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BIOMEDICAL INNOVATION

Looking for Cures Lost in Translation

New NIH Center Will Peer Into the Commercialization Valley of Death

SOURCE: AP Photo/Wong Maye-E, File A lab officer cuts a DNA fragment under UV light for DNA sequencing as part of research to determine genetic mutation in a blood cancer patient.

In a recent article in Slate magazine’s Future Tense project,  Pascal Zachary made a key observation about the strange estrangement of science from technology in U.S. policy when he wrote:

Neither candidate will ask, for instance, why taxpayers spend some $30 billion annually to try to understand the basic causes of diseases but virtually nothing on delivering effective new medical therapies to the ill.

Indeed, over the past 10 years, $340 billion in federal funds have been allocated for basic medical research to improve and lengthen the lives of Americans. But how much money does the government spend actually translating medical science discoveries into workable therapies? Surprisingly little.

While it is unlikely that the top presidential contenders will agree to a prime time debate on the gaps in our national investments in translating research into useful products and technologies, there have been some encouraging developments happening backstage. One key example is the brand new National Center for Advancing Translational Sciences, or NCATS.

A new center for translational science

While the NIH—through programs such as the Small Business Innovation Research Program, or SBIR, and the Clinical and Translational Science Awards, or CTSA—has apportioned money for translational medicine, most of the funding for the translational side has been supplied by the private sector. Pharmaceutical firms have invested $460 billion in R&D to invent drugs in the last decade, and have still struggled to convert basic advances or their own basic research and drug development into approved drugs.

According to the think tank Faster Cures, “The medical research enterprise is facing a serious productivity gap. The amount of money invested by all sources—government, industry, philanthropy—has been increasing while the number of new products approved is decreasing or stagnant.” In a glass-half-full statement, the NIH stated, “The process for translating scientific discoveries into new tools and treatments is ripe for innovation.”

President Barack Obama and NIH director Francis Collins have sought to make delivering research to the public a central priority and to tackle the productivity gap by establishing the National Center for Advancing Translational Sciences, or NCATS. Congress approved the center in the beginning of fiscal year 2012.

Some have expressed reservations about NCATS narrow focus on translational medicine (that is, the process of transferring discoveries from the lab to the marketplace). Mark O. Lively, a professor of biochemistry at Wake Forest University and a member of an advisory council to the research resources center, said, “NIH is not likely to be very good at drug discovery, so why are they doing this?”

However, NCATS hopes that by focusing research on translational technologies and high-margin research projects, the new agency can help attract industry and private investment to new areas of drug development. NCATS may also make progress by taking a second look at regulatory and other barriers that lead to long approval processes.

Drug development 101

Understanding the complexity of the new drug-creation innovation process allows better comprehension of the challenges facing NCATS and better comprehension of problems in the academic publishing incentive structure.

Innovation in therapeutics can be described in three stages: basic, translational, and clinical. Basic research is entirely focused on advancing science for science’s sake. Translational begins to apply basic advances to how to solve human diseases. And clinical begins the stage of testing and refining drugs.

Discovering a compound through basic research and then putting that drug through trials is a complicated process. Of 5,000 compounds discovered and screened, five might make it to clinical trials and one might then make it all the way through to the market. Drugs must go through three phases of clinical trials before they are approved. The process is enormously expensive. “As ideas survive the steps in the process, they become relatively less risky, but the research involved in moving them forward becomes exponentially more expensive, especially in later-stage trials in humans.”

In total, the Pharmaceutical Manufacturers of America estimate the cost to be about $1.2 billion per drug. Matthew Herper of Forbes reveals that, when one accounts for failed attempts to develop a drug, the cost to develop a single drug is staggering. Incorporating the cost of failure (total R&D divided by number of drugs), the cost per drug is over $4 billion.

The private sector

The high expense of developing new drugs discourages most private-sector actors from investing directly in R&D of new therapies. And private R&D may be slowing down. Private pharmaceutical companies reduced their R&D budgets by $2 billion from 2009 to 2010, and Reuters argued this trend will continue.

Part of the problem is that U.S. pharmaceutical companies are staying in business through mergers and buying up smaller companies that have taken on risky drug development rather than investing in research directly. To quote The Atlantic:

The industry is fleeing its R&D roots and focusing more and more on mergers, and on flogging drugs and devices that have already been approved. By some estimates, current pharma sales and marketing budgets are already twice those of R&D.

What’s more, the private sector is neglecting major areas of medicine. For instance, the entire field of mental health has only seen two major drugs in the past century—nearly every other drug has been a variation.

NCATS to the rescue?

NCATS is a reorganized, beefed-up version of the NIH’s previous avenues for funding translational medicine. In the words of former acting director of NCATS, Thomas Insel, “The most striking thing is how little is going to change. It’s essentially reorganization.”

Previously, the NIH spent $487 million to fund 60 research centers through the Clinical and Translational Science Awards, which was housed under the National Center for Research Resources, or NCRR. NCRR had a FY 2011 budget of $1.27 billion, but as of FY 2012 it has been dissolved, with the remaining budget parceled out to other agencies. NCATS will assume control of the 60 centers and this funding authority.

The two main focuses of the Center will be to centralize and advance translational medicine and to streamline the drug approval process. NIH Director Francis Collins hopes that NCATS will organize the translational research work of the NIH such that it is more productive and that it is easier for the private sector to pick up high-potential translational advances and move them into clinical stages.

Examples of NCATS programs:

Tissue chip for drug screening: NCATS will help the NIH partner with the Defense Advanced Research Projects Agency, or DARPA, and the Food and Drug Administration, or FDA, to develop “tissue chip” technology. Tissue chips use real human cells combined with a transparent microchip to simulate organ responses to drug candidates. The hope is that this technology streamlines the screening process by eliminating toxic chemicals before getting to human trials. This groundbreaking effort is also notable because it unites three different agencies with the common goal of developing a technology that will reduce barriers for the whole drug development process. The project has been allotted $70 million over the next five years.

Discovering new therapeutic uses for existing molecules: This program partners industry and NIH researchers to reexamine molecules that have already shown promise, but were not advanced because they were “unsuccessful in their original therapeutic indication” or did not make economic sense to continue with. So far, eight companies have volunteered 60 compounds. Each stands to profit if a method of bringing compounds to clinical studies is discovered. This program also includes an innovative bureaucratic shortcut called the Template Agreement.

The Cures Acceleration Network or CAN, is one way NCATS is reorganizing translational research at the NIH. Through CAN, NCATS will have the ability to make grants of up to $15 million per fiscal year to fund partnerships with the private sector, following a 1:3 funding ratio requirement.  Partnerships will focus on “improving the process by which diagnostics and therapeutics are developed.”  For example, funding could be allotted for the rescue and repurposing of drugs that failed during clinical trials.

Comparing commercialization investments

NCATS represents a sizeable commitment to translational research and symbolizes the NIH’s renewed commitment to translational advances. The new agency controls $88 million in addition to the CTSA’s funding of $488 million. What’s more, even though NCATS accounts for just 2 percent of the NIH budget, it compares to other large investments made by government agencies to convert basic research into applications.

For instance, NCATS is twice as large as the DOE’s Advanced Research Projects Agency–Energy, the DOE’s newest translational research program, which received $275 million for FY 2012. The Technology Innovation Program operated by the National Institute of Standards and Technology was appropriated just $65.2 million in FY 2011, but will shut down next year. NCATS is small only in comparison to the Small Business Innovation Research grant program, which spans multiple government agencies, and has a combined budget of over $2.2 billion. Thus, within the scheme of federal funding of commercialization activity, NCATS represents substantial and renewed investment in translation of medical cures to the market.

But although NCATS has a budget of hundreds of millions, this sum of money is still small compared to the amount necessary to produce a single drug.

NCATS’s best vantage point may come from being a center with immense insight into the translational process itself. Through its funding of 60 research institutes and its attempts to woo private-sector investment, NCATS could help fund the development of new processes and platforms that accelerate the innovation process itself–and that’s the goal. As former acting director Insel said:

We need a place to actually look at the whole process of translation in a way that can consider how it might be reengineered, consider how we can make a difference by partnering with both advocacy groups and with industry. Consider where the opportunities are for great innovation that are not just related to schizophrenia or autism or bipolar illness but that are really generic. They go across all of medicine.

For instance, in one suggestion provided by Faster Cures, NCATS could use its flexible granting mechanisms to evaluate reforming the academic grant system to shift its focus away from research on incremental advances to rewarding risk taking and divergent experimentation.

NCATS’ first steps are encouraging. By researching more efficient technologies to test basic advances and by critically reexamining downstream components of the drug-development process, NCATS has a chance to chip away at the bottlenecks and help find cures lost in translation.

Sam Finegold is a rising sophomore at Harvard College and a member of the American Progress intern class of 2012.

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