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Getting Started in Translational Research

The workshop was structured around five sessions, each focusing on a set of specific topics that the hypothetical voluntary health organization, the Colten Foundation, will need to consider as it establishes or develops its translational research program. In this chapter, the Colten Foundation is seeking advice on establishing and maintaining a productive and efficient translational research program. It is particularly interested in the criteria considered and the decision matrix used by other voluntary health organizations in their decisions to begin a research program for the development of a novel drug, biomarker, or diagnostic tool. Participants began by offering some initial considerations when getting started in translational research.

Creating novel mechanisms to support translational research is a large step, and for many voluntary health organizations it is a leap into the unknown. Several voluntary health organizations have spent decades in the core business of raising money and supporting basic research, providing direct patient care, supplying capital for facilities, or making small-scale individual academic grants. Louis DeGennaro, chief scientific officer of the Leukemia & Lymphoma Society, encapsulated some of the critical crossroad questions a foundation needs to ask when it begins thinking about new approaches to support a translational research program: what is the state of the art, the science, and the medicine?

Illustrating these points, DeGennaro discussed how 10 years ago, the Cystic Fibrosis Foundation was ready to begin supporting a translational research program. The science was at a stage where legitimate product development could occur. The foundation seized on the opportunity, and today the cystic fibrosis community has seen a rise of venture philanthropy–backed translational research.



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1 Getting Started in Translational Research The workshop was structured around five sessions, each focusing on a set of specific topics that the hypothetical voluntary health organization, the Colten Foundation, will need to consider as it establishes or develops its translational research program. In this chapter, the Col- ten Foundation is seeking advice on establishing and maintaining a productive and efficient translational re- search program. It is particularly interested in the crite- ria considered and the decision matrix used by other voluntary health organizations in their decisions to be- gin a research program for the development of a novel drug, biomarker, or diagnostic tool. Participants began by offering some initial considerations when getting started in translational research. Creating novel mechanisms to support translational research is a large step, and for many voluntary health organizations it is a leap into the unknown. Several voluntary health organizations have spent decades in the core business of raising money and supporting basic research, pro- viding direct patient care, supplying capital for facilities, or making small-scale individual academic grants. Louis DeGennaro, chief scien- tific officer of the Leukemia & Lymphoma Society, encapsulated some of the critical crossroad questions a foundation needs to ask when it be- gins thinking about new approaches to support a translational research program: what is the state of the art, the science, and the medicine? Illustrating these points, DeGennaro discussed how 10 years ago, the Cystic Fibrosis Foundation was ready to begin supporting a transla- tional research program. The science was at a stage where legitimate product development could occur. The foundation seized on the opportu- nity, and today the cystic fibrosis community has seen a rise of venture philanthropy–backed translational research. 9

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10 VENTURE PHILANTHROPY STRATEGIES The move toward translational research implies a critical change in how a voluntary health organization approaches its mandate, and there can be no one-size-fits-all approach. For the Leukemia & Lymphoma Society, for instance, the current state of science and medicine in blood cancers puts them somewhere in the middle. For example, there is a great deal of basic science that remains to be done, so the society continues to fund core academic research programs. Basic research is important be- cause it is necessary to lay a strong foundation in the basic understanding of the disease; only then can researchers effectively identify targets. The Leukemia & Lymphoma Society, for which there are real opportunities to drive therapies out of the lab and into the clinic, has been increasingly investing in translational research. For the society, that meant conducting a formal and extensive review of the existing research portfolio, explained DeGennaro. By looking at the research projects it was already funding through the lens of pharma- ceutical drug development and discovery, it found that more than 10 per- cent of its already funded projects were actually in the development stage. This showed that the state of the science and medicine in the soci- ety’s disease space was advanced enough for substantial clinical devel- opment work to begin. It had the kinds of targets, assays, and biomarkers ready and available to put a focused translational development project in place, said DeGennaro. Through the discussions at the workshop, many participants agreed that there are key factors that need to back up the decision to fund trans- lational research. Richard Insel, executive vice president of research for the Juvenile Diabetes Research Foundation, offered four key points to consider: • Know your disease • Know yourself • Know your partners • Identify your goal KNOW YOUR DISEASE To know where to begin and what needs to be funded, voluntary health organizations need a strong understanding of their target diseases and conditions—a map of their diseases. What is really known about the disease? What is unknown yet needs to be known in order to facilitate

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11 GETTING STARTED IN TRANSLATIONAL RESEARCH drug development? Celia Dominguez, vice president of chemistry for CHDI Management, Inc., noted that most degenerative diseases, even monogenic ones such as Huntington’s disease, have yet to be scientifi- cally described at a sufficient level of detail to even enable the drug dis- covery process. Katie Hood, president and chief executive officer of The Michael J. Fox Foundation for Parkinson’s Research, suggested that a simple tool, a checklist of knowns and unknowns, was extraordinarily helpful for the foundation to organize thinking around a disease. The list allowed the foundation to examine its disease space and focus its funding on check- ing off the unknowns as efficiently as possible. The objective of this me- thodical approach is to reach a tipping point where there is enough knowledge about the disease and basic research in place to create attrac- tive opportunities for the private sector to step in, continue research and development, and drive therapies into the clinic. This is fundamentally where voluntary health organizations can add the most value because they can operate outside the bottom-line focus of a publicly traded life sciences company. “We should be addressing things that other people don’t want to address because the risk is simply too high,” Hood said. She put forth some of the questions a voluntary health organization should ask about its disease space on the basis of her foundation’s work with Parkinson’s disease (Box 1-1). The answers to these questions will expose the critical area where the lack of funds and lack of knowledge meet. For any one disease, this assessment of the drug development pipeline will require examining the state of multiple targets and lead hy- pothesis. The development of this combined knowledge—the knowns and unknowns of a disease and close analysis of the drug development pipeline—has turned out to be a unique asset in the field for The Michael J. Fox Foundation. In addition, it is important to find out where the money is being spent, where it is not, and why. Over time, developing ways to share this analysis and assessment with the broader field, con- stantly communicating new developments as they occur, becomes an important contribution in the grant funding that voluntary health organi- zations provide.

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12 VENTURE PHILANTHROPY STRATEGIES BOX 1-1 Guiding Questions for Setting Up a Translational Research Program • Has the community congregated around a common set of hypotheses or mechanisms? • Is there a short list of high potential targets? • Are successful, functional, and predictable animal models in place? • Are there tissue banks and shared resources? • Do biomarkers exist? • Do clinical trial resources exist? • How advanced is diagnosis? (For Parkinson’s disease, the only defini- tive diagnosis is via autopsy, creating significant problems for clinical studies.) • How long does it take to measure the success or failure of a clinical therapy? (For Parkinson’s disease, the answer can be 5 years when evaluating a neuroprotective agent.) • Is there a clear path to and through the Food and Drug Administration? SOURCE: Hood, 2008. Biomarkers A major focus of translational research is on bringing potential tar- gets and candidates from the laboratory through development and to the patient, but this research also requires a focus on the development of tools like biomarkers to facilitate and speed this process. Workshop par- ticipants agreed that early biomarker development could greatly aid in shortening the time for industry to step in and fund research. Insel ex- plained that for type 1 diabetes, the focus of the Juvenile Diabetes Research Foundation, clinical trials last as long as 2 years, as opposed to a 3-month trial for psoriasis or a rheumatoid arthritis trial that takes 6 months. The identification of a reliable biomarker that could be used as a clinical trial end point could shorten trial times, increasing the attrac- tiveness of diabetes to commercial research. Biomarkers may have analogous roles as diagnostics in clinical practice, for example, to enable individualized medicine. Hood agreed and expressed that Parkinson’s disease drug develop- ment is slowed not just because markers do not exist to definitively diag- nose Parkinson’s disease or measure its progression, but because biomarkers of a drug’s effectiveness are also inadequate. For a voluntary health organization involved in translational research, investment in biomarkers is as important as investment in promising new therapeutics.

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13 GETTING STARTED IN TRANSLATIONAL RESEARCH For example, research in all types of biomarkers—diagnostic, disease progression, disease subtype, and drug activity or placement bio- markers—can be extremely valuable and improve therapeutic discovery. KNOW YOURSELF A recurring theme of the workshop was that a voluntary health or- ganization must explore its strengths, weaknesses, resources, and culture in order to pursue any new venture, especially something as dramatic as a move into translational research supported through venture philan- thropy. In many cases now, there is a unique role for voluntary health organizations because their value lies not only in funding, but also in their leadership, convening power, ability to bring people from different groups into the same room, and ability to articulate an overarching re- search agenda for the field. “I think it is critical to be very clear what you see as your mission, what your role is, what your niche is, and what your risk tolerance is,” said Insel. Developing a translational research program requires many things from a voluntary health organization: commitment, expectation management, the readiness to constantly examine and reex- amine progress and risk tolerance, and the willingness to change when things are not working. If an organization’s culture is resistant to this process, it may not be the right time to move into funding translational research. Joyce Nelson of the National Multiple Sclerosis (MS) Society warned that you must be prepared to face resistance. “Adapting to a new model means change, and change disrupts the status quo,” she explained. “That was particularly true for [the National MS Society] as we have been exclusively funding university research for some 60 years.” The idea of using charitable donations to fund private industry was a big cul- tural shift. Commitment Commitment from organizational leadership is key to support the program by hiring and developing the internal staff needed to bring the “big ideas” into reality, said workshop chair Timothy Coetzee. Beyond internal staff, there is also the commitment to educating other stake- holders and managing expectations. DeGennaro explained that “Volun-

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14 VENTURE PHILANTHROPY STRATEGIES teers, board members, patients, and stakeholders get very excited when you pull the trigger on a biotechnology company alliance that triggers the initiation of a clinical trial immediately.” His own group was lucky enough to have the resources to fund two such trials in the 12 months prior to the workshop. Such a ramp up in work beyond basic science turned heads. “There is a huge expectation built there that needs to be managed because the vast majority of such studies will be failures,” he explained. Expectations One of the biggest challenges that many voluntary health organiza- tions face is managing expectations, too much hype, and too much over- promise, explained Insel. Translational research is a difficult endeavor, and many times, he says, the public does not realize that. Because of this you need to educate stakeholders about what to expect. “You want hope, not hype.” In addition, it is important to have a clear line of sight to your goal and metrics to evaluate your success. This is made easier, Insel said, when everyone within the organization and all the partners are on the same page as far as time lines and milestones. Risk Tolerance The last critical area for self-awareness is the definition of risk. What level of risk is the Colten Foundation comfortable with? How does the foundation define risk? What level of risk are its donors comfortable with? As Insel explained, there are ways to build safety nets to manage risks, particularly with research facilities, by building in milestones and reviewing projects as they progress. It is a common business practice, but not one as common in academic science as it is in, say, commercial building construction. Once milestones are set and a review process is established, a sponsoring organization has the tools needed to halt a pro- ject if it goes off track. But Insel was quick to point out that the assump- tion of risk was where venture philanthropy had its strongest role. “If we don’t take on risk as a foundation,” he explained, “nobody else is going to take it on. So really the obligation is on us to take on risk.” Each of these areas—establishing commitment, managing expecta- tions, and analyzing risk tolerance—needs to be evaluated not just within

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15 GETTING STARTED IN TRANSLATIONAL RESEARCH the walls of the organization, but in the broader base of donors, patients, and advisers. Keeping these sometimes disparate groups of stakeholders motivated, committed, and involved is critical for success. The Importance of Opinion Sometimes, the most difficult piece of self-knowledge is simply knowing what you want. Hood related how The Michael J. Fox Founda- tion came to understand that it was important for the foundation to actu- ally have a vocal opinion about the priorities in the field of Parkinson’s disease research. The foundation began with the idea that it wanted to fund research faster, put fewer constraints on researchers, and facilitate quicker applications and action on promising lines of investigation. As it convened review committees and distributed funding quickly, the foundation realized that it did not know what other Parkinson’s dis- ease groups, the government, or biotech and industry were doing in the field. “What we were doing felt random,” she recalled. “We didn’t know the landscape of what other funders were doing in our space. So how did we know that what we were doing was actually needed?” The foundation launched a formal analysis to assess the research and funding landscape. Then, on the basis of these findings, it developed a plan for where its resources should be invested. Many organizations have voiced similar concerns and eventually have come to realize that opinions about what should be funded vary with who is in the room at any given meeting. Many have found that those in the room have different viewpoints and a different stake in the process, and therefore different needs. As a result it has become clear that a voluntary health organization needs to have its own opinion about where priorities are in this field. This underlines the significance of posi- tioning the organization as a central player in its field. Voluntary health organizations are in a unique role in that they can provide an overview of the state of the research, in addition to providing insight into and educa- tion for the patient community. An organization’s leadership and culture determine where the organization will tread, so it is important that every- one is on board.

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16 VENTURE PHILANTHROPY STRATEGIES KNOW YOUR PARTNERS Voluntary health organizations are not the only players in the battle against disease. The NIH, academia, and the private sector bring strength to the table, but nobody can fund the entire spectrum from basic science through to clinical approval. As Dennis Choi of Emory University high- lighted, forming partnerships with academia, industry, government, and other voluntary health organizations is necessary in order to take a par- ticular therapy all the way from idea to cure. Partnership management was a common theme throughout the work- shop. The importance of cooperation and collaboration was emphasized, as well as the challenges that inevitably arise from such relationships. The message to the Colten Foundation was this: know your strengths and weaknesses going into this program, and, as you enter into agreements and collaborations with partners, learn their strengths and weaknesses too. It is important to go into partnerships with the goal of leveraging the partners’ strengths and being sure to understand their motivation, sug- gested Dominguez. Working with the Private Sector Hood shared that in the first 4 years of the foundation’s existence, there was little meaningful communication with partners. “When you start thinking about your goal being a cure … the fact that we hadn’t engaged industry in any of our discussions meant that we were really getting only one side of the equation.” Engaging early in a dialogue with industry was one of the lessons learned. Try to understand what the needs are and what it will take from a scientific standpoint to get industry partners further engaged. This information could help to prioritize your grant process. Working with the private sector, however, implies an entirely new set of “know your partner” responsibilities that is beyond what most vol- untary health organizations are used to considering. As Insel shared, fi- nancial and organizational stability issues can come back to haunt you. While most companies are well funded and viable, there are no guaran- tees, and Insel explained that the foundation has had its share of prob- lems with unstable companies. He suggested that for the Colten Foundation, the way to protect the foundation was to enter into partner- ships with rigorous contractual requirements covering these issues and

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17 GETTING STARTED IN TRANSLATIONAL RESEARCH provide recompense when interruptions occur. (Specific legal issues are addressed later in this summary.) Public–private operational differences can contribute to misunder- standings, delays, and duplication of efforts. The worlds of academia and industry are different in several key ways, said Insel. For example, un- derstanding the difference between clinical research and clinical devel- opment is important. Oftentimes data that have been collected from clinical research trials are not applicable to company efforts; conse- quently, either the trial has to be completely redone or the data have to be reanalyzed. It will save a lot of time and effort to address this up front, Insel said. IDENTIFY YOUR GOAL As was discussed previously, knowing your target diseases and con- ditions, or having a map of your disease, is significantly helpful. A vol- untary health organization can then assess how translatable the findings from basic research are to industry partners, which will help gauge the disease’s attractiveness and the likelihood of a meaningful partnership. There exists a breadth of tasks that live under the umbrella of transla- tional research, and Insel highlighted the importance that venture philan- thropy may offer in bridging not only the funding gap, but other important gaps as well. Voluntary health organizations using venture philanthropy can help engage researchers and guide their efforts toward a “sweet spot,” Insel said, where proof-of-concept trials begin as quickly as possible in order to remove as much risk as possible from the broad gap between basic research and clinical development. Ultimately, volun- tary health organizations need to approach the process of translational research the same way pharmaceutical companies do. “The game is about creating a pipeline,” said Insel. He warned against betting on a sin- gle product; a better approach is to recognize that some level of failure is inevitable. The key is to figure out how to move each stage forward, keeping a line of sight to a product, while at the same time realizing that one organization cannot do everything. The trick, according to Cynthia Joyce of the Spinal Muscular Atrophy Foundation, is to do small things really well. There are many important gaps that a voluntary health organization may choose to focus on. For example, any target suggested by basic re- search must also be treatable with clinical therapies (pharmaceutical or

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18 VENTURE PHILANTHROPY STRATEGIES otherwise). Oftentimes, what works in an academic lab is not suited for the high-throughput world of drug development. In his experience, Insel said that the Juvenile Diabetes Research Foundation learned that many of the assays that had been developed in the academic community had to be reformatted for compatibility with high-throughput screens. Thus, a vol- untary health organization may choose to focus on validation. Another area, mentioned previously, is the identification of a reliable biomarker that could be used as a clinical trial end point that could shorten trial times, increasing the attractiveness of a given disease to commercial research. Biomarker research is an area where venture phi- lanthropy is critical because it is often hard to get other partners commit- ted to this area, said Hood. A focus on the achievable is especially important for a young organi- zation. Hood commented that The Michael J. Fox Foundation was founded with the idea that the amount of money it was going to be able to raise was going to be limited, so focusing its efforts and articulating why the funds raised were going to move the needle on developing a therapy for Parkinson’s disease was a key concept. PREPARATION NEVER STOPS Workshop participants articulated the need to constantly reexamine one’s organization to learn from mistakes, improve procedures, and adapt. The most successful voluntary health organizations are highly in- trospective and willing to change as needed. Hood explained her ap- proach: “We are constantly iterating on what we do. We look very carefully at what we think worked, what we think didn’t work, and who we need to talk to to get better at what we’re trying to do.” Coetzee summarized some key points at the end of the session (Box 1-2). As the Colten Foundation works toward developing a translational research program, understanding what is known and unknown about its disease, understanding its culture, and learning about its potential part- ners can help it decide if now is the time to move into translational re- search. Likewise, the foundation needs to be prepared to educate its constituents, even as it reexamines its efforts to invest in the best and most promising projects.

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19 GETTING STARTED IN TRANSLATIONAL RESEARCH BOX 1-2 Key Points: Getting Started in Translational Research • A large part of the initiation phase is a thorough analysis of the state of the science and medicine. • Do not rely on a single matrix for decision making; the process is unique to an organization in many ways. It is better to develop a process for coming to a decision. • Understand your target diseases and conditions; this will help you in your decision making, prioritizing, and communications. • Make a list of knowns and unknowns, and focus funding on address- ing and overcoming the unknowns as efficiently as possible. Once there is sufficient basic research in place, it becomes a more attrac- tive opportunity for the private sector to step in, continue research and development, and drive therapies into the clinic. • Examine and understand the drug development pipeline (i.e., where money is being spent and why). • Embrace the organization’s role as a key source of leadership, con- vening power, and research agenda setting. • Identify where critical unmet needs exist and establish a strategic plan for addressing them. • Be flexible when it comes time to examine and reexamine progress and goals. Keep this in mind when you encounter failure. • Be prepared to face resistance when you attempt to disrupt the status quo. • Encourage and foster commitment from organizational leadership to hire and develop the necessary staff who will drive ideas into reality. • Communicate well with stakeholders and manage expectations. • Devise metrics to evaluate your success and keep your goals in line. • Define your organization’s priorities early on, and understand that it is in the nature of a venture philanthropy program to assume a certain amount of risk that other nonventure philanthropy programs will shy away from. • Recognize that collaboration is key; leverage your and others’ strengths. • Get industry involved early through formal and informal collaborations and dialogue.

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