The National Institutes of Health’s (NIH’s) reputation has been built, in large part, on discoveries made during basic science research — original insights about pathways, receptors, and targets for drugs. These discoveries have led to a significant percentage of new drug approvals in most of the major classes of drugs. However, Francis Collins, M.D., Ph.D., director of NIH, wants to make clear, “NIH doesn’t only do basic science. A little more than half our budget is devoted to basic science, but a substantial fraction goes to applied science. And, much of this applied science has only been successful because of partnerships with industry.” NIH wants its relationship with industry to be even more productive.
A Turning Point For NIH And The Biopharmaceutical Industry
It could be argued that passage of the Bayh-Dole and Stevenson-Wydler acts into law was a watershed moment for NIH’s relationship with industry and therapeutics development. Prior to their passage in 1980, the federal government owned the IP resulting from research it funded. But, it was not efficient at transferring its technologies, licensing fewer than 5% of its patents. The Bayh-Dole Act stimulated technology transfer by NIH-funded organizations, allowing private institutions and public institutions, such as teaching hospitals, universities, and nonprofit research institutes, to have ownership of the inventions resulting from research funded by the federal government. And, if they chose to, these institutions could transfer the inventions through patent license agreements to the private sector for commercialization and public use. The Stevenson-Wydler Technology Innovation Act and the subsequent Federal Technology Transfer Act of 1986 granted new authorities to federal laboratories, such as the NIH intramural research program, to engage in technology transfer and partner with industry.
In 1982, the federal government established the Small Business Innovation Research (SBIR) program and, in 1992, the Small Business Technology Transfer (STTR) program, to which various government agencies devote funds. Fully 2.5% and 0.3%, respectively, of NIH’s extramural research and development budget ($24 billion), or $682 million in Fiscal Year 2011, is invested in these programs, which award grants to small businesses of fewer than 500 employees for the exploration of the technical merit or feasibility of an idea or technology (Phase 1) and, subsequent to that, for the full research and development of the technology toward commercialization (Phase 2).
New NIH Program To Benefit Start-Ups
In October 2011, NIH launched a program that marks the most recent milestone in its relationship with industry. This program makes it much easier for start-up companies — or companies that are less than five years old, have fewer than 50 employees, and have received investment of less than $5 million — to license inventions made by intramural scientists at NIH and the FDA.
Ten percent of NIH’s budget, or $3 billion, is dedicated to its intramural program, comprising NIH investigators who are federal employees and conduct research with an aim toward clinical applications. According to Collins, this research has led to “a substantial number of IP discoveries.” By reducing paperwork and costs, obtaining licenses to commercialize these inventions has been made easier for start-up companies. Now these companies can apply for any of the pending or issued patents for drugs, vaccines, or therapeutics in the NIH/FDA portfolio by submitting a business plan for how they propose to develop them. A start-up evaluation license costs $2,000 and can be converted into an exclusive Start-up Commercial License Agreement within a year. NIH is willing to share some of the risk with the companies such that royalty payments under the licenses are deferred for three years or until the company gets a cash investment. Royalty payments on product sales are limited to 1.5% of sales. The low financial bar for start-ups should help increase technology transfer.
But, as Collins puts it, “All of that’s good, but I wouldn’t say it’s sufficient, particularly because the science has moved along in such gratifying ways. We are trying to identify ways NIH can make an even larger contribution to therapeutic development. That’s the motivation for NCATS [National Center for Advancing Translational Sciences].”
The National Center For Advancing Translational Sciences
Dependent upon an appropriation in the Fiscal Year 2012 budget, Collins is preparing to establish the NCATS. He remains optimistic that there will be an appropriation for NCATS, due to the President’s and the Senate’s strong endorsement of it. “NCATS is the newest concept to add greater energy and strength to NIH’s relationship with industry,” Collins says. “The goal of NCATS is to identify bottlenecks in the process of going from a great idea to an actual, approved therapeutic, diagnostic, or device. We will look at the development pipeline itself as a scientific problem in the way that an engineer would — take it apart, look at the various steps, and identify those that are particularly vulnerable to failure. We will try to identify new approaches that might result in a shortened timetable, a higher chance of success, or failure earlier in the development process before a lot of money has been spent. After many conversations over many months with biotech and pharma, these areas have been identified as ones very much in need of attention.” Collins stresses that the goal of NCATS is not to become a drug development company, nor is it to compete with industry, but rather to work more closely together.
The proposed center will be formed by integrating translational research programs from the National Human Genome Research Institute, the National Center for Research Resources, the NIH Director’s Common Fund, the Office of the Director, and the Cures Acceleration Network, a program enacted as part of healthcare reform legislation to give the NIH director substantial authority to identify and direct funding to “high need cures” using flexible research authority. In addition, the network of 60 clinical research centers across the country that have received Clinical and Translational Science Awards (CTSAs) will also come under the direction of NCATS. These CTSA centers are located at many of the major medical centers in the United States and represent $500 million of NIH investments. They also represent what Collins refers to as “a strong clinical research engine for NCATS.”
Recognizing that translational sciences’ endeavors increasingly involve industry, government, academia, and other sectors working together, the central role of NCATS will be to work with these stakeholders to provide integrated, systematic approaches to link basic discovery research with therapeutics development and clinical care. To support these undertakings, NIH already has announced initiatives that will be centrally supported by NCATS. “Seeing appropriations for NCATS as a strong possibility, we wouldn’t want to have spent the last few months waiting around for ideas that might feed into it. So, there’s been a lot of activity to try to prepare for NCATS’ arrival,” Collins says.
The new center will not have a top-down approach, but rather ideas and proposals for projects will come from various stakeholders in the therapeutics development enterprise. Discussions with stakeholders have already identified components of translational science that could benefit from NCATS’ scientific approach. They include: therapeutic target validation, chemistry, virtual drug design, preclinical toxicology, biomarkers, efficacy testing, Phase 0 clinical trials, rescuing and repurposing compounds, clinical trial design, and postmarketing research.
During my discussion with Collins, he spoke about two of NCATS’ major initial activities in depth. The first of them involves a collaboration with the Defense Advanced Research Projects Agency (DARPA), the principal agency within the Department of Defense for development and demonstration of new technologies and systems that serve the country’s defense. DARPA’s better-known successes include the Internet and global positioning system (GPS).
NIH, DARPA, FDA To Work On Chip To Predict Drug Safety
In September, NIH announced its collaboration with DARPA and the FDA to develop a chip to screen for safe and effective drugs faster and more efficiently than current methods allow. The way drug manufacturers currently assess whether a drug is going to be safe in humans hasn’t changed much during the past decades. The current method of testing a compound in a few cell models, then small animals and large animals doesn’t always give an accurate assessment of a compound’s safety for, or toxicity in, humans. This sometimes results in compounds that might have been safe in humans being discarded early on or finding unanticipated toxicity in humans from compounds shown to be safe in animals.
The purpose of the joint initiative is to create a system that is a more reliable indicator of whether a compound is going to be harmful to human cells, without having to test it on human subjects. DARPA and NIH plan to create a collection of human cell types representative of human tissues — including the liver, heart, muscles, and kidneys — on a chip. Recent developments would allow NIH and DARPA to generate such cell types by using stem cell biology, and new tissue engineering methods would allow them to generate cells growing in three-dimensional form, closer to what happens in vivo.
“DARPA is excited about taking this to a very bold level where you would have as many as 10 different human tissues represented on this chip. NIH is excited about the science that would be built into the chip to give readouts showing how cells react when you hit them with a new, potentially perturbing influence like a drug. It’s fairly unprecedented for these two government research agencies to work as closely together as we will on this,” Collins says. “I have encountered a lot of excitement from people in industry about the potential of this chip for providing rapid and reliable information about whether particular compounds are going to be safe and, presumably, allow them to get this information about many more drug candidates than they can now through animal testing. This chip could allow very high throughput.” For the five-year effort, NIH plans to allocate $70 million, and DARPA will commit a comparable amount.
The FDA’s partnership in this initiative is key, as the agency will need to have access to the data generated to make decisions about changes to the regulatory process. The FDA also will provide an advisory role, making scientific input throughout to ensure the regulatory requirements and process are considered. “We want to create methods and technologies that get translated into a regulatory science change. We don’t want to create a chip that is just one more requirement, on top of many others. Our hope is that, after some proof of principle, the chip could substitute for the animal testing currently required before entering Phase 1 clinical trials in humans. This is where having a center at NIH that serves as a hub for a focus on translation would be extremely useful,” Collins says.
Collins envisions the new chips becoming a commodity for researchers; all biotechs, pharma companies, and academics with an interest in using the technology would be able to gain access to it. “This is a great example of how NIH can participate in an effort that insists upon open access to the information and, ultimately, to the technology. We’re big on that.”
Rescuing And Repurposing Compounds
Another initiative that would be organized through NCATS is the rescuing and repurposing of compounds. NIH held a meeting about this initiative in April, participating in detailed and specific discussions with industry about finding new uses for compounds that were found to be safe but failed in clinical trials due to lack of efficacy, the most common cause of failure in a Phase 2 trial.
Through this initiative, NIH would like to help the industry find new uses for its compounds. Collectively, biopharmaceutical companies have tested thousands of compounds in human subjects, with information attached to them about what pathways or targets they hit — but many of those failed to show efficacy for the disease being studied and so were abandoned. At the same time, NIH has an enormous amount of new information about the molecular basis of diseases, both rare and common.
“There is a lot of opportunity here when you look at the inventory of compounds not being used and the inventory of targets that haven’t been hit. NIH could serve a very useful role as honest broker/matchmaker to put those projects together,” Collins says.
Collins envisions biopharmaceutical companies making what compounds they have available, including information about their known targets, their appropriate dosing, and, ideally, the compounds’ structures. NIH could match investigators looking for new therapeutic options for a disease that has had its molecular basis identified with the inventory of available compounds that target those molecular changes and offer assistance in how to handle IP. Collins says that representatives of the pharmaceutical industry have already reviewed the model agreement that would be used in these cases and that it’s close to being finalized.
Because these compounds have already gone through all the steps in preclinical assessment, made it through an FDA IND (investigational new drug), and been tested in humans, investigators could go straight to a clinical trial for a new application. If the trial were successful, they could get approval for the drug in perhaps three or four years, according to Collins — a much shorter timeline than is usual.
“The initiative will be most successful if you have the largest collection of compounds and the largest network of ideas about uses. So, it will benefit from a community-oriented effort, which NIH is well positioned to organize through NCATS,” Collins says.
Though Collins is clear about the fact that NCATS does not formally exist yet, he was just as clear in his enthusiasm for the opportunities the new center would offer various stakeholders in revolutionizing the science of translation in a comprehensive, systematic, and creative way, ultimately improving human health. It’s up to Congress now, but it looks as though the odds are good.