NIH's New NCATS: Bridging the Gulf From Bench to Bedside

Abstract

Academia and industry have long been different environments with different values and goals. The National Institutes of Health (NIH) leadership is convinced that it's time the public sector applied some organizational leverage in the underexplored space between those realms. Director Francis S. Collins, MD, PhD, drawing a distinction between “worlds in collision” and “worlds in collusion,”1Collins F.S. FasterCures webinar on NCATS, March 16, 2011.https://fastercures.webex.com/ec0605lc/eventcenter/recording/recordAction.do?theAction=poprecord&actname=%2Feventcenter%2Fframe%2Fg.do&actappname=ec0605lc&renewticket=0&renewticket=0&apiname=lsr.php&entappname=url0107lc&needFilter=false&&isurlact=true&rID=3371042&entactname=%2FnbrRecordingURL.do&rKey=9c65e4b21ac99c88&recordID=3371042&siteurl=fastercures&rnd=5419819809&SP=EC&AT=pb&format=shortGoogle Scholar has launched an experiment with the potential to foster smoother transitions and more productive interdisciplinary partnerships in the tricky areas between basic science and product development. What Dr. Collins calls “a disruptive innovation, but in a good way” involves a new structure, though not a new aim. Translational medicine and therapeutics (TMAT, the term proposed by Garret A. FitzGerald, MD, director of the University of Pennsylvania's Institute for Translational Medicine and Therapeutics, for idea transfer from laboratory studies to clinical trials and product development, also termed T1 translation, or bench-to-bedside research) has been an explicit priority for NIH since Dr. Collins's predecessor, Elias Zerhouni, MD, devised the NIH “roadmap” in 2003, a general rethinking of the clinical research enterprise.2Zerhouni E. The NIH Roadmap.Science. 2003; 302: 63-72https://doi.org/10.1126/science.1091867Crossref PubMed Scopus (779) Google Scholar Several components of NIH are already pursuing TMAT. The National Institute on Allergy and Infectious Diseases and the National Cancer Institute, notes Story C. Landis, PhD, director of the National Institute of Neurological Disorders and Stroke, “have quite robust programs” in this area. The proposal for a new organization to coordinate them, the National Center for Advancing Translational Sciences (NCATS), has attracted attention and commentary in the research community, through NIH's public feedback mechanisms3Collins F.S. et al.NIH feedback: comment on proposed National Center for Advancing Translational Scienceshttp://feedback.nih.gov/index.php/category/ncats/Google Scholar and in the media.4FitzGerald G. Drug development needs a new brand of science.Nature. 2010; 468 (Accessed April 30, 2011): 869https://doi.org/10.1038/468869ahttp://www.nature.com/news/2010/151210/full/468869a.htmlCrossref PubMed Scopus (12) Google Scholar, 5Fox M. US takes step to government drug development center.Reuters. December 7, 2010; (Accessed April 30, 2011)http://www.reuters.com/article/2010/12/07/us-usa-institute-idUSTRE6B66ZG20101207Google Scholar, 6Kaiser J. NIH reorganization draws scrutiny from Congress.Science Insider. January 27, 2011http://news.sciencemag.org/scienceinsider/2011/01/nih-reorganization-draws-scrutiny.htmlGoogle Scholar, 7Philippidis A. Translational research is the NCATS' meow for growing NIH's R&D role.Genetic Engineering and Biotechnology News. April 6, 2011http://www.genengnews.com/keywordsandtools/print/3/22570/Google Scholar Some concerns about NCATS may reflect misinformation about its mission, general organizational neophobia, or beliefs that TMAT is not a proper governmental concern. A theme that's conspicuous by its absence from the discussion, however, is “don't fix what ain't broke.” Observers inside and outside NIH comment that the process of translating drug discovery into drug development in the United States, though far from broke, is very close to broken. The route from academic laboratories to pharmacy shelves is notoriously slow. From basic molecular studies and initial “hits” in high-throughput screening of potentially effective compounds through preclinical and clinical trials to final Food and Drug Administration (FDA) approval for a new drug, the process takes some 10 to 15 years, sometimes longer, depending on who's measuring. Even as the science of identifying disease-related targets has advanced, the process of tailoring molecules to them has grown more specialized and cumbersome, missing opportunities in some areas while overlooking risks in others. Many observers, not limited to frequent critics of industry practices, also see a disjuncture between market incentives and clinical needs, especially in rare or neglected diseases, including those affecting the developing world and disadvantaged populations. More molecules are patented than ever become commercial pharmaceuticals, and the factors determining which ones do (and which ones sit in company freezers, abandoned or understudied, imprisoned within walls of intellectual property rights) are far from rational. It is difficult to argue that the global population needs sildenafil or minoxidil more than it needs new products effective against, say, dengue fever or antimicrobial-resistant Neisseria gonorrhoeae, but the former 2 are blockbusters and the latter do not exist. NIH estimates of the failure rate of new compounds entering clinical testing are in the 90% range; industry estimates are even higher. Annual numbers of applications for new molecular entities are on the decline, despite—or, in some views, because of—expenditures estimated by the Pharmaceutical Research and Manufacturers of America to exceed $1 billion per new drug approved. Even though the FDA's Center for Drug Evaluation and Research began including therapeutic biologics along with new molecular entities in its application counts in 2004, in 2010 that center received only 23 applications, the second-fewest in the past 15 years; the graph of annual applications since 1996 shows a distinctly negative slope.8Food and Drug AdministrationNew molecular entity 2010 statistics.http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/UCM242695.pdfGoogle Scholar Approvals are holding steadier (21 in 2010) but will almost undoubtedly taper off if the application trend continues. In this context, Dr. Collins is acting quickly to institutionalize support for TMAT. According to the NIH Reform Act of 2006, significant structural changes in NIH require deliberation by the Scientific Management Review Board, an interdisciplinary advisory board comprising internal NIH directors and external leaders in medicine, industry, and academic science. Dr. Collins solicited this board's view in May 2010 on how best to advance TMAT; on December 7, NIH announced the board's recommendation that NIH set up a new center rather than incrementally adjust existing entities.9NIH Scientific Management Review BoardReport on Translational Medicine and Therapeutics. December 2010http://smrb.od.nih.gov/documents/reports/TMAT_122010.pdfGoogle Scholar As of October 1, 2011, NIH will include NCATS, dedicated not to a particular disease category but to unclogging the nation's research and development pipeline. The 2006 federal law caps the number of NIH centers and institutes at 27, and NCATS will officially replace the National Center for Research Resources. However, NIH officials say that NCATS is meant to complement and accelerate, not replace, the array of current federal activities promoting translational research. The Clinical and Translational Science Awards, the largest component of National Center for Research Resources, are among the programs expected to move into NCATS, along with the Molecular Libraries Program, Therapeutics for Rare and Neglected Diseases, the Cures Acceleration Network established by the 2010 Affordable Care Act, and others. At this writing, the “straw model” of the center's structure and the reassigned existing programs is still evolving, the search for an NCATS director is under way, and the center will have a dedicated line item in NIH's 2012 budget. Dr. Collins's proposal drew unwanted attention in January after a New York Times article10Harris G. New York Times. January 22, 2011: A1http://www.nytimes.com/2011/01/23/health/policy/23drug.html?_r=1&hp=&pagewanted=allGoogle Scholar described it—inaccurately, both quantitatively and qualitatively, say officials and outside observers—as “a billion-dollar government drug development center.” The first thing one needs to know about NCATS, these sources emphasize, is that it will not be a drug company and will in no way resemble one. Its leaders have no intention of competing with the private sector. Instead, NCATS will work with pharma firms, academic scientists, and nonprofit organizations to overcome obstacles at several points in the process, particularly the preclinical phase known in the field as the Valley of Death, where promising compounds often end up in limbo. Potential treatments get stuck in and around the Valley of Death for numerous reasons. “Probably the biggest one,” says Thomas R. Insel, MD, director of the National Institute of Mental Health and a member of the directors' NCATS Working Group, “is that we haven't had very good tools for screening chemical space to come up with highly specific and safe compounds. One of the things that we've been trying to do with this Molecular Libraries Program is to empower the academic community to get involved in this process. Up until very recently, this was the exclusive domain of industry, which is fine, but industry, of course, is not going to be particularly interested in rare and neglected diseases, or diseases in which there may not be much of a market, like orphan indications. Those are areas that NIH really does have a public mandate to address.” Though NCATS is not the first organizational remedy for the Valley of Death, insiders believe it has a chance of improving on past approaches, in part by connecting and centralizing them, in part by “derisking” steps that some companies have shied away from. “A lot of what's in NCATS already exists,” says Dr. Insel, “but what is exciting about it is it's bringing it all together into one home.” Psychiatry is one of the fields in which the existing pipeline has been particularly frustrating, he says, emphasizing lucrative variations on old themes rather than new approaches to the major therapeutic categories (antidepressants and antipsychotics) or promising treatments for other conditions. “The sad fact is there really has been very little innovation, that is, no really new molecular entities … for psychosis or depression in terms of their mechanism of action for about 3 decades,” Dr. Insel continues. “There are many compounds that have been marketed; they're basically me-too drugs based on the same pharmacology we had in the 1970s. What is intriguing to us is this opportunity to get the academic community focused on developing the next generation of compounds.” Rajesh Ranganathan, PhD, senior advisor to Dr. Collins and former head of the education office at Novartis Institutes for Biomedical Research, elaborates on scenarios in which studies overlook potentially useful applications for reasons of methodology and scale. “The problem is that [for] any given entity,” he says, “a particular company is not incentivized to tinker with the process itself to make it better for themselves, as well as for the rest of the industry. They tend to focus on what's required of them to get through the hurdles placed upon them by regulatory authorities.” In preclinical toxicology studies, he observes, “the rule of law is that you need to [test compounds in] 2 animal species, and if they're clean in both of those species, you can proceed … to the human setting. But we know, when we do that, that in certain organ systems—for example, the liver and the kidney—the predictive ability of those animal models is very poor. It's in fact less than 50% in some cases. You would be better off making a decision based on a coin flip than actually doing the experiment.” When the screening process yields nearly random results, he adds, “many drugs are getting thrown out for the wrong reasons, because it works in the reverse way as well: if it's 50% nonpredictive, presumably ones that are showing signals may well turn out not to have signals. But we never find out about them, because the company never takes that forward, and the regulators would not allow it.” More sophisticated toxicologic approaches, he speculates, might “use human stem cells to develop better organ models in tissue culture … . [I]t would still not be the same as providing it to the whole human body, but nevertheless it might be a better approximation than measuring something in a rat liver or a mouse brain.” Though a single company would be unlikely to develop more predictive models, they are something that “we as an intermediary, a neutral arbiter, might be able to achieve at the NIH.” “The entire industry is stuck in a certain mode” in screening, Dr. Ranganathan adds. “It does as many compounds as possible at 1 dose, but we know from biological studies in complex systems that often you can miss the effect of a compound in a particular dose, even if it's the highest dose possible … . [T]he actual beneficial or efficacious dose was perhaps at a lower dose. We would advocate experimenting with doing dose-responses right from the beginning.” By supporting both research and communication in what Dr. Insel and others call “precompetitive space,” acting as (among other things) an information clearinghouse to overcome siloing problems with entities holding patents to compounds, NCATS may be able to help realign incentives and remove obstructions. Dr. Ranganathan notes that the FDA has extensive records of “every trial that has come to them that has either failed or succeeded” but cannot release these data; they are the sponsors' property, whether a sponsor continues to work with a compound or not. “But if we're able to figure out a way to actually share those data, sufficiently blinded, so that we can understand that if we are testing a particular class of G-protein-coupled receptors, we consistently come upon liver toxicity, wouldn't that be interesting information for us to be able to then use to avoid those, or mitigate those, going forward in drug development?” Another area of interest, Dr. Ranganathan observes, is compounds with effects in different clinical realms, some of which the patent holder may or may not define as part of its portfolio; if not for proprietary barriers, a different firm might show interest in these approaches. “If a company's invested money in developing something which turned out not to be useful for the original purpose,” speculates Dr. Landis, “but based on genetic analysis or systems biology analyses appears to be useful for a different purpose, I would think that the companies would be quite interested in having some return on that initial investment.” Leaders from pharma, NIH, and nonprofits met on April 21 to 22 for an industry roundtable on ways to rescue or repurpose underexplored compounds. The meeting was not public, but participants, including Dr. Ranganathan and executive director Margaret A. Anderson, MA, of FasterCures, the Milken Institute's nonprofit group advocating research reform, describe it as productive. The discussions, Ms. Anderson said, showed “a real willingness on the part of industry to do this collaboration, to say ‘we don’t have all the answers.'” “What we're trying to do,” says Dr. Ranganathan, “is get [companies] to the table to say, ‘Well, what protections would we need to put in place for you to feel comfortable to hand over your 20 compounds that you feel we could test in a variety of systems?'” The risk that companies would provide only their least promising candidates is counterbalanced by the knowledge of their erratic track record in picking winners. In the event a previously ignored compound finds an application, NCATS would broker licensing arrangements that, in Dr. Insel's terms, “create shared intellectual property so that it will be easier for academic investigators and pharmaceutical companies to work together.” A possibly useful analogue for the concept of precompetitive space, Dr. Insel says, would be open-source coding standards that allow software developers to build modularity and connectivity into their products. “This is something that we would make freely available for people to innovate with, because it's in everybody's interest, just as it is with information technology, for innovation to flourish.” “The status quo is not working for anybody,” Dr. Insel continues. “If we could all work together here, and just take intellectual property off the table for now, could we come up with something that would have greater value?” Dr. Collins and Dr. Ranganathan are preparing a white paper on these and other concerns that NCATS aims to address. An interdisciplinary NCATS Working Group chaired by Lasker Foundation President Maria C. Freire, PhD, is identifying specific activity areas, technical challenges, and potential partnerships with private-sector entities, including venture funders. With the center's opening a few months away, its leaders envision multiple metrics for its achievements. The benchmarks at this early stage are qualitative. “If we choose to measure success the same way pharmaceutical companies measure success,” Dr. Ranganathan observes, “then I think we are in trouble.” If NCATS researchers develop new approaches to toxicology that gain adoption by pharma firms, he says, “I would call that an enormous success.” Another goal would involve NIH's sister agency: “To the extent that an FDA regulation based on regulatory science that we do jointly with them is modified to support the registration of drugs, I would call this a phenomenal success.” Training investigators in TMAT and establishing the field as a magnet for top talent would enhance the center's primary activities over the long run. The focus will initially be on small-molecule therapeutic development, Dr. Insel says, but he expects NCATS eventually to expand into diagnostics, devices, and biomarkers as well. “At the end of the day here,” says Dr. Insel, “what you're going to be looking for would be products, not simply papers, and that's one of the things that makes NCATS a little bit different” from other NIH centers. Beyond the patient-oriented T1 category of research, Dr. Ranganathan adds, NCATS will also look at the T2 space comprising comparative effectiveness studies and natural history studies, perhaps even large-scale longitudinal projects on the Framingham model. Some of the Clinical and Translational Science Awards, Dr. Insel reports, are also working in the T3 and T4 areas involving bedside-to-community practices, outcomes, guidelines, and policy implications. These stages commonly overlap because the T1 to T4 continuum is parsed differently in different academic translational centers,11Woolf S.H. The meaning of translational research and why it matters.JAMA. 2008; 299 (Accessed May 1, 2011): 211-213http://jama.ama-assn.org/content/299/2/211.fullCrossref PubMed Scopus (1272) Google Scholar, 12Selker H.P. Beyond translational research from T1 to T4: beyond “separate but equal” to integration (Ti).Clin Transl Sci. 2010; 3: 270-271Crossref PubMed Scopus (11) Google Scholar but their recognition implies an integrative research model incorporating feedback loops rather than linearity and fragmentation. Another unique feature, Dr. Ranganathan mentions, is that NCATS's funding mechanisms will benefit from the “other transactions authority” specified in the legislation creating one of its components, Cures Acceleration Network. This allocates 20% of the appropriated funds for flexibly financed projects, more akin to the streamlined procedures of the Defense Advanced Research Projects Agency than NIH's customary open-ended 5-year R01 grants. The scale of the 2012 appropriation will naturally be far smaller than Defense Advanced Research Projects Agency's, and under current congressional conditions no one within NIH expects budget increases. To date, no new money has gone into NCATS; its programs rely on preexisting funding. The initial Cures Acceleration Network authorization totaled $500 million (allowing $100 million for “other transactions”), but President Obama's 2012 Cures Acceleration Network request was reduced to $100 million total. Budgetary vulnerability, as in any other NIH program, is a serious concern for Dr. Collins's team. One of the reasons for reorganizing components such as the Molecular Libraries Program into NCATS (and out of its current administrative home, NIH's Common Fund or “incubator space”), Dr. Insel notes, is to ensure that even with relatively small appropriations, such efforts are perceived as long-term commitments rather than pilot studies and protected accordingly. A recurrent objection some researchers have raised over the NCATS proposal charges is that it may divert funds away from basic research. This concern implicitly links competition for federal dollars with a broader philosophic issue. The model for biomedical research and development in the United States has long depended on a public/private balance: public support for basic research, largely funded by the NIH and conducted at academic institutions, followed by technology transfer to private firms for development of findings into applications, funded through market mechanisms. This paradigm, as outlined by Vannevar Bush in the 1945 presidential report Science: the Endless Frontier,13Bush V. Science: The Endless Frontier. A report to the president by Vannevar Bush, director of the Office of Scientific Research and Development, July 1945. US Government Printing Office, Washington, DC1945Google Scholar has been enormously productive over the years on the biomedical front and others; because its basic and applied components are interdependent, few would suggest substantively disturbing it, though the iterations of it supported by NCATS may incorporate more orientation toward defined outcomes. “My sense is that NCATS does not propose to change the paradigm for public support of basic research as the driver of innovation,” says Dr. Freire. “NIH's commitment to funding of basic research remains unwavering.” Some academic researchers appear apprehensive that NCATS might represent, if not a paradigm shift, some form of paradigm slippage. However, “we cannot expect to have science and medicine advance at the pace that you and I would like if we have this great divide between academia and pharma,” says E. Albert Reece, MD, PhD, MBA, dean of the School of Medicine at the University of Maryland. “I believe that [Dr. Collins] and his team are mindful of the concerns that basic scientists have. I've said publicly, and I have no reason to doubt them, that they will be very careful in how they allocate funds and make every effort not to shift funding away from the basic science. I would be the one who would be very concerned; I would certainly speak up if I sensed that that was happening.” “Everything is incentive based,” Dr. Reece continues. The coming falloff in funding and hiring, after a period when Recovery Act stimulus funding provided “a huge shot in the arm for research,” is likely to exacerbate competition and tensions within the scientific workforce. Accelerating the pipeline requires a balance of the different capabilities and incentives of academic and commercial groups. The goal of NCATS is “not to replace pharma, because they have some unique elements that academia doesn't have, from their medicinal chemistry to their infrastructure support; that is not what academia has, nor what academia should have.” The best early outcome for NCATS, Dr. Reece and others believe, attracting both political support and buy-in by multiple sectors, would be a few quick wins in visible, high-impact clinical areas. Fields of special promise, he says, include interventions in cancer, hypertension and stroke, and trauma (particularly brain injury and spinal cord injury, the subject of an FDA-approved trial of stem cell treatments beginning at his institution and others), plus Dr. Collins's own specialty, personalized medicine or pharmacogenomics. As a work in progress on a fast timetable, Dr. Landis suggests, NCATS is preparing to deal flexibly with various uncertainties surrounding the field. Self-evaluation and improvisation will be critical. “One of the most important things with this reorganization,” she says, “the dissolution of National Center for Research Resources and the creation of NCATS, will be to make sure that in a year we look and see,” among programs moved from National Center for Research Resources to NCATS and other centers, “how are those working? And to tweak the programs and this new center. I think Dr. Collins was more interested in getting this started up than in having it be perfect to begin with, and that just to create the center was in and of itself an important step forward.” Engaging in both research support and negotiations with potential partners, NCATS may be able to uncover information clarifying little-known aspects of the business of pharmaceuticals, as well as the biochemistry. Dr. Landis notes that cost estimates for drug development are matters of dispute: “A lot of the money that's attributed to moving something through the Valley of Death actually is kind of funny money, in that the pharmaceutical companies take into account [forgone opportunity costs] if they had invested that money in the stock market. The way that calculation is done is unusual.” It is conceivable that NCATS will generate revisions of these estimates and of the public and private partners' different views of information transparency. Marcia Angell, MD, senior lecturer in global health and social medicine at Harvard Medical School's Division of Medical Ethics, editor-in-chief emerita of the New England Journal of Medicine, and author of The Truth About the Drug Companies,14Angell M. The Truth About the Drug Companies: How They Deceive Us and What to Do About It. Random House, New York, NY2005Google Scholar views the new center with guarded circumspection. “My opinion on NCATS depends on whether discoveries would be licensed exclusively to drug companies who would be allowed to charge whatever the market will bear for the drugs,” she says. “That is what happens now, and it means that the public pays twice—once for the research and again at the pharmacy. Drug companies have not bothered to do their own innovative research for some time now.” Around the handoff stage, it will thus be important to structure contracts so that private firms are motivated to develop products according to work performed under the NCATS aegis while protecting the interests of the public sector on the grounds that when taxpayer-supported scientists have laid the foundation for an advance, the taxpayer shouldn't cede all of the rewards. FasterCures's Ms. Anderson refers to this principle as a “confluence of interest,” rather than a conflict of interest. NCATS's public-private partnerships will likely be matters of negotiation and calibration, not all-or-nothing claims of exclusive rights. As an example of what well timed public sector involvement can accomplish, Ms. Anderson cites a recent TMAT success story in which the Therapeutics for Rare and Neglected Diseases program rescued an innovative but underfunded oral treatment for sickle cell disease, 5-hydroxymethyl-2-furfural, or Aes-103 (discovered by researchers at Virginia Commonwealth University and developed by a small Boston-area firm, AesRx), by providing orphan-drug funding at a stage when venture capital was unready to step in. Instead of languishing in the Valley of Death, Aes-103 begins phase 1 clinical trials this summer. From her ongoing discussions with officials, venture philanthropists, disease-specific advocates, and corporate representatives, Ms. Anderson views NCATS not as a cause for complaint but as a fait accompli. “I really think the conversation's shifted off of ‘money’s going to get shifted out of basic science into this effort' and onto ‘OK, let's roll up our sleeves; what needs to get done?'” But even NCATS's own planners struggle to find appropriate comparisons for the new center. Dr. Insel finds open-source standards organizations a useful metaphor; Dr. Freire speaks of NCATS in chemical terms, exerting a “catalytic role.” Dr. Ranganathan suggests analogies to the Singaporean Biopolis research cluster and the Innovative Medicines Initiative, a partnership launched in 2007 between the European Union and the European Federation of Pharmaceutical Industries and Associations—preferably without what he calls the “staggering level of bureaucracy generated to get this behemoth moving,” with participation by 26 member nations—as well as to Defense Advanced Research Projects Agency, the military research incubator whose projects have generated influential civilian applications as well, including the Internet's precursor ARPANET, the monitor/keyboard/mouse computer interface, and the global positioning system. As transformative federal initiatives go, the latter is among the more persuasive models. Perhaps NCATS also bears resemblances to another controversial effort to link entities that have long suffered from disconnection. In the transportation sector, the president has backed long-delayed efforts to invest in a high-speed rail system that would expand travel mode options, unburden both the airlines and the highways, and improve the nation's overall performance in both energy efficiency and environmental effects. Even more so than in the research sector, such an infrastructural innovation would produce positive network effects, increasing in value the more connections it creates. To date, however, the rail initiative has faced entrenched political opposition from interests that benefit from the status quo while shifting burdens to other parties. Though comparable opposition to NCATS has not emerged to date, the new center has comparable potential to redirect flows of resources and information, producing surprising change in complex processes that nearly all participants, observers, and potential partners would agree are bogged down.