PANEL I

MR. DONALD J. LISTWIN:

CANCER EARLY DETECTION

Background

Mr. Listwin is founder and chairman of the Canary Foundation, the nation’s only nonprofit organization devoted exclusively to early detection of cancer. A 25-year veteran of the technology industry, Mr. Listwin was CEO of Sana Security and Openwave and was the second-ranked executive at Cisco Systems. Mr. Listwin launched the Canary Foundation as a way to address the imbalance in cancer research—less than 15 percent of research funding goes to early detection. Mr. Listwin serves on the Boards of Directors of GenoLogics Life Sciences Software, Calix, Teradici, the Moffitt Cancer Center Comprehensive Research Center in Melanoma, Stratos Biosciences, and the Listwin Family Foundation. He is on the External Advisory Boards for both the Center for Cancer Nanotechnology Excellence and the Early Neoplasia Detection Center at Stanford University and is a member of the Board of Trustees at the Fred Hutchinson Cancer Research Center.

Key Points

• The Canary Foundation focuses exclusively on early detection of cancer and is developing strategies that utilize both blood biomarkers and molecular imaging. Effective early detection techniques could decrease cancer mortality for the overall population as well as reduce the economic burden associated with cancer management.
• The Canary Foundation research program is multidisciplinary and collaborative and is funded in conjunction with multiple sources, including other foundations, government, and industry.
• The Canary Foundation bases its funding model on that of the Department of Defense (DoD) Defense Advanced Research Projects Agency (DARPA) project that resulted in development of the Internet. DoD wanted to replace its hierarchical communications system, which became inoperable if a single component was disabled, with a highly distributed network that would remain operational in the event that some components were compromised. Two companies were each given $60 million dollars to develop prototypes of such a system, and one prototype led to the creation of the Internet. The development of this complex communications network was achieved because the challenge was addressed using a “systems approach.” Cancer is among the most complex systems but researchers continue to focus on point solutions to fight this disease, which is a flawed strategy.
• A flaw in the current approach to cancer research is that the majority of funding dollars is spent on late-stage cancers. Cancers detected at advanced stages are far more likely to cause death than those detected when the cancer is confined to the site of origin. The Canary Foundation estimates that only $1 is spent on early detection and prevention for every $1,000 spent on late-stage cancer treatment.
• A paper published in Science reported that it takes about 25 years for colorectal cancer to develop from its initial stages to metastatic disease. Yet, researchers continue to study the disease at its late stages to inform early detection strategies. Colorectal cancer is a genetically different disease at advanced stages compared with early stages. Research needs to target the early stages of disease and scientists must be given access to the right materials to do this.
• A model was developed based on Surveillance, Epidemiology and End Results (SEER) data to determine the probability of cancer cure by tumor size. For lung cancer, treatment usually begins when the tumor is 20 millimeters in diameter. At this size, the survival rate is about 20 percent. In order to achieve 80 percent survival, lung cancer must be detected and treated when the tumor is 1-2 millimeters in diameter.
• Currently available cancer diagnostics are not generally cost-effective, in part because they can lead to unnecessary surgeries. There needs to be a confirming step (imaging or biopsy) between a diagnostic test and surgery. The Canary Foundation has a three-stage strategy for developing cost-effective diagnostics: identification of high-risk populations, administration of a preliminary blood test, and confirmatory molecular imaging.
• This three-stage strategy is exemplified by Canary Foundation efforts related to ovarian cancer screening. The current approach for ovarian cancer screening involves two steps: measurement of the blood biomarker CA125 and conventional transvaginal ultrasound. This approach is currently being evaluated by NCI’s Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. The Canary Foundation is comparing this approach with two other strategies: (1) CA125 measurement and molecular ultrasound and (2) measurement of next-generation blood biomarkers (novel blood biomarker panel) and molecular ultrasound. Simulated results of these screening modalities show a reduction in ovarian cancer mortality of 5 percent with CA125 and conventional ultrasound, 16 percent with CA125 and molecular ultrasound, and 25 percent with the blood biomarker panel and molecular ultrasound.
• The current ovarian cancer screening approach is not cost-effective for the general population; however, with a better blood test and the use of molecular ultrasound, screening could become more cost-effective, even for low-risk populations.
• Researchers at Stanford University have built a magneto-nano sensor array that is 1,000 times more sensitive than an enzyme-linked immunosorbent assay and is able to measure 64 different molecules simultaneously. This technology has the potential to aid in the earlier detection of tumors.

DR. YUN-LING WONG:

ONE GREAT IDEA

Background

Dr. Wong received her Ph.D. from the Harvard School of Public Health. Her doctoral work entailed developing an inhaled vaccine for tuberculosis. She has been published in peer-reviewed journals, including the Proceedings of the National Academy of Sciences, and featured in Newsweek. Dr. Wong is a Program Officer on the Global Health Discovery team at the Bill & Melinda Gates Foundation. Dr. Wong leads the Grand Challenges Explorations (GCE) program, which is counted as one of the most successful programs for discovering and fostering new ideas in the field of health research for solutions to problems in the developing world.

Key Points

• The Bill & Melinda Gates Foundation is organized into three main program areas: Global Health, Global Development, and the United States Program. The Global Health Program focuses on ways to fight and prevent infectious diseases, such as HIV/AIDS, malaria, pneumonia, and tuberculosis, in developing countries. The mission of the Global Development Program is to increase opportunities for people in developing countries to overcome hunger and poverty. The United States Program helps to ensure greater opportunity for all Americans through the attainment of secondary and postsecondary education with genuine economic value.
• The Grand Challenges in Global Health initiative is focused on engaging creative minds to work on scientific and technological breakthroughs for the world’s most pressing health problems. GCE is a grant program within the initiative that fosters innovative, early-stage research to expand the pipeline of ideas that may lead to much-needed global health solutions.
• GCE is based on three basic tenets: low burden of entry, champion-based review, and an open path to success. The low burden of entry is facilitated in part by the fact that grant applications are anonymous—they cannot include indicators of an applicant’s background, experience, or qualifications. Anonymity was built into the application process so that innovative ideas would be considered equally, regardless of the applicant’s expertise or career stage.
• With a champion-based review, each reviewer has the ability to choose one proposal that will automatically receive funding; reviewers can also recommend additional applications for funding consideration. Disagreement can occur among reviewers about the merit of an idea; however, this approach results in a diverse, high-risk portfolio with projects that may “fail spectacularly” or exceed reviewers’ greatest expectations.
• An example of a successful innovative application for global health is the invisible mosquito net to combat malaria. An astrophysicist from Columbia University applied a technology he developed for looking across dust particles in space to develop the virtual net. The invisible mosquito net is composed of infrared light, which blocks the short-range navigation of mosquitos. This idea might have never come to fruition if it were not for the champion-based review process.
• The open-path-to-success tenet refers to the fact that the Gates Foundation will provide support and funding for an idea at the early stages and, then, if warranted, for subsequent steps in the development process. Grantees are responsible for contacting the GCE when they are in need of subsequent funding, which empowers the innovator to drive the research agenda forward.
• GCE is in its second year of funding. To date, 20,000 applications from over 130 countries have been received, and 432 grants ($43.2 million) have been awarded in 35 countries. Every six months there is a rolling call for proposals. The proposal topics vary depending on recent gaps that have been identified in the global health and development fields.
• The grant application process builds its own momentum. Innovators may propose an idea for one topic that is actually a better fit for a second or third topic, thus facilitating a steady stream of proposals for each grant application topic. Past topics have included: Poliovirus Endgame, Cure HIV Infection, and Low-Cost Cell Phone Applications.
• GCE has found that providing an open path to success and creating a low barrier of entry are critical for encouraging innovative people and ideas to enter the global health and development research realm.

DR. E. MELISSA KAIME:

HOW THE CDMRP ACCELERATES SCIENTIFIC INNOVATION

Background

Dr. Kaime joined the Congressionally Directed Medical Research Programs (CDMRP) staff in June 2005 as Deputy Director, overseeing the day-to-day operations of the program. She became Director of the CDMRP in July 2008. She came to CDMRP after 15 years of service at the Naval Medical Center, San Diego (NMCSD), where she was Director of the Breast Health Center and a staff physician in the Division of Hematology/Oncology. She served in Operation Iraqi Freedom II, providing trauma care for coalition forces, insurgents, and civilians in Al Asad and Fallujah, Iraq, from August 2004 to March 2005. Captain Kaime completed a B.S. in engineering from Vanderbilt University, graduating in three years with magna cum laude honors. She earned her M.D. from St. Louis University School of Medicine and then completed her internship and internal medicine residency at the Naval Hospital in Oakland, California, and a hematology/oncology fellowship at NMCSD.

Key Points

• CDMRP resides within the U.S. Army Medical Research and Materiel Command and is the second— largest research funding source for breast, prostate, and ovarian cancers.
• CDMRP was created in response to efforts of breast cancer advocacy organizations seeking novel approaches to fund innovative, potentially high-impact research. DoD was chosen to adminster the congressionally mandated funding because of its history of medical research and flexible administrative structure.
• CDMRP focuses on high-risk/high-gain research and provides opportunities for investigators to produce preliminary data needed for further funding. Two important aspects of CDMRP are the focus on innovation and the involvement of consumer advocates (i.e., survivors, family members, and caregivers affected by the disease being studied).
• Since its creation in 1992, CDMRP has received over 75,000 proposals and funded nearly 11,000 grants; 14,000 proposals were received in fiscal year 2009 alone. On average, CDMRP funds 10 percent of the applications it receives.
• CDMRP holds investigator meetings at which all program grantees report their results, both positive and negative. It is important to report research results to stakeholders, even if the findings are negative, since knowledge is gained through these so-called failures.
• The purpose of CDMRP is not to compete with other large funding agencies, such as NIH, but to complement them. CDMRP targets critical research gaps and makes efforts to focus its funding on areas that are underrepresented and underfunded. The Programs also focus on innovative research— they take risks on novel hypotheses and support visionary individuals. Some CDMRP award mechanisms—for example, Concept Awards, Idea Development Awards, and Hypothesis Development Awards—specifically solicit innovation. These are typically small awards that range from $35,000 to $150,000 over a 12-to 18-month time period. Reviews are focused on the scientific hypotheses since proposals do not require preliminary data and reviews are blinded.
• The CDMRP Integration Panels (IPs), which comprise visionary scientists, clinicians, and consumers, set the Programs’ annual investment strategies and, during programmatic reviews of proposals, make funding recommendations to support those strategies. The IP for each research program defines the focus of research efforts in response to dynamic changes in each respective field. This process allows rapid response to changing needs and implementation of funding mechanisms that are crafted to target those needs.
• Consumer advocates are full partners to the scientists and clinicians on the IPs and are key to pushing innovative ideas forward. The consumers ask questions the scientists might not ask and are constant reminders that the primary goal is to improve the lives of patients.
• For example, a Concept Award that was funded in 2004 to develop methods to visualize circulating breast tumor cells in vivo led to discovery of tubulin microtentacles on cancer cells, which attach to the endothelium and invade normal tissue. The two scientists on the IP who reviewed this Concept Award application gave the idea only a “very good” score (the scale is very good, excellent, outstanding); however, the consumer advocate thought the idea was amazing and her enthusiasm resulted in the award being funded. In 2010, the same Concept Award grantee was given an Era of Hope Scholar Award ($2.5 million) to assemble a multidisciplinary team in a physics-based approach to further develop this innovative idea.
• The Prostate Cancer Clinical Trials Consortium (PCCTC)—which is supported by CDMRP and the Prostate Cancer Foundation—was developed as a way to hasten the development of better therapies for patients through faster and more efficient clinical testing. Scientists and clinicians from the PCCTC member organizations collaborate to design, implement, and complete Phase I and Phase II trials in prostate cancer. PCCTC has not only met the initial goals established by the CDMRP award mechanism, but has laid the groundwork to define common clinical standards in the field of prostate cancer.
• CDMRP has also encouraged innovation by supporting visionary thinkers. Funding of Innovator Awards, which provide investigators with $5 million over a period of up to five years, is based on general creative ability rather than a specific research plan, and proposals are evaluated based on personal interviews.

DR. SCOTT CAMPBELL:

ACCELERATING CANCER DRUG DEVELOPMENT WITH BIOMARKERS,  PERSONALIZED MEDICINE, AND PUBLIC-PRIVATE PARTNERSHIPS

Background

Dr. Campbell is Executive Director and CEO of the Foundation for the National Institutes of Health (FNIH). He received his Ph.D. in basic biomedical sciences in 1985 from the University of South Florida. Following postdoctoral training in cardiovascular physiology at the University of Ottawa in Canada, he spent 12 years in academia at the Michael Reese Hospital in Chicago, the University of Missouri, and the University of South Dakota, where his primary areas of research interest were hypertension, heart failure, and the renin-angiotensin system. Following his academic career and prior to joining FNIH, Dr. Campbell served as National Vice President of Research Programs at the American Diabetes Association (ADA) from 2001-2010. In addition to overseeing all research-related programs at ADA, he was also responsible for helping acquire major donations to the ADA Research Foundation. He had primary responsibility for oversight of the ADA Research Grant Review Committee, Research Policy Committee, and Scientific and Healthcare Council. Internationally, Dr. Campbell was the ADA Research Program liaison to the European Association for the Study of Diabetes and the International Diabetes Federation.

Key Points

• FNIH is the sole organization authorized by Congress to support the mission of the NIH by creating and managing public-private partnerships. FNIH is a nongovernmental organization with an independent Board of Directors; the NIH Director and the U.S. Food and Drug Administration (FDA) Commissioner act as ex-officio Board members. This 501(c)(3) nonprofit organization has raised over $560 million in the past 15 years in support of over 400 projects. There are currently over 100 active programs, including major research partnerships, scientific education/training, conferences, and facilities.
• FNIH creates innovative public-private biomedical partnerships that complement NIH priorities and advance public health. It provides a neutral forum for bringing partners together. The Foundation uses a structure that enables efficient, effective collaborations and flexible donor relationships. The Foundation has received a four-star Charity Navigator rating for the past four years and is ranked among the top ten charities in the area of medical research.
• The majority of FNIH funding comes from the Bill & Melinda Gates Foundation and the pharmaceutical industry. The Gates Foundation Grand Challenges in Global Health Program has provided over $200 million in funding.
• Some initiatives with which FNIH is currently involved include the Alzheimer’s Disease Neuroimaging Initiative, for which the Foundation has raised $48 million; the Observational Medical Outcomes Partnership, for which $25 million has been raised; and The Biomarkers Consortium, for which $40 million has been raised.
• The Biomarkers Consortium was launched in 2006 to identify, develop, and qualify biological markers to support new drug development, preventive medicine, and medical diagnostics. There is broad participation from stakeholders across the health enterprise—government, the pharmaceutical industry, academia, patient advocacy, and other nonprofit private-sector organizations. The consortium was founded by FNIH, along with NIH, FDA, the Pharmaceutical Research and Manufacturers of America, the Centers for Medicare and Medicaid Services (CMS), and the Biotechnology Industry Organization.
• The Biomarkers Consortium has 62 contributing members, which include 28 companies and 34 nonprofit organizations, advocacy groups, and trade associations. To date, 13 projects have been approved and 10 have been launched. It is of particular importance that all biomarkers associated with an approved project be qualified by the FDA.
• The goals of The Biomarkers Consortium are to use new and existing technologies to develop and validate biomarkers for specific applications in diagnosing disease, predicting therapeutic response, or improving clinical practice. The Consortium is also focused on generating information to inform regulatory decision-making and making consortium project results broadly available to the entire scientific community.
• The Consortium is governed by an Executive Committee, which includes representation from NIH, FDA, CMS, industry, the general public, and FNIH. The Consortium is focused on four disease areas (cancer, metabolic disorders, neuroscience, and inflammation and immunity), each of which has its own Steering Committee. The Steering Committees usually have both NIH and industry representation and screen all relevant project ideas.
• One area of focus in the cancer arena is fluorodeoxyglucose injection (FDG)-positron emission tomography (PET), which is being evaluated in both lung cancer and lymphoma. FDG-PET exploits the reliance of tumor cells on glucose and glycolytic metabolism to image cancers. FDG-PET is approved for use in diagnosis, staging, and restaging of a variety of cancer types, but has not yet been approved for biomarker usage. FDG-PET can provide an early measure of response to treatment with approved therapies in a number of clinical settings. With a few additional studies, FDG-PET could facilitate both drug development and patient care by helping define and monitor response to chemotherapy and facilitating shorter-duration Phase II studies, which should accelerate testing in Phase III trials and drug approval. Additionally, better patient care will result by identifying ineffective therapies earlier.
• The decision to examine FDG-PET in lung cancer and lymphoma was made because both of these cancers have unmet medical needs requiring new drugs or therapies, and there are existing clinical FDG-PET data for diagnosis and staging for both of these diseases. In lung cancer, there are existing retrospective data on early response. In lymphoma, there are established treatment response criteria that can be refined by FDG-PET.
• To date, 70 non-small cell lung cancer patients have enrolled in the lung FDG-PET study, and 61 patients have enrolled in the lymphoma study. By the fourth quarter of 2010, the lymphoma study had completed 24 months of follow-up in 31 patients.
• The interim goals for these studies are to: evaluate image analysis methods and develop consensus standards for use in clinical trials; coordinate efforts with the Radiological Society of North America through the Quantitative Biomarker Alliance initiative, in consult with the FDA; and prepare initial briefing documents for consideration by the FDA Biomarker Qualification Review Team.
• There are benefits for all stakeholders involved in the FDG-PET studies. Patients will benefit from the availability of better clinical data, which should result in more effective treatment and disease management. The FDA will receive the necessary information for evidence-based regulatory policy. The pharmaceutical industry will have a more efficient drug development and approval path and better early-response criteria. There will be a larger market for PET/computerized tomography (CT) and PET/magnetic resonance imaging (MRI) scanners for the device industry. Study data will help CMS determine whether FDG-PET should be considered part of “reasonable and necessary” care.
• The current development model for an FDA-approved drug takes 10 to 15 years, 1,000-6,000 patient volunteers, and approximately $1 billion. Inefficient clinical trials account for a majority of the time and cost associated with the failures of this drug development system. An FNIH-supported biomarker project aims to implement a more efficient clinical trial process. The more efficient process would reduce time to conclusive results, reduce the number of required patients, reduce the cost of conducting trials, and increase collaboration and data sharing.
• FNIH is the sole funder of the I-SPY 2 trial, which builds on the prior, NCI-funded I-SPY1 trial. The I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2) is a clinical trial for women with newly diagnosed, locally advanced breast cancer to test whether, prior to surgery, adding investigational drugs to standard chemotherapy is better than standard chemotherapy alone. The I-SPY 2 adaptive trial design will stratify patients into two arms based on HER2 receptor status. Patients will receive standard treatment along with new experimental agents. In regard to trial design, five critical, innovative components are being implemented that have the capacity to change how future clinical trials are designed: neoadjuvant setting; adaptive trial design; molecular and imaging biomarker guidance; testing of multiple drugs simultaneously; and efficient organizational structures.
• I-SPY 2 is being conducted as a large-scale public-private partnership with many stakeholders coordinated by FNIH. These stakeholders include the National Cancer Institute and the FDA as well as multiple pharmaceutical companies, laboratories, nonprofit organizations, and academic institutions. The lead institutions are the University of California, San Francisco and The University of Texas MD Anderson Cancer Center.
• FNIH plays multiple roles in the management of I-SPY 2. FNIH holds the master Investigational New Drug (IND) application with the FDA, manages projects, and negotiates and holds contracts with trial sites, pharmaceutical companies, biomarker companies, and other entities. FNIH also serves as a trusted third party to manage data and intellectual property generated by the trial to maximize public health benefit.
• Researchers hope I-SPY 2 will improve outcomes for the highest-risk breast cancer patients and establish the general value of biomarkers, as well as illustrate the utility of the specific cancer biomarkers used in the trial. It is also hoped that the trial will demonstrate how adaptive design can streamline clinical trials. In addition, future studies should benefit from the work that I-SPY 2 investigators have done with the FDA to develop appropriate regulatory pathways for adaptive trials. I-SPY 2 may also provide a model for collaboration among scientists from academic medical centers, government, and industry.
• It is expected that I-SPY 2 will help generate biomarker profiles that will help predict and/or monitor the effectiveness of each of the investigational drugs included in the trial. Agents will be able to move to smaller, more focused Phase III trials, resulting in lower costs, fewer patients, and an accelerated regulatory process. Results with different agents will provide insight into which molecular signaling pathways are most amenable to intervention. Breast cancer science will move toward the personalized medicine era, with targeted treatments for tumors with different molecular profiles.
• The work of FNIH exemplifies the ability of public-private partnerships to expedite needed changes in cancer clinical trials. These changes include advancing the consensus needed for regulatory science, making data broadly available, sharing intellectual property, qualifying biomarkers, promoting personalized medicine, and testing novel clinical trial designs.

MR. WILLIAM J. TODD:

THE GEORGIA CANCER COALITION: AN INNOVATIVE MODEL, A NATIONAL EXAMPLE

Background

Mr. Todd has been President and CEO of the Georgia Cancer Coalition (GCC) since 2003. Mr. Todd's 39-year career has focused on health care and technology management in Atlanta, Georgia. He was the founding President of the Georgia Research Alliance, which was established in 1990 and has helped build Georgia's reputation as a center for discovery and invention and fostered major advances in science, medicine, and technology. He founded Encina Technology Ventures in 2000. His career began at Emory University hospitals, clinics, and the medical school, where he held a variety of administrative posts over two decades, ultimately serving as Assistant Vice President for Medical Administration at the Robert W. Woodruff Health Sciences Center. Mr. Todd is a graduate of the College of Management at Georgia Institute of Technology and attended the Institute for Educational Management at Harvard University.

Key Points

• GCC is an independent, nonprofit organization that unites government agencies, academic institutions, civic groups, advocacy groups, corporations, and health care organizations to strengthen cancer prevention, early detection and screening, diagnosis, and treatment. GCC was created in 2001 by Hamilton Jordan and Georgia Governor Roy Barnes and was funded primarily by tobacco settlement funds.
• The mission of GCC is to reduce the number of cancer-related deaths in Georgia. The cornerstone of realizing this mission was to recruit and retain world-class cancer clinicians and scientists—referred to as Distinguished Cancer Clinicians and Scientists (DCCS)—to Georgia to strengthen the state’s research talent, capacity, and infrastructure. By 2010, 158 scholars were recruited, which exceeded the original GCC goal of 150. GCC provides three levels of funding for these scholars, ranging from $50,000 to $150,000 per year for five years.
• GCC helped initiate the first NCI-designated Cancer Center in Georgia—the Winship Cancer Institute of Emory University. The DCCS scholar fund was a key component in developing the research necessary for NCI designation.
• As the DCCS effort has matured, some of these cancer scholars have joined community cancer centers throughout Georgia, including centers in Albany, Savannah, and Decatur. These scholars are working in the community to translate science from the bench to the bedside more quickly.
• The DCCS program has a 6-to-1 return on investment; for every state dollar put into the program, GCC requires at least one private dollar and one Federal dollar. The Coalition has received over $300 million in Federal and private funding to date. However, there is a need for even greater collaboration and coordination. The GCC would like to support models for funding high-risk, high-priority research, such as the model followed by the CDC Foundation. The CDC Foundation helps CDC pursue innovative ideas that need support from outside partners.
• One of GCC’s most ambitious goals is to establish a statewide clinical trials network. It is hoped that the state’s cancer clinical trial participation rate will increase with implementation of Georgia’s new multispecialty statewide research network, which comprises 186 academic and community oncologists, 57 research sites, 26 cities, and 360 adult clinical trials.