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6 Final Reflections on Ways to Maximize the Goals of CAN Key Messagesa C AN could break the status quo by supporting individuals and companies that are outside the mainstream. CAN's portfolio could focus not only on cures but on transforming the process that will lead to cures. Personal passion and a tolerance of failure will be important components of CAN's success. Possible ways to define success of CAN include -- installation of NCATS staff with therapeutics development expertise; -- implementation of milestone-based contracts and increased accountability; -- establishment of greater collaboration and robust publicprivate partnerships; -- advancement of regulatory science and tools for drug development tools; and -- development of cures: new therapeutics and diagnostics. a Identified by individual speakers. As part of the final session of the workshop, several speakers and workshop participants reflected on what they had heard over the course of the previous day and a half. Their ideas were meant to be provocative and thought-provoking as stakeholders consider the implementation and future of CAN. 65

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66 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK RESPONDING TO FRUSTRATION1 Joshua Boger, Vertex Pharmaceuticals, reminded the workshop partici- pants that the legislation leading to CAN resulted from frustration with the status quo. He cautioned that CAN will be tempted to do the same thing over and over while expecting different results, which, as Albert Einstein noted, is one definition of insanity. "CAN needs to have a very low toler- ance for the status quo, and frankly for consensus, which is the basis of the status quo," said Boger. It should instead search for companies, individuals, and collaborators who are outside the mainstream, he said. The small amount of funding initially allocated to CAN is likely to force it to work on tools rather than specific diseases, Boger said. But he added that tools are best developed in the context of a specific project. "Technology is rarely the problem," he said. "We need to close the appli- cation gap." He commented that individual projects are the best way to create system change. Boger also expressed concern about a misalignment of goals among funders. Investors do not necessarily have the goal of creating cures. In that sense, the best co-investor is often a patient group, he said, because those are the groups most closely aligned to the mission of CAN. Finally, he reminded the workshop participants of how difficult it will be to achieve the goals of CAN. "With all due respect, [designing] a Mach 20 aircraft is easy compared to a typical drug." Ninety-nine out of 100 drug development projects fail to make a significant medical impact. CAN's portfolio therefore needs to focus not only on cures but on trans- forming the process that will lead to cures. Good project management is necessary but not sufficient. "Expect most projects to fail. Don't be defen- sive about that. Don't over promise, and therefore you won't have to fear people or the Congress. They can handle the truth." CAN should not be used to convert academic researchers into trans- lational scientists, Boger said. But it can increase knowledge about the constraints on either side. In this way, it can help reshape the engagement of academic investigators with translational work. The essential ingredient of successful drug development is personal passion sustained over long periods of time, Boger said. "All successful projects fail at least once. That should be built into the process. I know of no exceptions to that rule for any successful drug. They have all failed once. If the projects are set up to weed out failures, it will weed out suc- cesses." Even spectacular failures, if done in good faith, can amount to wins. "Insist on great science, but insist on projects that can only come about through challenging the existing process." 1 This section is based on remarks by Joshua Boger, Founder, Vertex Pharmaceuticals.

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FINAL REFLECTIONS 67 A RALLYING CRY2 Carol Mimura, Assistant Vice Chancellor for Intellectual Property and Industry Research Alliances, University of California, Berkeley, labeled the workshop "a rallying cry to action . . . to change the whole ecosystem that enhances human health." Challenges abound, she said, but the work- shop demonstrated the existence of an energy and a commitment to col- laboration to overcome them. Many people commented during the workshop that partnerships will be an important way to overcome barriers. She said that she has been involved at Berkeley with the establishment of hundreds of col- laborations with industry; the university signs more than 350 new agree- ments every year. Its involvement with industry has evolved to the point that it now engages in multiparty agreements with governments and industries around the world. It also stays engaged with industry farther into the translational research arena than would be the case under the traditional technology transfer model. Innovation is not a linear process, where money goes into one end of the pipeline and drugs emerge from the other. Iteration is essential to improve on the existing situation and to align goals. "Solving the grand challenges of science requires just the right mix of talent and funding and desire and passion through successive waves of innovation." From Mimura's perspective, the typical reason why a partnership fails is because of personal egos, not the clash of institutions. Individuals need to believe that a collaboration is worthwhile and not let personal disputes get in the way of the collective good. Mimura emphasized the point that changes anywhere in an inter connected ecosystem can drive change in the entire system. For example, very early-stage research aimed at a commercial product typically is not ready to be picked up by biotechnology companies or pharmaceutical companies. But it can be pursued by spinoff companies from universities. In that regard, institutional innovations such as new ways to raise venture capital for small start-up companies can have wide-ranging effects. MASTERING THE DETAILS3 Robert O'Neill, Senior Statistical Advisor, CDER, FDA, also com- mented on the sense of enthusiasm that surrounds the formation of CAN. But he cautioned that the devil is in the details. Changing the culture of organizations can be very difficult, but there are ways to do it. For 2 This section is based on remarks by Carol Mimura, Assistant Vice Chancellor for Intel- lectual Property and Industry Research Alliances, University of California, Berkeley. 3 This section is based on remarks by Robert O'Neill, Senior Statistical Advisor, CDER, FDA.

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68 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK example, the contracting mechanisms pioneered by DARPA were "an eye opener," he said, because they can help make things happen that would not have happened otherwise. In that regard, he said, CAN needs to have a well-structured and carefully thought-out mechanism for prioritizing demonstration projects that have widespread impacts rather than just promoting a single project. O'Neill also pointed to the CTSAs as a resource that needs to be reexamined to see how they can support CAN's mission. To get products to patients, the developers of those products need to be familiar with regula- tory processes, and outside the drug development world not many people understand these processes. Standardization on both the medical side and the regulatory side can ease this disconnect. "Without that, we are not going to be able to do all this cross-study, cross-product research," he said. BEYOND ROCKET SCIENCE4 Robert Califf, Professor of Medicine, Duke University Medical Center, pointed to the immense challenge inherent in the name given to CAN, which implies that cures will be developed in a short period of time. NIH grantees have learned to be expert at claiming victory on small advances, but they are far less expert at describing diseases they have cured, he said. Califf also agreed that biomedical science is much more complicated than rocket science. With an engineering project, contracts can be exe- cuted ahead of time and are relatively predictable, while failures are not unexpected and typically result in the provision of more time and fund- ing. To some extent, medical devices can be developed that way, "but drugs are horrendously more complicated." Finally, he observed that clinical trials now can cost on the order of $500 million. "You could reduce that by 50 percent per clinical trial and probably end up with better data," he contended. But, he said, FDA is sending industry the opposite signal--that it has to spend more money to hope to survive the regulatory gauntlet. CHANGING THE CULTURE AND SHOWING DELIVERABLES5 Sudip Parikh, Battelle Memorial Institute, agreed that CAN has been designed to change the culture. The rest of NIH still has $30 billion to do 4 This section is based on remarks by Robert Califf, Professor of Medicine, Duke University Medical Center. 5 This section is based on remarks by Sudip Parikh, Vice President of Health Policy, and Managing Director, Centers for Public Health Research and Evaluation, Battelle Memorial Institute.

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FINAL REFLECTIONS 69 hypothesis-driven research. CAN is supposed to open new spaces, even at the cost of failure. "It is not about 20 different projects at half a million dollars each planting a seed. If that is what comes out at $10 million, it will be gone next year. I can guarantee it." Far better to fund a single project that would be deemed a success, he said. Parikh said that he wants to see the research enterprise funded and valued in the way that it has been for the past 50 years, but "we have to be able to show some deliverables," encompassing a range of successes from cultural change to treatments and interventions. As an example of a cultural change, he cited the option of hiring program managers who would focus on specific diseases with a laser-like intensity. If something does not work, what other paths can a program manager take? CAN is a vehicle to figure out the next step in the path. CAN is an embodiment of that cultural exchange. It enumerates cures, treatments, devices, those sorts of things that can be gleaned from focused activities, Parikh said. The initial funding amount may be small, but disease foundations have demonstrated that important advances can be made for relatively little money. "THE STATUS QUO IS NOT ACCEPTABLE"6 Kathy Hudson, NIH, delivered closing reflections on the workshop. "The status quo is not acceptable," she began. "We are infusing that into the brains and the hearts of everybody who works with us. The ques- tion is now whether or not we can deliver on showing that CAN can cut through red tape, create culture change, and create new tools and new processes that will make a demonstrable difference." The proper balance between developing tools and supporting specific projects remains uncertain and will need to be addressed by the CAN Board, she said. CAN needs to have a catalytic role, especially because of its limited funding, but it also has to have a disease focus. The challenge will be to pick projects that use innovations in ways that demonstrate the potential for other projects to save time and money and "ultimately get medicines out the door faster." The procedures CAN has been following in its initial stage are very unlike traditional procedures at NIH, which will help to change the cul- ture. CAN expects to run programs in a "DARPAesque way," Hudson said, where milestones will be met or funding will be withdrawn. In general, in its early days, CAN plans to look closely at DARPA as a 6 This section is based on remarks by Kathy Hudson, Acting Deputy Director, NCATS, and Deputy Director for Science, Outreach, and Policy, NIH Office of the Director.

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70 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK model--for example, to learn how to use OTA and to derive best practices for collaboration between the program and contract office. In its initial year, CAN has very little money, and it has no guarantee that funding will continue in the future. "We have an important duty to make sure that these dollars are spent well," she said. She commented that the input of the workshop was extremely beneficial. "We appreciate it very much, and we hope that we will be able to make you proud as we implement this program."