May 15, 2011 (Vol. 31, No. 10)
John C. Reed, M.D., Ph.D.
National Center for Advancing Translational Sciences Essential to Capitalize on Basic Research
In his recent opinion piece (NIH Pharma Co. Is a Bad Idea, March 15), Henry I. Miller, M.D., argues against the NIH’s proposal to create a new center specifically designed to speed development and testing of novel diagnostics and therapeutics aimed at a wide range of human diseases.1 I disagree with Dr. Miller.
This center, to be called the National Center for Advancing Translational Sciences (NCATS), is not only a good idea, it’s a necessary one. In this article, I will explain why the public sector must participate in the search for new medicines and how NCATS will help. I will also give several examples of how federal funds are already advancing drug development and saving lives.
Dr. Miller believes that drug development is better left in the hands of private pharmaceutical and biotechnology companies. While I am equally frustrated with the slow pace of new drugs coming out of the pipeline, private industry cannot bear this weight alone.
Pharmaceutical companies are extremely good at taking promising new compounds through the later stages of preclinical development, clinical trials, and the FDA approval process. They are even willing to spend billions of dollars and as many as 10 years doing it. However, private companies and venture capitalists are increasingly reluctant to fund the crucial early stages of preclinical development—the research necessary to “translate” promising discoveries made in laboratories into optimized candidate therapeutics ready for testing in clinical trials.
This gap includes many steps in the drug discovery and development process, including assay development, high-throughput screening, medicinal chemistry, exploratory pharmacology, and rigorous preclinical testing of drug efficacy and safety in animal models of disease.
This situation leaves us with the aptly named “Valley of Death”—the large research and funding gap that sets federally funded basic researchers (those of us in nonprofit research institutions, academia, hospitals, and federal laboratories) on one side and the pharmaceutical industry on the other. Few companies are able to reach far enough backward to bridge that gap—the costs and risks are just too high for organizations that are responsible for delivering financial results to their investors and shareholders.
Enter the NIH’s newly proposed center for translational sciences—just the shot in the arm basic research needs to reach forward across that valley.
The goal of this new NIH center is not to make, test, and market drugs in competition with private industry. Rather, this translational science center will provide federal funding to help advance initial laboratory discoveries at least to the point where private industry might be interested in partnering to help carry these findings through the rest of the FDA-required process. NCATS will take the NIH’s investment in basic research closer to helping people who suffer from disease.2
NIH funding to catalyze drug discovery is not a new idea. While Dr. Miller claims that the NIH has a poor track record of producing pharmaceuticals, he cites only one example dating back to 1963. According to a New England Journal of Medicine paper published just this past February, 153 new FDA-approved drugs, vaccines, or new indications for existing drugs were discovered through research carried out in public-sector research institutions over the past 40 years.
These drugs included 93 small molecule drugs, 36 biologic agents, 15 vaccines, eight in vivo diagnostic materials, and one over-the-counter drug. These are medicines that are now saving countless lives—the authors conclude that these drugs discovered by the public sector will have a disproportionately large therapeutic effect on human health.3 Several of these important medicines were delivered through Cooperative Research and Development Agreements and other mechanisms where government funding is leveraged with for-profit company investment. For example, many of the most effective drugs used by oncologists to treat cancer today originally arose from programs funded in whole or in part by the National Cancer Institute, the largest institute within the NIH.
Rare and Neglected Diseases
Another reason why the proposed NCATS is so timely is found in rare and neglected diseases. Here, the market opportunity is often too small to entice for-profit company investment, obligating the public sector to fill the void. The NIH’s Office of Rare Diseases Research estimates that approximately 8% of the U.S. population (25–30 million Americans) suffers from a rare disease. Historically, persons suffering from rare diseases, including many hereditary disorders affecting children, have probably benefited the most from government-funded drug development.
Thanks to the Orphan Drug Act, a 1983 law mandating the FDA to fast-track approval for rare disease therapeutics, the regulatory path exists to aid this objective. Since the act was passed, more than 325 orphan-designated products received marketing approval, a big improvement over the fewer than 10 that reached the market in the previous decade.4
With NCATS, even more progress could be made. If the NIH, through NCATS, funds the early stages of discovery and development of candidate therapeutics for rare diseases, chances are much greater that an industry sponsor will come forward to carry the ball across the FDA-approval goal line.
Plenty of other diseases are largely neglected by the pharmaceutical industry for reasons other than market size, leaving the burden to the public to find solutions. Take, for example, traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD), leading causes of death and long-term disability among military personnel serving in combat. Few (if any) large pharmaceutical companies are currently developing countermeasures specifically for TBI or PTSD, and the handful of small companies working toward therapeutics for these disorders are mostly funded not by investors but by the government—namely the U.S. Department of Defense.
How many lives could be saved if NCATS is able to pick up the slack for more common diseases currently ignored by for-profit companies? For instance, each of us has reason to be concerned about the rise of antibiotic-resistant microorganisms and the decline of effective drugs to treat them. Yet only four new classes of antibiotics have been introduced in the past 40 years.5 Most antibiotics currently under development are improvements on existing drugs. Why? Because more profits can be made developing medicines that treat chronic conditions, such as high cholesterol, where patients pay for a steady supply of medication—sometimes for the rest of their lives.
In contrast, antibiotics provide a relatively cheap one-time cure for acute conditions. The pharmaceutical industry just doesn’t have the incentive to develop high-risk/low-reward drugs such as antibiotics, even if they are desperately needed to fight life-threatening illnesses.6,7 The federal government does.
Validation of Targets
To understand how NCATS will help further catalyze drug development, consider just one of the ongoing NIH programs slated to move into this new center: the Molecular Libraries Probe Production Centers Network (MLPCN). Created as part of the 2004 NIH Roadmap for Medical Research,8 MLPCN established the first federally funded network to facilitate drug discovery by producing early-stage small molecule leads.9
These centers, most of which reside in universities and nonprofit research institutes across the U.S., provide federally funded researchers and even small biotechnology companies with access to drug discovery capabilities previously found only within large pharmaceutical companies. Those capabilities include large chemical libraries, assay development, ultra high-throughput robotic screening, cheminformatics, medicinal chemistry, project management, and several other drug discovery-related services that typically don’t exist in academic labs and departments.
The MLPCN initiative is probably too young for us to critically evaluate its impact on human health, but several unique opportunities are emanating from this federally funded enterprise. In MLPCN, academic researchers use chemical probes to explore a wide range of targets10 that are not yet validated to the satisfaction of the pharmaceutical industry.
As recently as 2006, the entire repertoire of approved drugs was determined to address only 324 targets, clearly indicating that further efforts are needed to generate chemical modulators of more targets. And there’s probably no better and more clinically relevant way to validate a target than with a chemical probe that modulates the activity of a disease-relevant protein.
Moreover, researchers interfacing with MLPCN are tackling many classes of targets largely ignored by pharmaceutical companies because they are considered technically challenging, and thus too risky for organizations that must worry about generating a return on R&D investments. The nonprofit, public-benefit research community has the flexibility to follow up on any interesting lead, no matter what the target or disease.
Not uncommonly, a MLCPN screening campaign with the objective of identifying antagonists of a particular target leads instead to the discovery of agonists—interesting compounds that can be pursued for different indications than originally envisioned. In contrast, a for-profit company screening for new drugs for a particular therapeutic area might be forced to leave findings that could cure another disease languishing on the shelf. Unfortunately, worries about the bottom line and demands from powerful marketing groups don’t always leave room for scientific curiosity.
Dr. Miller is right on one point—at the other end of the drug pipeline, the FDA approval process creates another bottleneck that keeps new medicines from reaching the market as quickly as we’d like. Here too, through NCATS, the NIH’s leadership is proposing a more robust partnership with the FDA to advance regulatory science.11 This way, FDA regulations can keep pace with the scientific innovations that are creating promising new opportunities to improve human health.
As it becomes increasingly difficult to obtain funding from any source, the infrastructure that allows nonprofit researchers to advance the next generations of innovative therapeutics and diagnostics is at risk of being lost. Without NCATS, many potential therapies will never reach the FDA in the first place, let alone the patients who need them. For this reason, I enthusiastically support the NIH’s newly proposed—and much-needed—National Center for Advancing Translational Sciences.
1. Miller, H.I. NIH Pharma Co. Is a Bad Idea. GEN. 31, no. 6 (Mar 2011).
2. Philippidis, A. Translational Research Is the NCATS’ Meow for Growing NIH’s R&D Role. GEN (April 2011).
3. Stevens, A.J. et al. The role of public-sector research in the discovery of drugs and vaccines. N Engl J Med. 364, no. 6 (Feb 2011):535-41.
4. Baunn, M.M. et al. Emergence of orphan drugs in the United States: a quantitative assessment of the first 25 years. Nat Rev Drug Discov. 9, no. 7 (Jul 2010):519-22.
5. Cooper, M.A. & Shlaes, D. Fix the antibiotics pipeline. Nature 472, no. 32 (April 2011).
6. Braine, T. Race against time to develop new antibiotics. Bulletin of the World Health Organization 89 (2011):88–89.
7. Walsh, C. Where will new antibiotics come from? Nat Rev Microbiol 1 (Oct 2003): 65-70.
8. Zerhouni, E. The NIH Roadmap. Science 302 (Oct 2003).
9. Molecular Libraries Program homepage: http://mli.nih.gov
10. Overington, J.P. et al. How many drug targets are there? Nat Rev Drug Discov 5 (Dec 2006):993-996.
11. NIH and FDA Join Forces to Advance Translational Medicine and Regulatory Science. GEN (Feb 2010).
John C. Reed, M.D., Ph.D. (firstname.lastname@example.org), is the CEO, professor and Donald Bren chief executive chair at the Sanford-Burnham Medical Research Institute in La Jolla, CA.