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National prescription for drug development

Vowing to reengineer drug discovery, NIH bets big with a new translational research center. Meredith Wadman reports.

Even as extramural centers see their funding evaporate, these robots at the National Center for Advancing Translational Sciences (NCATS) will remain available to screen potential probes as part of the Molecular Libraries Program.

When President Barack Obama sent his 2013 budget proposal to Capitol Hill in February, only one division of the National Institutes of Health (NIH) was nominated for anything but an all-but-flat budget: the National Center for Advancing Translational Sciences (NCATS), for which Obama requested an 11%, $64-million increase, to $639 million. The center, which has become the defining priority of NIH director Francis Collins, is a hugely ambitious effort to streamline drug discovery, speeding therapeutics, diagnostics and devices to the clinic by attacking and eliminating obstacles that have flummoxed the multibillion-dollar pharmaceutical industry.

That the center proposes to do this, beginning with a budget of $575 million this year, is seen as hubris by some critics and naïveté by others. At that level of funding, “it's difficult for many of us to see how NIH can make an impact” on the huge and thorny problems that are stumping the combined brains of the industry, says Mark Lively, a professor of biochemistry at Wake Forest University Baptist Medical Center in Winston-Salem, North Carolina.

But the center also has a devoted fan base. “NCATS is the right thing to do at the right time,” says Margaret Anderson, the executive director of FasterCures, a not-for-profit center of the Milken Institute, an economic policy think tank in Washington, DC. “I believe that this will be Dr. Collins' signal achievement.”

Is consolidation the answer?

Part of what makes sense to Anderson about NCATS is that it comprises, almost entirely, preexisting NIH programs that are now being brought together under one roof—from rare disease research to efforts to 'repurpose' drugs discarded by industry. Eighty percent of the new center is composed of the Clinical and Translational Science Awards, a six-year-old program that now supports 60 translational medicine centers nationwide at a cost, in 2012, of $487 million. NCATS houses most of the program's budget (Fig. 1).

Figure 1

NCATS components in FY 2013 budget ($ millions).

The logic behind putting all of this in NCATS—that, with all the pieces housed together, the whole will be greater than the sum of the separate parts—is part of what has animated Collins' determination to establish the center. But his quest was also driven by an urgency that the former head of the Human Genome Project is perhaps uniquely poised to feel: the ultimate mission of his agency, after all, is to reduce the burdens of human illness. “Patients suffering from debilitating and life-threatening diseases do not have the luxury to wait the 13 years it currently takes to translate new scientific discoveries into treatments,” Collins said on the late December day that President Obama signed the new center into law.

That was exactly one year after Collins' plans to establish NCATS first became known to the public. This is warp speed, in the government world, and has caused angst on the NIH campus, where the $1.3 billion National Center for Research Resources (NCRR) was dissolved and its component pieces parceled out to other NIH institutes and centers as part of the reorganization.

“My main concern is that, in a time of scarce resources, NIH should really be focusing on its nest egg, which is the development and discovery of basic knowledge,” says Lively, who served on the external advisory council of the now-defunct NCRR.

Making the case to a skeptical industry

The new center has also raised eyebrows in industry. Given the chance to be NIH director “I probably would not have started NCATS,” former Merck CEO Roy Vageols told a Congressional subcommittee last month. “Does anyone in the audience believe that there is something that NCATS is going to do that the industry thinks is critical and that they are not doing? That is incredible to think that. If you believe that you believe in fairies.”

NIH leaders say that Vagelos and other critics have fundamentally misunderstood their intentions. They argue that the center is being created from existing programs, not by raiding basic science accounts. Asked the day after Obama's 2013 budget was released whether that message is consistent with the president's request to boost the budget of the translational center alone among NIH institutes, Collins said, “One shouldn't put too much on that, in terms of emphasis shifting from basic to translational in a big way. That's a small number compared to the overall $31-billion” NIH budget.

Neuroscientist Thomas Insel, who directs the National Institute of Mental Health and is serving as acting director of NCATS during the search for a permanent director, says that the center's goal is not to have “products instead of papers,” but to reengineer the processes that will speed therapies to the bedside. Like others in industry and academia, “People in the biotechnology sector right now are often really stuck, and not able to figure out how to do translation cheaper, faster and better than the way it has been done in the past,” he says. “What NCATS hopes to do is to provide some tools and some experiments on the process of translation—tools and experiments that could help all of us.”

In March, for instance, NCATS announced a new collaboration with drug maker Eli Lilly of Indianapolis. It will apply state-of-the-art Lilly assays designed to reveal new mechanisms and pathways to some 3,800 medicines—some of them investigational, some already approved—in what is called the NCATS Pharmaceutical Collection.

Insel also points to a drug-repurposing program that NIH launched last year, with the goal of establishing a “virtual medicine cabinet” of compounds abandoned by industry. The translational center is working to establish a “master agreement” that would allow applicants, including biotech companies, to use shelved drugs for new purposes and is providing the resources and experts to systematically troll through the compounds for new uses against new targets. NCATS makes the perfect institutional home for such an effort, Insel says. “I don't want to see NIH do that 27 different ways for 27 different institutes.”

Others with industry experience say that the NIH initiative is on the mark, with therapeutic pipelines languishing despite the tidal wave of information that has flowed from the decoding of the human genome and attendant technological advances. “The old way of thinking was: if you do great science, the therapies will just follow from that. It's really not that simple,” says Jeffrey Conn, who headed neuroscience drug discovery at Merck's campus in West Point, Pennsylvania, before moving to Nashville, Tennessee, where he is co-director of the Vanderbilt Center for Neuroscience Drug Discovery. “I'm really thrilled that the NIH understands that translation has to be deliberate. It can't be left to chance.”

By late January this year, with the 105-employee NCATS up and running, James Greenwood, president and CEO of the Biotechnology Industry Organization (BIO; Washington, DC), was sounding a cautiously optimistic note. The new center “is potentially a good thing,” he said during a January 23 telephone conference with reporters. His group suggested to Collins “that rather than thinking of this as a model where NIH would develop a drug from beginning to end, what would be particularly useful would be to do science that would raise all boats.”

That, says NIH, is precisely what it intends to do.

And indeed, NCATS is forbidden by the legal language that established it from funding late-stage clinical trials. The law further instructs the new center to avoid “duplication, redundancy and competition with industry activities.”

The breakdown

Here, in order of magnitude, are some of the programs within the new center that may be of interest to biotechs hoping to benefit from NIH's ambition.

Clinical and Translational Science Awards (CTSA; $461 million, or 80%, of NCATS' budget in 2012). These multimillion-dollar awards were administered by the NCRR. With mandates that include community engagement, training and comparative effectiveness research as well as translational activities, their mission does not entirely overlap with that of the new center. And indeed, at NCATS, their emphasis may shift: in a report accompanying the law that created NCATS, Congress instructed NIH to enlist the Institute of Medicine of the National Academy of Sciences to review the CTSA mission in light of its new institutional home.

“We're beginning to call this CTSA 2.0,” says Insel, who adds that a key goal for the coming months is to improve inter-CTSA collaboration in order to create “a national network that can allow us to move [clinical] trials much more quickly than we have in the past.”

The CTSA centers, says Insel, “will be evolving to do some new and exciting things. We expect that one of these will be working with partners in industry to broaden their efforts—not only for therapeutics but for biomarkers, diagnostics and devices—the whole range of what's needed for translational science.”

Several CTSA initiatives are already connecting industry and academic partners. The Indiana Clinical and Translational Sciences Institute administers the matchmaking website i2iConnect, for “bridging inventors and industry” ( The CTSA program as a whole maintains a website listing publically available licensing opportunities from all its centers ( And the CTSA Pharmaceutical Assets Portal ( allows scientists seeking to repurpose 'shelved' drugs to directly ask for them from participating companies. In turn, the companies can seek academic collaborators for repurposing such drugs.

But while CTSA mandates are under assessment, there is discernible angst among CTSA principal investigators, as they compete for the highly competitive five-year grants, about how they are going to be asked to change. “This will be a tough and very competitive process,” confirms Josephine Briggs, the acting director of the NCATS division that oversees the CTSA. “We will be asking the sites to tell us how they are going to reengineer human subjects' research.”

Components of the Molecular Libraries Program ($24.4 million funded from the Office of the Director in 2012). Central NIH funding for the eight extramural centers supported by this $92-million program is due to be phased out by 2014. However, an intramural center, the NIH Chemical Genomics Center, will remain active as part of NCATS, and will serve both NIH and extramural investigators with assay development, high-throughput screening and medicinal chemistry, drawing on an annotated library of over 380,000 compounds (Box 1 and Table 1).

Table 1 MLP funding

Therapeutics for Rare and Neglected Diseases (TRND; $24 million in 2012). This three-year-old effort to attack diseases that don't commonly draw industry money provides in-kind support (administrative work or reimbursement for completed work) to biopharmaceutical companies, patient advocacy groups and academics. TRND focuses on drug candidate optimization and preclinical development, as well as research aimed at improving drug development itself. Depending on the situation, TRND support—for instance, helping companies get access to high-throughput screening, medicinal chemistry and toxicology—can continue into first-in-human trials. It is stopped once a project can attract outside support, or if it fails to meet predetermined milestones.

The TRND program is supporting projects that include work on a schistosomiasis drug by Concert Pharmaceuticals of Lexington, Massachusetts; a therapy for creatine transporter deficiency being developed by Lumos Pharma of Austin, Texas; and an exon-skipping drug to treat a genetic subset of patients with a specific mutation causing Duchene muscular dystrophy, a program of AVI BioPharma in Bothell, Washington.

Chris Garabedian, the company's president and CEO, says that TRND support is saving the company “a few million dollars” and allowing them to pursue accelerated development of a candidate that otherwise would have had to wait. It is “a tremendous benefit to the researchers, the industry and, ultimately, the patients,” he says.

Cures Acceleration Network (CAN; $10 million in 2012). In late 2009, then-Pennsylvania senator Arlen Specter wrote a new, $500-million program into the bill that would become the Affordable Care Act. It described a program that would dish out one-year grants of $15 million—with potential for renewal—to companies and other applicants working to develop any therapy that the NIH director deemed to be a “high-need cure.” There was only one string attached. Such a drug, device or biologic had to be one whose development was unlikely to occur otherwise, because of the lack of commercial incentives.

These would be no typical grants. For one thing, they would require most recipients to match every federal dollar with 33 cents of their own. In addition, the NIH director could apply something called “flexible research authority” to 20% of the money—legal parlance for power granted to NIH to, among other things, issue such grants in a hurry, and, similarly, to stop them on a dime if they are failing to deliver. The law also requires NIH to ensure that communication between awardees and the Food and Drug Administration happens early and often.

By early 2011, it was clear that fiscal pressures would prevent Congress from actually funding the program for anything like $500 million. Congress delivered just $10 million for the program in 2012, although in February, Obama asked them to raise that funding to $50 million next year. For now, the $10 million, Insel admits, “is at most, an admission ticket.”

Biotech companies are keen on the CAN idea, but disappointed at the amount of funding. “I love the proposal,” says Rachel King, the CEO at GlycoMimetics in Gaithersburg, Maryland, and a member of the Emerging Companies Section Governing Board at BIO. “But we need to get this meaningfully funded.”

Paul Hastings, the president and CEO of OncoMed Pharmaceuticals, in Redwood City, California, says that CAN grants, if they are ever awarded, would allow biotechs to fund projects that can't begin to be approached with the mainstay government grant available to companies like his, the Small Business Innovation and Research grants, which top out at $1 million. “With $15 million we could take a preclinical candidate and probably get it through phase two,” says Hastings, who, like King, is a member of the BIO board section on emerging companies.

Whether, and when, NCATS will receive the resources to fund CAN grants is entirely in the hands of Congress. In the meantime, center officials are taking the first, necessary steps to make that happen—establishing a 24-member board to oversee CAN. As stipulated in the law, that board will include at least one biopharmaceutical company representative, at least four venture capitalists and at least eight members of disease advocacy groups.

There is also “active discussion,” says Christopher Austin, the director of NCATS' Division of Preclinical Innovation, on whether to use a chunk of the $10 million on a project “so cool that Congress will say, 'Here's another $100 million'.”


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Wadman, M. National prescription for drug development. Nat Biotechnol 30, 309–312 (2012).

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