The National Institutes of Health (NIH) has a nickname for the process of translating basic research into a viable product: the "Valley of Death." That’s because during this transition period, although a developing technology might have promise, often its commercial potential remains uncertain. And thus it is difficult to attract the necessary funding for continued development.
In an opinion piece in the October issue of Nature Medicine, researchers Jerry Avorn and Aaron S. Kesselheim of Harvard Medical School and Brigham and Women’s Hospital in Boston, MA, emphasized the growing frustration with translational research.
The valley has also been the subject of mainstream news articles, such as a 2010 cover story in Newsweek by journalists Mary Carmichael and Sharon Begley (2). In their research, Carmichael and Begley found that from 1996 to 1999, the U.S. Food and Drug Administration (USFDA) approved 157 new drugs. A decade later, from 2006 to 2009, the agency approved only 74 drugs, which did not provide effective treatments for a variety of diseases.
"Frustration is growing with how few seemingly promising discoveries in basic biomedical science lead to something that helps patients, especially in what is supposed to be a golden age of genetics, neuroscience, and biomedical research in general," wrote Carmichael and Begley.
According to Carmichael and Begley, the problem is not so much the pharmaceutical companies’ lack of investment in drug discovery as it is the culture within the NIH, which values basic discoveries over translational research. "If we are serious about rescuing potential new drugs from the valley of death, then academia, NIH, and disease foundations will have to change how they operate."
In response to this growing frustration, NIH director Francis Collins has made it his mission to overhaul the process of translating scientific discoveries into new drugs, diagnostics, and devices through the newly established National Center for Advancing Translational Sciences (NCATS). The center has been billed as the missing link between basic research discoveries and effective treatments and cures for a variety of disease, but can this new center ever really live up to this hype?
Center Established, Hunt Begins
When President Barack Obama signed the 2012 federal spending bill on December 23, 2011, he also formally established NCATS with a budget of $575 million. NCATS opened its doors the very same day.
In all, the bill provides NIH with $30.7 billion in funding, increasing funding for the agency by $299 million over last year. Of this amount, only 2.3% was designated for the new center; the remainder of the center’s funding would come from the incorporation of other NIH programs such as the Therapeutics for Rare and Neglected Diseases and the Clinical and Translational Science Awards. In addition, the spending bill allowed NIH to spend up to $10 million to support the Cures Acceleration Network, which will create new funding mechanisms to expedite the development of "high-need cures."
Until a permanent director can be found, National Institute of Mental Health (NIMH) director Thomas Insel has stepped in as the acting director of the new center. NIH deputy director for science, outreach, and policy Kathy Hudson is serving as NCATS acting deputy director. Meanwhile, Insel and National Human Genome Research Institute director Eric Green are co-chairing the search committee for the permanent director.
NCATS is now one of the 27 institutes and centers of NIH. By law, the NIH is only allowed 27 institutes and centers, so to make room for NCATS, one of the institutes, the National Center for Research Resources (NCRR), was shut down. According to Insel, all of the NCRR functions are being preserved and transferred to other agencies along with most of its employees.
"NCATS will be administering the Clinical and Translational Science Awards, which is of great importance to the academic community, as well as the Related Small Business (SBIR/STTR) grants," says Insel. Other components will be taken over by other NIH branches as well as the NIH Office of the Director.
The assumption is that there are hundreds of potential drug targets or compounds that have been identified but are not being adequately exploited. NCATS would fill this gap by pursuing the leads that drug companies or investors did not feel were worth their time or money. In addition, by bringing together similarly oriented mechanism-based researchers currently separated in the NIH’s disease-specific institutes, NCATS hopes to facilitate the exchange of ideas about common therapeutic approaches for different conditions.
In the end, Insel is confident that NCATS will accomplish its mission. "We only have drugs for only about 250 of the more than 4400 conditions with defined molecular causes. And although many researchers around the world are working hard to figure out how to use advances in molecular understanding of disease to improve human health, there has been no broad and systematic effort aimed at revolutionizing the science of translation."
Many of these thousands of conditions are rare diseases, so pharmaceutical companies have little incentive to follow-up on drug development because the number of potential patients that require treatment is relatively small. As a result, NCATS researchers are already working on several of these rare diseases, including sickle cell anemia and Niemann-Pick disease type C (NPC), a lipid storage disease that associated with mutations in NPC1 and NPC2 genes.
Another area that NCATS will be focusing on is toxicity. Insel notes that animal models are not good at predicting toxicity. "One-third of all drugs are dropped in Phase 2 trials because of toxicity concerns, primarily in the central nervous system or the liver. This is a job that NCATS will be taking leadership in and the pharmaceutical industry is delighted," says Insel.
Misguided Treasure Hunt for Cures?
By and large, Lowe believes that the NIH has given the American public the idea that there are hundreds of drugs waiting to be discovered. "I cannot prove that everyone is trying every single thing that could possibly be tried, but I really don't see how there's this treasure chest of great discoveries that aren't being followed up on. Drug companies of all sizes are always watching for such opportunities," he says.
Similarly, Avorn and Kesselheim also expressed doubts, although they believe it could fill a niche in the development of some antibiotics. "But for treatments for conditions such as common cancers or Alzheimer’s disease, how likely is it that a new NIH center will be able to develop candidate therapies that armies of smart investigators, drug companies, and venture capitalists have all somehow overlooked? It also isn’t clear that a governmental agency will generate more creative decision-making than the time-tested approach of investigator initiated research."
In addition, they raise the concern that government-funded research historically has benefited drug companies and not the American public. For example, even though the NIH provided funding for the initial research, pharmaceutical companies have profited greatly from drugs like AZT, Gleevec, and Taxol. Collins has spoken about the NIH sharing the royalties that flow from successful ventures, but there are no details on how this will take place or if there will be a formal arrangement.
In the end, Kesselheim supports the NCATS mission and hopes the NIH will take a more active role in ensuring that the public benefits from its discoveries. "I believe that we need the government to step in and help spur research into all areas of medicine. But, I also believe that it is important that the public benefit from the results of this research, which historically it has not."
- Avorn, J., and A. S. Kesselheim. 2011. The NIH translational research center might trade public risk for private reward. Nat Med 17(10):1176.
- Carmichael, M. and S. Begley. 2010. Desperately seeking cures: How the road from promising scientific breakthrough to real-world remember has become all but a dead end. Newsweek, May 24, 2010.