Mr. Shah introduced himself as the CEO of BioEnterprise, “northeast Ohio’s development catalyst for growing the biomedical sector.” He said that health care had been the leading growth sector of the Cleveland region for most of the past decade. He included not just health care delivery, led by the Cleveland Clinic, but industry as well.
“Nor is this an accident,” he said. “In 2001, our health care leadership and civic leadership came together and established the goal of making northeast Ohio a nationally recognized center for health care innovation. Those leaders recognized that this could not be the role of any single institution, but had to be a collective commitment, including investments in translational research capabilities, the identification of capital sources, and supportive state policy in the form of the Third Frontier program. It required investments in talent to help professional service firms reposition themselves and allow manufacturing firms to realign the supply chains. It required changed perspectives of clinicians and clinical institutions in their willingness to work with new innovations.
There was also recognition, he said, that a collaborative spirit was essential to connect those elements and develop an innovation environment. “That’s the essential ingredient in any thriving cluster, in any sector.” Substantial and aligned investments were made across all of those initiatives toward this common goal, he said—investments by health care institutions, regional foundations, the public sector, the business community. Today, he went on, 10 years later, the success of that aligned community has become apparent. Over the last six years, northeast Ohio is averaging $150 million a year in private investment into biomedical ventures, up from $30 million a year six years prior to 2001. The funding is fed from all around the country, and today there are more than 600 health care companies in the region, up from 250 companies in 2001. “Most importantly,” he said, “the region’s self-identity and
to some extent our national identity now includes health care innovation as a component.”
Mr. Shah introduced the panelists as “three experts on the topic of translating research and clinical insights into innovations,” beginning with Dr. Frank Douglas. Dr. Douglas had recently arrived in Ohio from Boston, where he was the founder and executive director of MIT’s Center for Biomedical Innovation.
Dr. Douglas acknowledged at the outset that “this is actually a very broad and difficult topic,” so that instead of trying to cover all its aspects, he would focus on one movement that has “everything to do with biomedical research and everything to do with how we manage our health.” That movement has been called “personalized health,” and includes a greater emphasis on prediction and prevention. He said he was one of a group of experts who participated in preparing a “Personalized Health Manifesto,” written by David Ewing Duncan, director of the Center for Life Science Policy at the University of California at Berkeley. This “manifesto,” and Dr. Douglas’ talk, both emphasized some of the “gaps” that exist in current health care, and the need to implement a new epoch of personalized health.
Toward a More Integrative Approach
Some of those gaps derive from our custom of looking at patients from an illness perspective, said Dr. Douglas, rather than a wellness perspective. He said that it was the historic strategy of the pharmaceutical industry to look for “one-pill-fits-all” solutions, a reductionist approach as opposed to an integrative approach.
A major gap, he said, is the mismatch between the “biological space and the chemical space.” Scientists have become very skillful in chemistry—making many kinds of small organic molecules that can be used to “fill any structure space you can think of.” On the biological side, however, especially concerning proteins and other large molecules, much less is known; definitive molecular structures are elusive because it is so difficult to discern the crystal structure of large molecules. “So although genomics has enabled us to identify potential targets for therapy,” he said, “without knowing the structure of these enzymes or proteins and often membranes, it’s very difficult to develop and market small organic molecules as agonists or antagonists to those targets.”
A second gap in biomedical research, Dr. Douglas said, is the activity of pathways. We now know much more about biochemical pathways and signaling pathways, he said, but we have barely begun to put together the maps
that show us when particular enzymes or receptors and “various other players within a pathway come together through activity or feedback action.” Part of the reason for both of these gaps, he said, is the isolation of specialists in “professional silos” that impede collaboration. A result of this reductionism, he said, is that we know little about basic disease questions: What is the normal natural course of a disease? How does that normal natural course change under certain situations and environmental conditions? “We do not know in a real sense what the progress of disease is.” Nor, he said, do we have biomarkers that indicate treatment failures—for example, in a particular patient sub-population—and we do not have good predictive models of diseases or how to halt them. A familiar case is when a healing agent works well in a mouse model but not in a human patient, or in one patient but not another.
Filling Biomedical ‘Gaps’ Through Interdisciplinary Platforms
Many of these gaps, Dr. Douglas said, could be corrected by using a more integrative approach. For example, wider use of chemical and biological “platforms,” studied in interdisciplinary fashion, would raise the chances of identifying disease targets, understanding the targets, and finding drugs to use against them. Such platforms have been introduced in basic research, he said, and “I think the time has come to do something similar within the transformational medicine space, to develop transformational medicine platforms.”
Since he left the pharmaceutical industry, he said, where he managed the R&D program of Aventis, he has thought hard about how to bring the industry into closer engagement with personalized medicine. He concluded that every large pharmaceutical company, instead of supporting its own massive research enterprise, would benefit by reaching out to clusters of academic and bio-tech company researchers in approaching large research questions. These might resemble the clusters northeast Ohio was forming in flexible electronics, photovoltaics, and other technologies. A pharmaceutical company could investigate much broader phenomena, such as the pathways of disease, by enlisting a diversity points of view and expertise.
Moving Closer to Personalized Medicine
Dr. Douglas suggested that other fundamental changes in biomedical research and health care could make the field more predictive and move it closer to personalized medicine. These included shifting budgets away from sales and marketing toward R&D, not granting intellectual property rights until later in the clinical trial process, and more emphasis on partnerships for pre-competitive research problems that no one institution can resolve.” If these changes were to happen,” he said, “then pharma would look more like integrators of many small specialty players. The VC companies would become true translators, and more
directly help translate research into products. And of course you will have more academic/industry/government collaborations.”
Finally, he said, external forces, notably the Federal government, could help give new shape to the bio/pharma space. “What if the government and other players said they will only fund certain conditions, such as Alzheimer’s, some cancers, and some orphan diseases, and not the rest? What if they mandated the use of generics by drug class? What if proof of efficacy and identification of side effects were required for approval of all non-generics? What if preventive health measures were preferentially reimbursed? What if we gave approval at Phase 2, and in Phase 3 you do large, normal-use trials to confirm the efficacy or widen the knowledge about side effects?”
Not every therapy lends itself to personalized medicine, Dr. Douglas emphasized. But merely shifting the balance away from “one-size-fits-all” toward prediction, prevention, and individualized care can capitalize on vast new stores of knowledge about human biology. He reiterated some of the major points of the “Personalized Health Manifesto,” asserting that “a reordering of priorities is required to stress the application and translation of what has been learned to improve health and to reduce health care costs. If you think about these kinds of changes in a major industry,” he concluded, “I think you begin to see tremendous opportunities for innovation and job creation.”
Dr. Cosgrove, a heart surgeon, began with the development three decades ago of a closed-loop system for delivering a drug that controlled blood pressure. The system got FDA approval, and eventually received a patent and a contract with a company. “That process resulted in my walking into the office of the CEO of the Cleveland Clinic and giving him a check for $50,000. That was the first time that the Clinic had ever patented anything or received any royalty. I remember the look of amazement on the CEO’s face that I could do anything other than find my way out of the operating room. He said, ‘Well, perhaps we could make a business out of this,’ and gave me probably the greatest gift an innovator could have. He assigned David Morgenthaler to try to tutor me.”
The Need for Incentives and Support
Dr. Cosgrove recalled the process of reviewing the Clinic’s activities with Mr. Morgenthaler, trying to understand where intellectual property of value might be. After many early failures, they tried in 2000 a two-pronged approach: first, a free-standing venture capital firm, and second, a tech-transfer organization they called Cleveland Clinic Innovations. After hiring a director, they began to realize all the things that were required to make technology
transfer happen. First, they had to encourage doctors to bring forth their innovative ideas. Second, they had to provide some financial and support resources for them, including legal advice, space, and other forms of encouragement.
Over time, Cleveland Clinic Innovation became successful. Looking back on the past 10 years, he said, he could count some 352 patents granted and 1,600 filed—“a slow, laborious process.” The group has attracted $450 million in equity investments and another $148 million in commercialization grants, mostly from the state. It has returned $46 million to the Clinic inventors, and created 740 jobs, 528 of which are in Ohio.
Aside from receiving royalties, he said, the organization had begun to spin off companies. It had formed 36 of them, 30 of which are still active. One of them, IntElect, had recently been sold for $28 million to the Cleveland Clinic. “This has been a profitable endeavor for us,” he said, “and continues to gather momentum.” One of the catalysts for encouraging doctors to participate was the Sones Award, a $50,000 award named after F. Mason Sones, a pioneer of coronary angiography. This award, given annually for any type of innovation, and an equal share of royalties for the inventor has brought increasing attention to the importance of innovation at the Clinic, he said.
In the beginning, Dr. Cosgrove and Mr. Morgenthaler thought they would find potential new companies only based on medical devices. While it is true that only a single diagnostic company had been formed, the Cleveland Heart, more healthcare IT companies are appearing as younger physicians generate new ideas in this field. This requires special expertise to handle the intellectual property and patenting, and to judge which ideas have commercial potential.
Commercializing New Devices: The Need for New Skills
Dr. Cosgrove summarized their progress under two headings. First, they have learned that they sit on a “reservoir of intellect” that can produce new products and devices, and they have developed a procedure to commercialize them. Several medical organizations have asked if they will serve as their tech transfer entity, recognizing that it does take an investment of time, effort, and money to develop these capabilities. They currently have a relationship with MedStar, one of the largest medical systems in the Mid-Atlantic States, and are discussing the issue with several other organizations. Secondly, they have succeeded in closing major sales of startup companies.
Dr. Cosgrove concluded that “it’s been a long trip of trial and error,” and said that he and Mr. Morgenthaler had learned that the process has more than one stage. “It is essential to encourage physicians to bring their ideas and their inventions forward,” he said, “but it is just as important to stay with them all the way through to commercialization.”
Dr. Barker began by saying that “we are probably at an inflection point in biomedicine and cancer, and I think this will be the century when a lot of these diseases are conquered. But this will require a redefinition of the way we do medicine.” She agreed with her fellow panelists that the journey toward personalized medicine had begun, and that it would be and difficult though ultimately rewarding one.
Dr. Barker said that when she arrived at the National Cancer Institute in 2002, her goal was to “see if one could actually innovate in the government,” and if one could help advance the field toward personalized medicine. She also noted that the 40th anniversary of the National Cancer Act has arrived, the act which launched the “war on cancer.” Even after those decades of hard work, one in three people still die from the disease, a reality so familiar that “people often accept it as inevitable.” She made this reality more specific by pointing out that Ohio this year would have 65,000 new cases of cancer.
Mortality Rates Have Remained the Same
Dr. Barker pointed to a graph that showed that unlike heart diseases and cerebro-vascular diseases, where mortality has fallen by more than half in the last 50 years, the mortality rates for cancer have remained virtually the same. This creates crushing personal and financial burdens not only in the U.S., but around the world. The global scourge of cancer currently includes some 7.6 million deaths (2008) and $895 billion in spending. Deaths are projected to rise to 10.3 million by 2020. “I would argue that it will become almost destabilizing in terms of these costs,” she said. For example, in China, there are 350 million smokers. They are not likely to quit soon, she said, because the tobacco industry is a national industry. By 2035 about 23 percent of their population will be over 65, when the chance of getting cancer goes up “quite dramatically.”
Referring to the talks of both Dr. Douglas and Dr. Cosgrove, she said that 21st-century medicine is likely to be as different for cancer as it will be for diseases generally. At its base, she said, “personalized medicine” was molecularly based medicine. It would focus on identifying the particular genomic changes of each person—either genetic changes inherited from parents or somatic changes acquired after birth. “The genes begin to be the basis for how we actually diagnose, treat, and ultimately prevent disease. And I would argue that this whole continuum has got to move further and faster toward prevention. We tend to focus on treating established disease, not preventing it. We will have the tools to prevent cancer, we will have the tools to prevent other diseases; the issue is how we change the mindset.”
We are living in an era of convergence, Dr. Barker said, among the molecular sciences, bioinformatics and computational sciences, physics, and engineering. “Now that’s a mouthful, but that’s exactly what’s happening. And it’s happening as we speak, and I think it will drive a new wave of disruptive innovation. We are beginning to sort out genomic changes in all these diseases, and how they affect the pathways. We’re modeling that; we’re bringing in the bioengineers to figure out metastasis. That’s all moving quickly into patients and into communities in ways we can’t envision. And social networking is going to have a huge impact on medicine, because consumers will be as informed or more informed than their physicians.”
Changing the NCI: ‘Not for the Faint of Heart’
Dr. Barker cautioned that bringing change to a place like the NCI, however, “is not for the faint of heart. It’s very difficult to do innovation in the government, and there is a lot of push-back.” She recalled setting out to improve protocols for biospecimens—biological materials, such as blood, tissue, cells, and DNA to be stored for future research. “We had no rules for biospecimens in this country, no standards, no protocols for stewardship, no approach for access. That is the stuff of personalized medicine. We are beginning to change that.”
Another gap of modern medicine, she said, is that “research is not connected to the bedside in any meaningful way. We talked in the first panel this morning about the silos, and we have to break through them.”
In the area of cancer, Dr. Barker said, the human genome has now been sequenced, and that has given scientists the tools they need to sequence cancer genomes. “Francis Collins and I started a program called the Cancer Genome Atlas,” she said, “and that’s one of the places we had to start with personalized medicine. When we finished the human genome, we had a normal genome to compare with an abnormal genome. I’m going to let you look under the tent with me at some science, and you can see why I’m so excited about this.”
Cancer as a Disease of the Genome
“Cancer is a disease of the genome,” Dr. Barker continued. “You inherit these mutations or you get them after you’re born. We set out to identify all of the genomic changes in all the cancers. That’s a big undertaking, so we started with 20 cancers, most of the major ones. The specimens flow to the characterization centers, the sequencing centers and the data comes out the other end—a lot of data. We are currently approaching generating petabytes of data.”
The first cancer was glioblastoma, a brain tumor, and they were able to characterize this tumor into three different subtypes. “I can tell you [the atlas] is already changing practice for brain tumors. Now we can actually look at a patient and say: you shouldn’t have this treatment, you should have that treatment based on your subtype. The other thing the project has done is drive
technology development. We are moving toward technology that can sequence a genome for $1,000.”
Cancer as a Complex System
Dr. Barker said that cancer is not going to be easily defined. “It is an emergent, complex system. The sum of the parts is actually much different than the parts per se, so we have to look at it differently. We try to bring people together from the intersections of fields. We have to start thinking about research differently. We have been stuck with just empiricism for a long time, sort of developing a parts list for cancer, cardiovascular disease. Now we need unifying theories for these diseases.”
She said that the snowflake is a good analogy for the complexity of cancer, “the kind of complexity that physicists understand.” Just as no two snowflakes are alike, she said, it now appears that no two patients’ cancers are alike. The cancers show up in these patterns like snowflakes, “and you don’t have to be a scientist to see that the cancers are different. It’s a little discouraging. We’ve got all these communities that live in silos, and we need them to work together.”
In summary, Dr. Barker said that creating a system of personalized cancer medicine will require the IT infrastructure, a system of handling biospecimens, a compendium of all the genomic changes, and a responsive translational research infrastructure. All this will require new funding. “We can’t afford this amount of innovation,” she concluded. “But in fact we can’t afford not to innovate. I think you’re at the inflection point, and it’s the right time to enter this space.”
A questioner asked what preventive tools should be used for cancer, and how successful they might be. Dr. Barker said that the most important prevention is to not smoke, to eat a healthy diet, and to avoid being overweight. However, for the approximately 28 percent of those who, despite their best preventive efforts, get cancer based on “a whole range of genetic issues, we will be able to identify those genes.” She noted that the industry “has never really been able to embrace chemo prevention—that is, making drugs that people can take every day.” She said she would argue that Lipitor is a chemo preventive, and that the issue of chemo prevention is on the horizon. “So I think if you add up all the factors that are controllable to what can be done through research, you could prevent most of these diseases, with certain exceptions. And I think we have to do that, because the cost of treating cancer with a drug from the pharmaceutical industry today is about $250,000 per an additional year of life. That’s staggering.”
Mr. Bendis said that an impediment to better translational research is the conflict of interest policies set by the Federal agencies for Human Genome
Sciences and MedImmune. This evolved out of NIH when conflict of interest policies were different, he said, but the government may have gone too far in the other direction. “What do we have to do to convince Congress and everybody else to come back to the middle so we can open up some pathways.” Dr. Barker said she had had to deal with such ethics issues at NCI, and went to a lot of Congressional hearings, “and we did have some problems. I think you’re absolutely right it’s swung too far back the other way. If you have investigators who can work on nothing that they’ve developed, especially the trials, then you’re not going to move anything forward.” Dr. Cosgrove said he would second that, and that the Cleveland Clinic had “tried to take a fairly aggressive policy, where all our physicians list all their financial relationships and make them public on the Internet. I think that’s the first and a very reasonable step to take.”
Robert Schmidt, of Cleveland Medical Devices, asked about some major medical trends, including the Internet and miniaturization. “Things that used to fill up a room and cost millions of dollars are now a few thousand dollars and then $49 at CVS.” With cutbacks in Medicare and Medicaid and higher insurance costs, he asked, will more medical devices be moving into the homes, and what other changes could be anticipated? Dr. Cosgrove agreed that technologies are changing, as are disease distributions. “We’re no longer seeing acute diseases in hospitals like we used to; now the majority are chronic diseases. And over the last 25 years, we have 200,000 fewer beds for 70 million more people. So healthcare is moving from inpatient to outpatient and eventually to homecare. In terms of the recent legislation and changes in government programs, hospitals are going to come together in systems. I think there will be fewer independent hospitals simply because of the complexity that is required in the back office to manage a hospital. I think there will probably be 500 to 1000 fewer hospitals across the U.S., as well as hospitals rolling up into systems.”
Towards a More Open, Holistic Research Model
Dr. Wessner asked what Federal or state investments the panel members would wish for. Dr. Barker said that “the short answer is everything,” but that she would begin by directing Federal money into regional public-private partnerships and clusters. “The emphasis could be IT or centralized biospecimens or networks for doing clinical trials, all are needed. I would start with measures that have promise in the personalized medicine space. Frankly, I don’t see this entire system developing quickly absent some Federal investment.” Dr. Douglas agreed on the priority of clusters. “You could insist on having a number of clusters, and those clusters would include IT, engineering, and biotech companies able to take innovations rapidly to commercialization. This would not require new money; the government could support a regional cluster with money already there.” Implicit in support for clusters, he added, is support for shifting toward a multidisciplinary, holistic approach. Dr. Cosgrove
said he was concerned about inadequate funding for research or innovation in a more and more constrained economy. “One thing I see coming may be more open research projects. Michael Milken has suggested that he will fund research around prostate cancer if in fact results are shared openly and immediately. That’s a huge step in the right direction. Rather than hoarding information in hopes it will be published in Nature, we speed up the efficiency. There has been a very interesting proposal to put problems on the Internet and reward people who come up with solutions regardless of where they are in the world. That draws in the best brainpower and mobilizes more diverse resources.”