ten years later, venture capital companies funded 483 new companies but their total investment was only $3.4 billion and there is a paucity of funding for early-stage start-up companies. Many venture capital firms have simply lost the fortitude to take risk—a critical element in the success of translational science.4 Thus, unless the NIH or the Federal government is actually willing to make substantive investments in the creation of new biotechnology companies and their drug development efforts, it is unlikely that significant new opportunities for drug development will arise from either the NCATS or from President Obama's new Federal initiatives.
Finally, NCATS will focus on using state-of-the-art technology to make better use of the data emanating from genome-wide association studies, the use of whole-exsome or whole-genome sequencing to identify new drug targets by deciphering the identity of loss-of-function mutations in individuals with rare genetic diseases, or by applying quantitative, holistic systems biology to the development of individualized treatment strategies.4,5,6 These novel approaches may identify new therapeutic targets; however, the NIH must not ignore the possibility that existing generic compounds may have as yet undefined therapeutic benefits. Take for instance tetracycline. Subtherapeutic concentrations of tetracycline are the most effective means of inhibiting the production of proinflammatory cytokines. However, the only cytokine-related disease for which tetracycline has an approved indication is periodontal disease. Think how much money could be saved in total healthcare costs if low doses of tetracycline could be shown to have the same efficacy as the very costly anticytokine biologics infliximab and etanercept—both agents currently used in the treatment of rheumatoid arthritis and inflammatory bowel disease. The NIH should set aside money to fund clinical studies aimed at evaluating new uses of existing compounds and applications for the money should be reviewed by separate review panels as traditional study sections rarely see excitement or novelty in clinical studies that propose to study new uses for existing drugs.
It is encouraging to see that translational medicine has reached the national stage. There is little doubt that discoveries that will come from translational research will improve the health of the American public. Indeed, simply improving the translation of information from basic and clinical research to the practitioners in the community—the T3 of translational medicine—should improve the quality of care that is delivered in the United States and lower our overall healthcare costs. New discoveries may also lead to the creation of new companies and new jobs. However, politicians should not be glib in their promises nor should they underestimate the enormous voids that separate the basic research laboratory from the clinical research enterprises or from the physician who is practicing in the community. We would be far better served if the President, our Congressional leadership and the NIH, asked for the participation of the leaders in the Clinical and Translational Sciences in crafting policy regarding the nation's translational research agendas. They might then understand some of the important roadblocks that litter the translational highway and with the help of the leadership of the Society for Translational Science create programs designed to mitigate these roadblocks in the drug discovery pipeline. Changing the intellectual property laws to provide a longer runway for drugs that have expended their patent life, encouraging the investment community to take chances on new and innovative but unproven technologies and developing ways to support the evaluation of old drugs for new uses are but a few of the means by which we can improve the translation of basic science research to the clinical arena. CTS