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2 Approaches to Accelerating Translational Science Key Messagesa Promise for Translational Science New technologies would help change the translation process in positive ways rather than simply enhancing processes that are already in place. Open innovation could decentralize and speed the development of new drugs and diagnostics. Approaches for CAN Partnerships among institutions help accelerate the rate at which new dis coveries are translated into products that can improve health. CAN could incentivize, de-risk, and facilitate research at the academiaindustry interface. CAN could curate features of promising and successful alliances among aca- demic, philanthropic, and industry groups and make available a compilation of the most promising features as guidelines or best practices templates. Planning on a programmatic, not episodic, basis will help facilitate overall effec- tiveness of drug development and the impact of CAN to improve and accelerate development of cures. Effectiveness of and communication among the project management team is a key element of success. A consensus-based traditional funding review process could undermine sup- port for needed breakthrough projects. a Identified by individual speakers. 15

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16 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK CAN is part of a much broader effort in NCATS and NIH to help accelerate the translation of biomedical discoveries into products and pro- cesses that improve human health. The second session of the workshop focused on ways to achieve this goal, with an emphasis on exemplary projects that have met with success. Past experience has provided lessons about how to replicate successes and what to avoid. CAN will have the capability to support translational science both through projects aimed at specific diseases and through the development of more generic tools, and the proper balance between these two was discussed throughout the workshop. CYSTIC FIBROSIS AND THE NEED FOR PARTNERSHIPS1 Cystic fibrosis is caused by mutations in the CFTR gene, which encodes a protein that pumps chloride across epithelial cell walls. As a result, mucus gradually plugs the lungs, degrading their function. Cystic fibrosis causes a loss in lung function of about 2 percent a year. Once lung function gets below about 50 percent, severe disability results. When lung function drops below 40 percent, death is likely from one of a variety of causes. About 15 years ago, Vertex Pharmaceuticals and the Cystic Fibrosis Foundation began working together to lower lung decline to 1 percent per year, said Joshua Boger, who founded Vertex Pharmaceuticals in 1989 and still serves on its board. If that could be achieved, people with cystic fibrosis could live nearly a normal life expectancy. Yet, at the time, that goal seemed out of the realm of a pharmaceutical intervention. Vertex took two approaches to enhance mutant CFTR function. One was to find small molecules, known as CFTR potentiators, that could increase the channel activity of CFTR protein at the cell surface, resulting in enhanced ion transport. The other was to identify molecules known as CFTR correctors that could increase the quantity of functional CFTR protein at the cell surface, also resulting in enhanced ion transport. In the late 1990s, these goals were generally considered to be science fiction, said Boger, especially given that many patients would need both treatments. The most important step in making these goals a reality, said Boger, was to create a good assay for the performance of test molecules. "Once we had the right assays, compounds that did exactly what we wanted them to do were relatively easy to find." More than 300,000 compounds were screened, resulting in the identification of several effective com- pounds, including a drug now known as ivacaftor. Clinical trials dem- 1 This section, including subsections, is based on the presentation by Joshua Boger, F ounder, Vertex Pharmaceuticals.

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APPROACHES TO ACCELERATING TRANSLATIONAL SCIENCE 17 onstrated that treatment with ivacaftor in patients who have a particular mutation can produce a 10 percent increase in lung function within a matter of weeks. Young patients who struggled to keep their weight up gained weight almost immediately with the drug. And adverse effects were greater in the placebo group than in the treated group because the placebo group was sicker. Beginning with patient observations in 2008, three Phase 2 trials were held and a New Drug Application was filed in October 2011. Regulators acted with great speed and approved the drug in just over 90 days. The drug development process cannot be done much faster than it was done for ivacaftor, Boger said. "This is a success story in large part due to unique cooperation between Vertex and the Cystic Fibrosis Foundation, which has become a model in the field," said Boger. Partnerships and Approaches Until the late 1990s, the Cystic Fibrosis Foundation supported "won- derful science," according to Boger, but the foundation's leadership real- ized it was not directly helping patients. As a result, leadership shifted the organization's research focus from late in the laboratory to early in the clinic. They also founded the partnership with Vertex, which Boger termed a "very bold idea" that would not have gotten through most review processes in government or disease foundations. Total support for the collaboration from the foundation was about $75 million. This is about the maximum size of the project that CAN could support if appropria- tions were available, Boger noted. The development of ivacaftor was a "high-wire act from beginning to end," Boger commented. Success was never obvious or guaranteed. "If you are looking for dramatic changes in medicine, you are not looking to be comfortable in research and development." Such a project would not be possible in most of NIH because, as Boger said, "every breakthrough project that I know about has passionate detractors." A review process that depends on consensus will not support breakthrough projects. He noted that breakthroughs require human passion. "In any sort of multi- stakeholder project that is being talked about through CAN, think about how you are going to put human passion into it." He also noted the importance of developing assays that report rel- evant information. Boger emphasized that assays are different from vali- dated models (which tend not to be aimed at breakthroughs) and from disease models (which may or may not be part of determining how to treat that disease).

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18 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK Critical Needs for Translational Science These observations from the example of cystic fibrosis point to sev- eral critical needs for translational science, according to Boger. One is for technologies that positively change the translation process, not just add to processes already in place. For example, how can a technology make translation faster, cheaper, or more effective? How can risk be lowered while safety is enhanced? How can technology enable greater leaps? Technologies that are simply more accurate are not sufficient answers to these questions. Technologies need to contribute to systems that replace other systems. Today, a drug development effort can be shut down with one negative result. Some drugs can be rescued, but even more important is to create a process that eliminates false negatives in the first place. "I am positive that we have fantastic drugs that have been killed in development," said Boger. "False negatives, I believe, are the biggest problem in the drug development process right now." Cures for the kinds of diseases that are a focus of the CAN legislation also require that a significantly more effective and efficient regulatory system be envisioned "from scratch," said Boger. The current process is built on historical precedent, but, he said, even though regulators do their best, the process is too expensive and too long. Safety, risk, and efficacy assessments need to be conducted on the continuum of both premarket and postmarket, not as an ad hoc, focal point process that evaluates only one drug, one development process, at a time. Boger emphasized that public health and overall societal benefits need to be incorporated into the evaluation process on a routine and continuing basis. Expenditures of time and money need to be optimized, and patients need to receive benefits sooner. ALZHEIMER'S DISEASE AND THE DRUG DEVELOPMENT ECOSYSTEM2 The biomedical enterprise is capable of stunning successes, but it is also falling short of meeting the needs of patients in many ways, said R. Sanders (Sandy) Williams, President, the Gladstone Institutes. The suc- cessful treatment of some cases of cystic fibrosis, as described above, or the soon-to-be-accomplished victory over hepatitis C virus, demonstrates what can be done. But failures in such areas as Alzheimer's disease, heart disease, or the development of an HIV vaccine illustrate both the scientific and business challenges of drug discovery. 2This section, including subsections, is based on the presentation by R. Sanders (Sandy) Williams, President, the Gladstone Institutes.

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APPROACHES TO ACCELERATING TRANSLATIONAL SCIENCE 19 In a 2010 interview, NIH Director Francis Collins described the pressing need for "new paradigms of publicprivate partnership[s] . . . effectively `de-risking' projects for downstream commercial investment" (Collins, 2010). New forms of partnerships among academic experts, industry professionals, and public and private sources of investment can improve what Williams and other workshop participants called the "drug development ecosystem." This ecosystem is diverse, encompass- ing universities, independent research institutions, biotechnology and pharmaceutical companies, voluntary health organizations, foundations, philanthropists, investors, and government. CAN, within the NCATS umbrella and through relationships with other federal agencies and other players in the ecosystem, has an unprecedented opportunity to replace failing processes with effective complementary teamwork, providing measurable results to Congress, to disease advocacy groups, and to the taxpayers who support the effort, said Williams. Academia and industry have differing skills, mindsets, and incentive structures. CAN can help find new and creative ways to form flexible alliances that combine their complementary attributes with funding sufficient to achieve measurable goals. "If we can do that, we can preserve and advance America's leader ship position in medical sciences and industry and, most importantly, bring new solutions to the most vexing and resistant medical needs." To illustrate his points, Williams focused on Alzheimer's disease. More than 5 million Americans are currently living with Alzheimer's disease, and by 2050 that number will climb as high as 16 million. Alzheimer's disease will cost the United States $200 billion in 2012 and $1 trillion in 2050 if nothing changes. Alzheimer's disease plays out within the daunt- ing biological milieu of 100 billion neurons and over 100 trillion synapses in the human brain. A great variety of pathological events occur in the brains of Alzheimer's patients at the cellular and molecular levels, includ- ing proteinopathies, vascular insufficiency, and inflammatory responses. "It is little wonder that, time and time again, preclinical research geared largely to test reductionist unidimensional models is not predictive of success with patients," said Williams. Suggestions for CAN Williams offered three suggestions for how CAN could address the scientific dimension of what is needed to accelerate cures. First, CAN could support and catalyze research to develop and validate a new gen- eration of animal models created to exhibit clinically relevant phenotypes. This likely will require multiple genetic manipulations that are carefully selected to bring the models into more faithful representation of human disease. For example, CAN could issue a request for proposals to fund

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20 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK development of better mouse models. Williams suggested that some of the mouse models could then be deployed in an iterative manner to inform innovation in adaptive clinical trials.3 This concept is being cre- atively tested at present within the cancer research community, Williams said, but the possibilities may be much broader. In particular, the creativ- ity of academic labs could be released more productively for this purpose, particularly if combined with industrial know-how within an intellectual property landscape that allows industry and academia to collaborate. Second, CAN could support the revolution in stem cell biology, in which techniques have been discovered that can generate induced pluripotent stem cells that subsequently can be induced to form virtually any differentiated cell type. A next generation of cellular reprogramming techniques is now emerging by which mouse or human fibroblast or white blood cells can be converted directly into a variety of cell types to model human diseases in culture. In particular, reprogrammed human neurons can form multi cellular networks and recapitulate important features of neurodegenerative diseases. The extent to which reprogrammed human cells from diseased patients and relevant controls can be useful for target validation, primary and secondary drug screening, toxicology, or other purposes remains to be seen, but CAN could stimulate progress toward this end. Third, CAN could support newly emerging scientific approaches that can reveal more fully how the targets of medications function within systems, pathways, and networks within cells. An example is the new ability to define the set of proteins within human cells that form physical complexes with the proteins elaborated during HIV infection. CAN could stimulate the creation and validation of this and other enabling platform technologies with the potential to reveal molecular signatures of disease progression and drug responses. Business Challenges Challenges exist in the business arena as well as in the science of drug discovery, noted Williams. The vast reservoir of talent, imagina- tion, and expertise in academia could be connected more effectively with the complementary pools of talent, professionalism, discipline, techni- cal prowess, and financial power in companies. As Williams and Susan Desmond-Hellmann wrote in Science last year, "needed now are creative programs that transcend the traditional technology transfer functions of non-profit research enterprises to promote fruitful academic/industry partnerships for drug development" (Williams and Desmond-Hellmann, 3 See later in this chapter for further discussion of the need for and utility of animal models.

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APPROACHES TO ACCELERATING TRANSLATIONAL SCIENCE 21 2011). Accelerating cures requires deeply embedded partnerships, focused on defined projects and carried out by teams that work together over time. A number of new and creative relationships of this nature have sprung up around the country, with research responsibilities divided according to each party's individual strengths and capabilities. For example, even in a period of limited funding, CAN could curate, to the extent possible, features of promising and successful alliances among academic, philan- thropic, and industry groups and make the compilation of these attributes available as guidelines or templates for best practices that can inform subsequent contractual negotiations. As CAN's funding increases, the program is ideally placed to develop a diversified portfolio of projects over time. Other worthwhile actions for CAN include facilitation of early engagement of industry experts into academic projects, rescuing and repurposing of drugs, strengthening computational pharmacology, and supporting regulatory science. Williams said that he favors an emphasis on smaller and midsize projects built on investigator ideas as opposed to a few really big infrastructure projects or a few large clinical trials, "but all would be worthwhile." NUT MIDLINE CARCINOMA AND OPEN INNOVATION4 Understanding of the cancer genome has undergone a revolution, said James Bradner, Instructor in Medicine, Dana-Farber Cancer Institute, and Assistant Professor, Harvard Medical School. Hundreds of thousands of somatic mutations in different cancers are known, and hundreds have been identified as the drivers of cancer pathogenesis. But the ability to act on this understanding is in its infancy, Bradner added. A small-molecule therapeutic is available for only about 14 cancer genomic rearrangements or mutations. Bradner described a very rare and very lethal cancer called NUT midline carcinoma, which affects approximately 100 people per year in the United States. A molecular pathologist at Brigham and Women's Hospital named Christopher French cultivated cells from patients who have the disease, and Bradner and his colleagues used these cells to test 4 This section, including subsection, is based on the presentation by James Bradner, Instructor in Medicine, Dana-Farber Cancer Institute, and Assistant Professor, Harvard Medical School.

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22 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK small molecules that would inhibit the cancer. In particular, they focused on a molecule named JQ1, which interferes with a protein called BRD4. Although there was no mouse model to study the cancer, Bradner at the time was caring for a 29-year-old firefighter succumbing to the disease, who provided a cell sample that was successfully grown in laboratory mice. When mice with tumors received the drug, they survived, whereas those that did not receive the drug died. JQ1 was a prototype drug not yet optimized for drug-like properties such as solubility or oral bioavailability. In order to access the infrastruc- ture required to bring a molecule into the clinic, Bradner and his colleagues decided to be creative. Using Google, they created a registry for people with midline carcinoma, which revealed a lot of information about the disease profile, such as where it is diagnosed and by whom. Many people have the disease but do not know it, Bradner said. "They should, not just because targeted therapy may soon be available, but because this is the poorest prognostic group of all squamous carcinomas, with a 6.7-month median survival." At a cost of $45,000 to his laboratory, Bradner and his colleagues made the drug freely available to anyone who wanted to learn about its effects in other diseases. A TED lecture on the drug had more than a half million viewers, and at least 200 people wrote to ask Bradner and his team to share the molecule. "They're under no special obligation to call us back, but they almost always do, to share the exciting findings of their research." In multiple myeloma, JQ1 downregulates what Bradner called "the central horseman of the cancer apocalypse," a gene called MYC that trig- gers growth. Mice with multiple myeloma driven by MYC had a complete response. In mixed-lineage leukemia, leukemia cells exposed to JQ1 "for- get they're leukemia and become more mature-appearing, normal mono- cytes," Bradner said. And in Burkitt's lymphoma, the downregulation of MYC again demonstrated the efficacy of JQ1. Why particular cancers respond is a major area of ongoing research. Open Innovation Leading to Bringing the Compound to Humans Bradner and his colleagues have found through sharing the com- pound with scientists at other institutions that in 10 to 15 percent of cases of every major form of cancer, the cancer "just melts away to this drug." These data establish a compelling rationale to bring this compound for- ward into humans, said Bradner. With internal funding from the accelera- tor program at Dana-Farber, Bradner and chemist Jun Qi led a medicinal chemistry effort that resulted in the creation of 400 to 500 chemical deri- vates. Ultimately, they were able to produce a stable of drugs of high potency and high stability in pharmacological studies.

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APPROACHES TO ACCELERATING TRANSLATIONAL SCIENCE 23 Bradner and his colleagues also have taken a creative approach to translation. For example, they determined that Xanax, a bromodomain inhibitor, is very similar to the JQ1 molecule; however, the amount of Xanax that would be needed to be administered to have an effect on can- cer would be excessive. A literature search revealed that GlaxoSmithKline had a bromodomain inhibitor for the management of acute septic shock. They negotiated with the company for investigational use in cancer. Although the molecule is 10 times less potent than JQ1 and performs less adequately in the animal models of the disease, it is available for testing in humans immediately. Bradner cited the development of JQ1 as an example of open innova- tion, which has been extremely successful in the information technology field. "We are so much smarter than each of us," he said. The drug they were examining was a prototype and immature, but the index technology sparked rapid innovation when it was publicly and broadly disseminated. Bradner termed patent documents and Investigational New Drug (IND) applications some of the best kept secrets in the pharmaceutical world and argued that such documents should be publicly available to all. If findings about other small molecules were publicly available for scientific research, more drugs like JQ1 could be brought to patients much more quickly. SICKLE CELL ANEMIA AND THE NEED FOR HEDGEHOGS5 Sickle cell disease was the first disease discovered to be caused by a genetic mutation--by Linus Pauling in 1949. Yet only one drug had been labeled for use in sickle cell--the anticancer agent hydroxyurea, which does not work for all patients and can have adverse side effects. Stephen Seiler, Founder, AesRx, described the biotechnology com- pany's efforts to develop a therapeutic specifically for sickle cell disease. The company has put together a multistage, multi-institute, public private translational research program centered on the compound Aes-103. The members of the collaboration include AesRx, the National Heart, Lung, and Blood Institute, the Therapeutics for Rare and Neglected Diseases program--which used to be part of the National Human Genome Research Institute and is now part of NCATS--the NIH Clinical Center, and the NIH Clinical Pharmacy. Two weeks before the workshop, the collaboration announced that it is starting a clinical trial with sickle cell patients. The collaboration has made rapid progress. The IND application was filed less than a year after the collaboration was announced, the healthy vol- 5 This section, including subsection, is based on the presentation by Stephen Seiler, Founder, AesRx.

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24 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK unteer safety trial was completed in less than 15 months, and the first dose was administered to sickle cell patients in less than 18 months. A successful type C meeting with FDA clarified the clinical endpoints and regulatory pathway, which, Seiler noted, is very helpful in de-risking a drug. Small biotechnology companies like AesRx have been an important part of the drug development supply chain since the 1970s. They have taken early-stage ideas, typically from academia, and converted them to more mature products. They have then handed these products off to big pharmaceutical companies, have been bought by those companies, or have become fully integrated pharmaceutical companies themselves. Over the past 5 or so years, this system has undergone a dramatic change, according to Seiler. "The ecosystem has changed so dramatically that it's become doubtful whether companies like us can continue to pro- vide the role that we have traditionally had in the drug development sup- ply chain." Venture capital funds are dramatically reducing their commit- ment to early-stage biotechnology companies for several reasons, Seiler said. First, the suppliers of venture capital increasingly have required more mature programs, which has put early-stage biotechnology projects beyond venture capital's investment horizons. Also, whether or not the perceptions are correct, suppliers of venture capital perceive there to be more regulatory risk. Finally, venture capital focuses on chasing the "next big thing" and yielding a quick return. Lessons Learned Seiler drew several lessons from his experiences developing Aes-103. The first is that a key element for success is to have programmatic and not episodic planning. AesRx started with early preclinical development and had a goal of taking the drug all the way across the biotechnology valley of death, with planning and budgeting done up front for the entire program. This programmatic planning allowed for early investments in resources that will be needed after project initiation but prior to the data emerging from the first experiments. Another key to success was an effective management team with a genuinely collaborative focus. Good science is a necessary, but not suf- ficient, condition for success, Seiler said. "Many venture capitalists spend as much time doing due diligence on the management team they're going to invest in as they spend doing due diligence on the science. So if you're trying to set up a partnership, do the due diligence on your partners well." Flexibility provided the capability to pursue new programmatic insights and unfolding data. The project was run as a virtual model with very low overhead. At the same time, the personnel involved with the

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APPROACHES TO ACCELERATING TRANSLATIONAL SCIENCE 25 project brought experience with clinical trials from the perspective of many different kinds of companies. The ingredients that drove the program so quickly and so far were focus and quick and transparent decision making, according to Seiler. He observed that small biotech companies bring incredible focus to a project. He noted that key decisions could be made in less than 2 weeks, adding that management is very impatient to move them forward. In contrast, collaborators at government agencies or in academia have many other responsibilities. Seiler recalled the statement attributed to the ancient Greek poet Archilachus, which is that the fox knows many things and the hedgehog knows one big thing. Programs like the development of Aes-103 "need a lead hedgehog," he said. One of the corresponding challenges to success was the government procurement process. Because it was a virtual program, some of the pieces had to be procured from contractors, and the procurement process is com- plicated, expensive, and slow. Another challenge is that diffuse responsi- bility can make tight budget control difficult. LEUKEMIA AND LYMPHOMA AND THE NEED FOR PARTNERSHIPS6 The goal of the Leukemia & Lymphoma Society (LLS) is supporting advancement of therapies for patients. The resources of LLS to find cures for the hematological malignancies are limited, said Louis DeGennaro, Executive Vice President and Chief Mission Officer, LLS. The society therefore needs to select and prioritize its projects carefully and foster publicprivate partnerships to drive the translation of science into treat- ments. One way that the organization selects and prioritizes projects is through a careful examination of the survival rate, age of onset, and incidence of the diseases that fall within its purview. By comparing these factors to the dollars dedicated to those diseases in the current research portfolio, funding can be compared to unmet medical needs. DeGennaro noted that although the analysis is not perfect, it is an example of multiple tools that could be brought to bear to think about how to prioritize where dollars should go in terms of research. LLS also has a new Therapy Acceleration Program (TAP), which seeks to fill the gap between academic research and new therapies. The pro- gram has a dedicated staff that searches for small biotechnology compa- nies with promising assets that have potential. Staff members also mine the society's research grant portfolio for projects that have moved out of 6 This section, including subsection, is based on the presentation by Louis DeGennaro, Exec utive Vice President and Chief Mission Officer, the Leukemia & Lymphoma Society (LLS).

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26 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK basic research and into the development stage. The TAP staff prioritizes the projects and does due diligence of the medicine, the science, and the business in the case of biotechnology companies. In part through accessing outside resources such as medical experts, business experts, and intellectual property experts, the program's funding is distributed not through grants but through contracts with timelines, milestones, deliverables, and cost- sharing components. These contractual standards serve as built-in metrics for every project, to determine how well the project is going. "We bring industry-quality project management to every program," said DeGennaro. Partnerships DeGennaro emphasized that cost and risk sharing can work. LLS does not have sufficient resources to fund the full development program, so its goal is to partner with biotechnology and pharmaceutical companies to get the projects through key hurdles. At that point, the companies can approach the capital market to raise additional dollars or partner with another company to continue the project. DeGennaro added that the LLS portfolio of about 14 projects has an annual investment of $16 million, not far from what is currently allocated for CAN. At this point LLS has more than a dozen drugs in the pipeline. Roughly half are being developed through partnerships with small biotechnology companies. By supporting late preclinical Phase 1 and Phase 2 trials, and even one Phase 3 registration trial, the society has been able to accelerate the rate at which these programs have moved through development. As just one example of success, DeGennaro cited a partnership with Celator Therapeutics to conduct a controlled Phase 2 trial on acute myeloid leuke- mia. The agent for secondary acute myeloid leukemia resulting from this trial has doubled the number of patients achieving complete remission, cut treatment-related mortality by a factor of five, and tripled the number of patients still alive at a year. DeGennaro concluded by briefly mentioning a novel partnership among the society, NCATS, and the University of Kansas to repurpose existing drugs to treat hematological malignancies. A memorandum of understanding set objectives and responsibilities, with commercialization a prominent objective. To enable that, the partnership includes a coopera- tive R&D agreement with NIH to make certain that the intellectual prop- erty generated could be used in commercialization. Within 12 months, two Phase 1 clinical trials of existing FDA-approved agents that are being repurposed to treat hematological malignancies have begun.

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APPROACHES TO ACCELERATING TRANSLATIONAL SCIENCE 27 CROSS-CUTTING ISSUES During the discussion period, several topics arose that cut across the five talks on approaches to accelerating translational science. The Alignment of Partnerships and Culture One sticking point in partnerships is that academic and commercial organizations have very different operating procedures, goals, and metrics of success. University researchers have incentives for the advancement of their students and their own research. Similarly, as Seiler observed, the style of programmatic organization in the private sector is very different from the typical NIH grant cycle. Williams added that industry has a legitimate but sometimes over- stated need for confidentiality. This issue often arises when trying to settle on contract language, where new types of agreements may be needed to get more expertise involved in collaborations. He also noted that science in academia tends to develop through deeply embedded relationships, not through the "short touches" that characterize academic researchers' involvement with industry, such as consulting arrangements or scientific advisory boards. Bill Chin, Harvard Medical School, noted that many of the obsta- cles to collaboration reside in academia and not in industry, saying that behaviors reinforced over time in academia can be obstructive to get- ting groups together. For example, most university researchers have little understanding of what biotechnology companies actually do and of the levels of expertise, creativity, and imagination that are required. "There's a tendency to think of the latter stages of the development pathways as turning the crank on routine, uninteresting work, and that's a mispercep- tion." He also said that academic researchers have a tendency to over- value what they have, "and therefore they don't come to the table with realistic views." DeGennaro emphasized the importance of better training for clinical investigators about the regulatory process. "The more of those clini- cal investigators we can train, and the better they understand the regula- tory process and their obligations, the faster the trials can get conducted." A particularly promising approach is to make use of the CTSAs to align the training and the education of a large number of clinical investigators toward regulatory science. The Use of Animals Boger remarked that Vertex has put three drugs into the market and none has had an animal model. He termed animal models "overrated,"

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28 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK because they do not take into account the complexities of the system that dictates drug responses in humans. Bradner pointed out that the successful development of cancer drugs has for years relied on the early assessment and demonstration of a thera- peutic window in animal models. Animals obviously are used as spar- ingly as possible, but for drugs relying on new mechanisms, establishing the therapeutic value in animals has been valuable. On the other hand, he noted, there is no obvious animal model for sickle cell disease, but that has not been a barrier to moving the science forward. Williams sought to distinguish the demands of the science from the demands of regulation. He said that although animal models are not required for drug development, each situation has different requirements. Some diseases will have more authentic animal models that produce evidence capable of overcoming the obstacles to a cure. He argued for an integration of all of the tools that could be applied. Cool Tools The presenters also discussed the "cool tools" that Kathy Hudson, NIH, called for in her opening remarks. Bradner said that tools could be "absolutely revolutionary" if they could perform the exhaustive and expensive predictive toxicology studies mandated in regulatory pathways at an early enough stage to prompt candidate selection. "Any of these technologies that can be released early on regarding drug metabolism would be hugely beneficial to our work." As an example of a cool tool, Tom Insel, NCATS, mentioned the NCATS pharmaceutical collection, which is a collection of all approved compounds in Europe, the United States, and Asia. Currently almost 4,000 compounds are in a repository and can be used to go directly from an approved compound to a new indication. He also mentioned the hun- dreds of thousands of compounds in a molecular libraries program that are publicly available as part of the National Chemical Genomics Center at NCATS, which NCATS will continue to streamline. Among the other tools, methodologies, and approaches mentioned by presenters were systems pharmacology, models representing various biological processes, informatics, crowdsourcing, prizes, small-molecule databases, chemical probes, and collaborative tools.