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# NCATS Purrs: Emerging Signs of Form and Function

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Science Translational Medicine  18 May 2011:
Vol. 3, Issue 83, pp. 83ed2
DOI: 10.1126/scitranslmed.3002232

Sometimes the questions are complicated and the answers are simple.

—Dr. Seuss, author of The Cat in the Hat

It is 5 months since Francis Collins, the director of the U.S. National Institutes of Health (NIH), first announced his proposal to found a new National Center for Advancing Translational Science (NCATS). The proposal, currently being considered by Congress, is due to be realized in October 2011. The announcement provoked some dismay, particularly on the part of stakeholders in programs supported by the National Center for Research Resources (NCRR). Indeed, reactions to the planned dissolution of NCRR and the reallocation of its programs to NCATS; the Division of Program Coordination, Planning, and Strategic Initiatives; and other Institutes in NIH dominated the media, crowding out a rational discussion of the Center’s purpose. Within this void, some commentators projected their own vision of NCATS’s objectives, which were ones, they argued, that would threaten the U.S. research enterprise. It was even interpreted as a plan to drain away a billion new dollars to build a drug company on NIH’s Bethesda campus (1).

Gradually, tempers have cooled, and information has helped to promote more nuanced views of the proposal. For example, none of the NCRR programs will be discontinued, and no foundation stones are being laid for BethesdaPharm. Rather, existing resources pertinent to translational medicine within NIH are being aggregated to create a visible seat at the table (2). Importantly, the objective is to add value rather than to compete with the translational efforts already extant at other NIH centers and institutes. The only potential new source of funding for NCATS is from the Cures Acceleration Network (CAN) (3, 4). However, although $100 million is slated for CAN in the president’s 2012 budget and up to$500 million annually has been authorized, no money has yet been appropriated. The hope is that CAN will provide NCATS with money that it can use flexibly and quickly—in much the same way that the Defense Advanced Research Projects Agency (DARPA) deploys funding to catalyze research.

## FUNCTION FOLLOWS FORM

So much for the form NCATs will take; what about its function? Some of this aspect began to take shape at a meeting on drug repurposing and rescue that was convened by Collins at NIH in Bethesda at the end of April 2011. The stuttering progress in bringing new drugs to market is old news, and skepticism about the current model of drug discovery and development abounds (5). Collins stated the objective of NCATS as being “to advance the discipline of translational science and catalyze the development and testing of novel diagnostics and therapeutics across a wide range of human diseases and conditions.” He stressed that NIH did not plan to compete with the private sector but, rather, to facilitate its efforts in drug discovery and development.

Several initiatives were up for consideration. The first was to develop NIH’s role as an “honest broker” by collecting and cataloging data on all drugs—their structures, mechanisms of action, efficacies, and adverse effects—and integrating those data with mechanistic information on human physiology and disease. Indeed, scientists have already begun to assemble such a pharmaceutical assets portal (6) wherein drugs can be sought by synonym, target, and clinical indication. Although this is a considerable step forward— acetaminophen is listed by roughly 350 names in regulatory databases—the assets portal presently is confined to compounds approved for use as drugs. Could this resource be expanded to include investigational drugs and to serve as a source for provision of the actual molecules to academic investigators for use in screens designed to seek new indications? Once structures are disclosed, a considerable commercial capability exists for custom synthesis, but this remains an expensive undertaking for most academic laboratories.

An analysis presented at the meeting of the pipelines of several drug companies revealed that, despite a variable degree of aversion by industry to disclosure, much of the information on mechanisms of action and, indeed, structures of investigational drugs already is publicly accessible, albeit not gathered in one convenient place. Furthermore, through a collaboration between NIH and the U.S. Food and Drug Administration (FDA) that is scheduled to be housed in NCATS, NIH may have the opportunity to scan drugs currently in development as well as those for which development was discontinued; FDA data sets might afford convenient source information for such a portal. An outstanding question is whether companies should be encouraged by financial incentives to share such information or be forced to do so by new government regulations. At the recent conference, industry representatives pointed out that drugs in development are often deprioritized for reasons other than toxicities, especially in this era of repeated mergers. Perhaps these compounds and related data can be made available to academic investigators. FDA could play a role by querying companies about such assets at regular intervals, inquiring as to the companies’ willingness to disclose all data and abandon intellectual property restrictions. Finally, NIH could gather its own scattered drug-development data as a first step toward enhancement of this portal.

Meeting participants also telegraphed future visions of industry-academia collaborations. Vertically integrated companies likely will give way to a shifting modular assembly of the heterogeneous skills necessary to move from a newly discovered therapeutic target through to an approved drug. Such modules will be drawn from Pharma, the biotechnology industry, and academia, assembling in varied coalitions of the willing according to a particular challenge (7). Several presentations on the development of drugs for rare and neglected diseases highlighted the efficiency of this approach; each of the speakers emphasized the fear of liability within industry and the need for persistence, project champions in both industry and academia, and a deep level of trust among the participating groups. Furthermore, FDA might foster such collaborative research by issuing guidelines for the repurposing of approved drugs for rare and neglected diseases that create a “safe haven” for studies designed to explore such indications. Additional incentives might be provided by patent legislation to extend the exclusivity periods for such indications.

As Pharma has been divesting from research and development, agreements with academic institutions have begun to proliferate. Highlighted at the meeting was an expansive partnership between Pfizer and Washington University that was built on a longstanding relationship. Discussion centered on how industry-academia partnerships might be facilitated and expanded. The Clinical and Translational Science Award (CTSA) program, soon to be housed in NCATS, will offer external partners a single point of contact from which to develop interactions, perhaps in part through further development of the CTSA assets portal (8). CTSA recipient institutions are also repositories of the skill sets necessary to conduct the deep phenotyping studies intrinsic to the progressive personalization of medicine and, with time, should develop the capability to perform such studies at scale. Participants also discussed the formation of a common materials transfer agreement among companies, across CTSAs, across institutes and centers within NIH, and ultimately across all of these sectors. Participants also pondered an initiative to use drugs with well-characterized adverse effects as positive controls in preclinical studies designed to decipher novel signatures of predictive toxicity.

So it seems clear that one objective of NCATS will be to foster industry-academia interactions, at least initially focusing on derisking approved compounds and exploring their potential efficacy in rare and neglected diseases. NCATS will also push for an expansion of the precompetitive space (9), seek new opportunities to innovate in the therapeutics development pipeline, and, through training initiatives, foster the development of human capital in translational medicine and therapeutics (7). Through its close relationship with the NIH Clinical Center, NCATS can exploit the Center’s capabilities in biomechanics, imaging, and metabolic phenotyping; less clear is how the Center’s diverse resources might be integrated with other elements of NCATS. One thought is that the Center can serve as a national resource for investigators to phenotype their patients with respect to drug response in ways that they could not in their home institutions or to study drug action in patients with rare and neglected diseases. The Center might also serve as a venue in which approved drugs with preclinical evidence of an off-target effect could be tested in a set of standardized evoked-phenotyping screens in healthy volunteers; such studies could pave the way for disease-specific clinical trials. It is likely that the coming months will give further shape to the intentions of NCATS. Drug combinations, biotherapeutics, stem cells, devices, and diagnostics were not considered in any detail at the recent meeting, nevermind the role of the CTSA program beyond the domain of translational therapeutics. However, as the complex questions become defined, perhaps NCATS can provide some simple answers as to how academia, industry, and FDA can collaborate to foster more successfully the provision of safe and effective therapeutics.

## Footnotes

• Citation: G. A. FitzGerald, NCATS Purrs: Emerging Signs of Form and Function. Sci. Transl. Med. 3, 83ed2 (2011).