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IOM Prescribes Upgrades to Successful NIH Translational Clinical Science Program

Shaw, Gina

doi: 10.1097/01.NT.0000433887.23547.df
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The Institute of Medicine released a report, stressing seven recommendations, for making the National Institutes of Health Clinical and Translational Awards Program more streamlined and efficient.

The seven-year-old Clinical and Translational Science Awards Program (CTSA), the centerpiece of the National Institutes of Health's efforts to kick-start basic science findings into meaningful clinical advances at the bedside, has been highly successful, but could potentially be even more effective with some key changes and enhancements. That's the conclusion of a new report from the Institute of Medicine (IOM), “The CTSA Program at NIH: Opportunities for Advancing Clinical and Translational Research,” released in June.

“For the past seven years, the efforts have focused primarily on developing academic homes for clinical and translational research at individual CTSA sites,” the report said. “The challenge for the next phase of the CTSA Program will be to establish a more integrated and collaborative national network that will further catalyze the development of new diagnostics, therapeutics, and preventive interventions while driving innovation in clinical and translational research methods, processes, tools, and resources and leveraging the ever-expanding capabilities of health informatics tools and other research technologies.”

The report offered seven recommendations, which will be moved forward immediately, according to Christopher Austin, MD, director of the National Center for Advancing Translational Science (NCATS), which is home to the CTSA program. [See “IOM Recommendations for the CTSA Program.”]

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When the CTSAs were originally launched in 2006 — then just 12 sites, compared with 61 today — there was some trepidation in the neuroscience community that they might disproportionately focus on internal medicine.

“The CTSA program emanated from the general clinical research center program, which was largely focused on internal medicine, and the people associated with it were from the internal medicine community,” said Michael Rogawski, MD, PhD, professor of neurology and director of the Center for Neurotherapeutics Discovery and Development at the University of California, Davis (UC, Davis). “But that hasn't turned out to be the case.”

Without the CTSA at UC, Davis, Dr. Rogawski said, it would have been almost impossible for him to pursue the unique clinical trial of a possible neuroprotective agent for people with traumatic brain injuries. The drug, allopregnanolone, is a neuroactive steroid and, unusually, was generated and manufactured at the university rather than by a pharmaceutical company. “I'm not sure that has ever happened before,” Dr. Rogawski said. “Because the drug was developed here, we don't have a pharmaceutical company sponsor, but we still needed to run the trial in a rigorous fashion.”

The cost of engaging a contract research organization (CRO), as a pharmaceutical company would, was prohibitive — but the CTSA made it unnecessary. “Within our CTSA, we have basic expertise in the things that the clinical research organizations do: adverse event reporting, oversight, regulatory support, all the things that a pharma company would traditionally outsource to a CRO,” Dr. Rogawski said.

The drug is now in the third year of a five-year clinical trial.

“For neurologists, I think that the CTSAs offer a lot,” said Walter Koroshetz, MD, deputy director of the National Institute for Neurological Disorders and Stroke (NINDS). “The general clinical research centers were primarily for endocrine research and neurology had little to do with it, but the paradigm now is not specialty specific. For clinical neuroscience people who are generally in smaller departments, the resources for training, education, and support from CTSAs are really wide open. That's important for all the subspecialties, but clinical neurosciences can really take advantage of the resources of a big program with resources they wouldn't be able to have on their own.”

THE FULL REPORT, briefs, and slides are accessible at http://bit

THE FULL REPORT, briefs, and slides are accessible at http://bit

Dr. Koroshetz joined NINDS in 2007, the year after the CTSA program launched, and has served on the CTSA executive committee ever since. “We are continually trying to figure out ways that neuroscience could take advantage of what the CTSAs can do. For example, we're trying to encourage neuroscience departments to set up their own designated people who would interface with their CTSA — because all politics is local. To take advantage of what your CTSA has to offer, you need to know how to talk to them.”

CTSAs aren't funded to do neurologic research specifically, of course — that's what the Institutes do — but “they should be able to make our research more successful,” Dr. Koroshetz said. Indeed, he said, NINDS' successful NeuroNEXT program, which was spotlighted in the IOM report as a model to emulate in reorganizing research infrastructure, wouldn't have gotten started had the CTSA program not existed. “From the beginning, anyone writing a proposal to NeuroNEXT had to indicate, if they were at a CTSA site, how the CTSA would help that project move.” [For more about NeuroNEXT, read the Neurology Today article, “NeuroNEXT: New Neuroscience Network Aims to Speed Up Phase 2 Trials:”]

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And one of NeuroNEXT's signature principles — the central institutional review board (CIRB) process — would not have been possible without CTSA influence at those sites. All NeuroNEXT hub sites have executed reliance agreements with the CIRB, with a dazzling average time to execution of 25 days. When this was first proposed, however, Dr. Koroshetz noted, there was a lot of pushback. “People called me and said, ‘My hospital will never let me do this. The person in charge of our IRB said no way.’ I told them to talk to the PI of their CTSA and ask them to go back to the hospital IRB. They have a lot more clout, and were able to say how important this is.”

But not all 61 CTSAs may survive the era of sequestration. As NCATS director Dr. Austin told ScienceInsider, a health policy blog for the journal Science: “The program is going to have to be right-sized to fit the budget that we now have.”

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To that point, the report calls for CTSAs to collaborate with one another and take advantage of specific areas of expertise, rather than trying to be all things to all people.

Dr. Rogawski thinks that makes sense. “Right now, the different CTSAs are relatively similar in how they're structured and what they're doing, and don't seem to have individual personalities. But each institution has unique expertise. For example, here at UC, Davis, we have a Good Manufacturing Practice GMP) facility. It's been crucial to my own research, and other CTSAs could take advantage of it as well. We're also pretty good at regulatory support. There are unique resources like these at each of the CTSAs, and by bringing them together in an integrated fashion, you could be much more efficient.”

“It's kind of like when you build a house,” said Dr. Koroshetz. “Every house needs a foundation, and the CTSAs build a strong foundation for clinical research. But once you have that foundation, what do you add on? A pool, a back deck, a garage? The IOM is calling for the CTSAs to play to their strengths as they move along.”

The report also emphasizes community-based research, something that Gregory L. Holmes, MD, chair of neurological sciences at the University of Vermont, said is essential to advancing translational neuroscience research at any time, but particularly in this austere era.

“This report emphasizes that we have to be smarter in administering our money, and having a community-based approach can be very useful,” he said. “Moving the research enterprise beyond just the major academic medical centers and getting more local involvement will not only reduce costs, but will help to make sure the studies we are doing are meaningful and feasible before we launch them.”

He pointed to the ongoing accrual challenges faced by virtually every major study in the neurosciences. “The NIH is spending millions and millions of dollars on these studies, and every one that I've been involved with has had problems with accrual. That's inevitable when you're trying to recruit your patients almost exclusively in academic and tertiary centers.”

Dr. Koroshetz added that the report's emphasis on innovations in training and mentoring within the CTSA program is also particularly important. “We have set up this infrastructure to do translational research, but we've never really trained people in translational research,” he said. “We train people to be doctors. If you're trying to develop a new therapy — well, you haven't learned how to do that in medical school. And right now, with NeuroNEXT, an expensive network to do first-in-human studies, we do not have enough studies to fill the network. There are plenty of people with ideas, but they're not mature enough to go into human trials yet. That's in large part a training issue.”

He noted that officials at NINDS and other institutes have found that much of the published research that has led to major clinical trials can't actually be reproduced. “And when you look carefully at the papers, there is no evidence that really rigorous experimental design was used in the studies. That, again, is a training issue,” he said. “I think the CTSAs can address that by elevating the science of doing translation to make it a much higher quality process. But it will take time.

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The Institute of Medicine report offered seven recommendations for the National Center for Advancing Translational Science (NCATS), which is home to the CTSA program:

  • Strengthen NCATS leadership of the CTSA Program
  • Reconfigure and streamline the CTSA Consortium
  • Build on the strengths of individual CTSAs across the spectrum of clinical and translational research
  • Formalize and standardize evaluation processes for individual CTSAs and the CTSA Program
  • Advance innovation in education and training programs
  • Ensure community engagement in all phases of research
  • Strengthen clinical and translational research relevant to child health
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•. NIH Clinical and Translational Science Awards Program:
    •. NeuroNEXT:
      •. FDA site on Good Manufacturing Practices:
        •. Neurology Today archive on clinical trials protocols:
          © 2013 American Academy of Neurology