Good morning, everyone, andÊ thank you for joining us today.ÊÊ It is a real pleasure for me as the Director ofÊ the NIH to help launch this important listeningÊÊ session on the proposed Advanced Research ProjectÊ Agency for Health, otherwise known as ARPA-H.ÊÊ As you know, we at NIH are working closelyÊ with White House science advisor, Eric Lander,ÊÊ and his staff at the Office of Science andÊ Technology Policy, OSTP, on this bold proposal.ÊÊ We are grateful for your interest andÊ for taking time to attend this session. As you know, ARPA-H is a high priority forÊ President Biden and his administration. ItÊÊ is designed to catalyze ambitious ideas andÊ approaches that will shape the future of healthÊÊ and medicine for all Americans. As designed,Ê ARPA-H will follow a model built upon theÊÊ Defense Advanced Research Projects Agency (DARPA)Ê experience at the Department of Defense (DOD). It will focus on high risk and high rewardÊ programs, led by visionary program managers,ÊÊ recruiting research contributors who mightÊ otherwise never apply to NIH for support,ÊÊ and driven by explicit milestones, with anÊ intention to track those closely and make sureÊÊ that programs that are not successful can failÊ early. Today NIH and OSTP want to hear from you,ÊÊ our stakeholders. You areÊ critical to this endeavor. To set the stage, you will be hearingÊ from several NIH and OSTP leaders.ÊÊ Then we will hear from select speakers representing advocacyÊÊ for research, in this case on aging andÊ arthritis and musculoskeletal and skinÊÊ diseases because that is our focus today andÊ then this will be followed by a brief panelÊÊ discussion before we close, but thatÊ is our opportunity to hear from you. So, we will, in fact, entertainÊ questions after we have hadÊÊ the presentations from these select speakers andÊ we’ll do that by inviting you to submit questionsÊÊ to the Q&A function in your Zoom. So, youÊ can start putting those in at any time. We may have a challenge to try to sortÊ through all of them in our discussion period,ÊÊ but we will do our best. So, I just want to sayÊ this is one of ten sessions that NIH is organizingÊÊ with stakeholders and we decided to organize theseÊ around particular themes which gives us a chanceÊÊ to have institute directors to come and join us. Today we're fortunate to have Dr. RichardÊ Hodes, the director of the National InstituteÊÊ on Aging (NIA), and Dr. Robert Carter, who isÊ the deputy director of the National InstituteÊÊ of Arthritis and Musculoskeletal and Skin diseasesÊ (NIAMS), and each of them will have some openingÊÊ remarks, then we will hear from this veryÊ interesting group of stakeholders who haveÊÊ been invited, each to make presentations.Ê Then we will turn to the full discussion.ÊÊ So, without further ado, let me hand the programÊ over to Dr. Tara Schwetz, who is assistantÊÊ director for Biomedical Science InitiativesÊ at OSTP in the White House. Dr. Schwetz. Thank you, good morning, everyone, and thankÊ you for joining this meeting today. We veryÊÊ much appreciate you being here and reallyÊ look forward to a thoughtful and livelyÊÊ discussion on various aspects of ARPA-H, and IÊ am excited about the opportunity to share a bitÊÊ about the importance of ARPA-H and howÊ it will be transformative for a varietyÊÊ of diseases and conditions andÊ societal challenges related to health. So, as I know you all know, we have anÊ incredible biomedical ecosystem here in the U.S.,ÊÊ much of which is undergirded by the importantÊ fundamental research that is supported by NIHÊÊ and this is work that is often leveragedÊ by the vibrant biopharmaceutical industryÊÊ to create products for patientsÊ in a multitude of disease areas.ÊÊ And NIH continues to be a keystone in theÊ U.S. biomedical enterprise, and the work itÊÊ supports has made great progress in uncoveringÊ the underlying mechanisms of health and disease. However, our current system has gaps andÊ blind spots, and we all know projects thatÊÊ fall into the gap between traditional publicÊ support mechanisms and industry and we'reÊÊ missing out on some really exciting scienceÊ that has the potential to bring innovationÊÊ to health and healthcare and that isÊ exactly the gap that ARPA-H hopes to fill. While it is not the model that should be usedÊ for everything, it will provide us with a newÊÊ lens for thinking about exciting biomedicalÊ science and how to improve human health.ÊÊ So, if we just imagine for a moment, for example,Ê if we could program mRNA to pre-vaccinate youÊÊ against the top 50 to 100 of the most common formsÊ of cancer, giving your body the ability to targetÊÊ and eliminate those cells before they can everÊ even create a tumor. What if we could developÊÊ drugs that have very precise molecular zip codesÊ that would allow for unprecedented targeting, evenÊÊ across something like the blood-brain barrier,Ê to specific cells in your body? We would be ableÊÊ to deliver a therapeutic with dramatic accuracyÊ and greatly increase the efficacy of the drugÊÊ while mitigating or potentially eliminating sideÊ effects all together. And these are just a coupleÊÊ of samples of course of the types of capabilitiesÊ and platforms that ARPA-H could develop. I am sure you all have ideas as well,Ê likely ones that are much more ambitiousÊÊ and exciting than I just mentioned. ButÊ advancing these ideas will require a novelÊÊ approach to supporting biomedical research. This has been applied to other areas of R & D,ÊÊ if we think of organizations and agencies suchÊ as DARPA and ARPA-E and others. And our goal isÊÊ to create a distinct and bold entity whereÊ ARPA-H leadership will have the autonomy,ÊÊ independence and resources to tackle some ofÊ the biggest challenges facing human health.ÊÊ We know this ARPA-H model worksÊ and we think it is about timeÊÊ to deploy it, to lay the groundworkÊ for constructive innovation in health. So, thank you again for being hereÊ today, and we look forward to your input. Thank you very much, Dr. Schwetz. So now we are going to turn to two instituteÊ directors that I previously mentioned; first, Dr.ÊÊ Richard Hodes from the National Institute on AgingÊ (NIA), and then he will hand it off to Dr. BobÊÊ Carter from the National Institute of ArthritisÊ and Musculoskeletal and Skin diseases (NIAMS),ÊÊ and then it will come back to me,ÊÊ to introduce our stakeholders. So,Ê Dr. Hodes, please, take the floor. Thank you, Francis, and thank you, Tara, andÊ thank you all for joining with us. We are trying,ÊÊ as you’ve heard, to be a part of the great visionÊ that can come with ARPA-H, doing things that areÊÊ just on the horizon of what we can imagine.Ê The theme from molecules to society has beenÊÊ often cited as an exemplar of the scope of whatÊ we're doing. So, for example--in the theme of canÊÊ you imagine--can you imagine the circumstanceÊ in which, with a small sample of blood,ÊÊ we could track all of the proteins, all ofÊ the metabolites, in individuals, trackingÊÊ them through the course of their life or risk ofÊ disease, and in a very personalized way understandÊÊ what that trajectory was, using big science,Ê machine learning. Similarly, the societal end,ÊÊ and the patient or person oriented way, canÊ you imagine having access not just to theÊÊ health records but for digital manifestations ofÊ function as well as both cognitive and physical,ÊÊ for tying this to the environment for riskÊ factors, by geospatial methodologies, andÊÊ in the end, perhaps tying those two together so weÊ have a full spectrum of what is going on in peopleÊÊ and how they are reacting to their environmentÊ so we can manipulate that for the common good.Ê Ambitious? Inaudible words. Yes, andÊ we look forward to the excitement thatÊÊ gets kicked off with this group today. AndÊ let me turn to my great colleague, Bob Carter. Thank you, Richard. I’m Bob Carter, deputyÊ director of the National Institute ofÊÊ Arthritis and Musculoskeletal andÊ Skin Diseases (NIAMS), speaking onÊÊ behalf of Lindsey Criswell, our director,Ê as well as other members of the institute.ÊÊ ARPA-H will bring a new way of doingÊ science to the NIH. This will includeÊÊ use driven projects as Tara described, with aÊ focus on rapid development and testing of boldÊÊ new approaches that are risky but yieldÊ potentially transformative deliverables.ÊÊ This will be complementary to the traditionalÊ NIH focus on basic and clinical knowledge. During my time at NIH, I have had theÊ opportunity to work on large initiativesÊÊ that involved new partnerships andÊ new ways of conducting research,ÊÊ and I have seen the tremendous benefit of theseÊ new models. I hope my comments today encourageÊÊ the community to begin thinking about how to makeÊ the specific working goals, particularly of NIAMSÊÊ for us, to broaden new, enabling technologies and paradigms that could be developed throughÊÊ ARPA-H to be even more transformativeÊ in terms of addressing research gaps. To that end, I want to highlight a fewÊ possible approaches. They are relevantÊÊ to NIAMS but also broadly applicable. So, let’sÊ start with wearable devices. Sensors on the skinÊÊ could measure systemic inflammation to predictÊ flares or guide therapy for autoimmune diseasesÊÊ and not just in the skin, but, also, say,Ê in inflammatory diseases of the joints.ÊÊ Similarly, an implanted healingÊ chip that monitors repair processes,ÊÊ could adjust the delivery of factors, to improveÊ outcomes in skin wounds, or fracture repair, orÊÊ after joint replacement. Health equity is anotherÊ area where ARPA-H may be uniquely positioned toÊÊ develop creative technology solutions to supportÊ the eradications of adverse health effectsÊÊ of racism and discrimination. ARPA-H couldÊ develop diagnostic and treatment algorithmsÊ that account for issues that are relevant toÊ populations affected by health inequities,ÊÊ which could be used by those, for example,Ê suffering from chronic musculoskeletal pain,ÊÊ to incorporate health equity equation to addÊ patient decision-making for joint replacementÊÊ surgery. Another example where a concerted pushÊ might revolutionize approaches in gene therapy. The good news is that new approaches areÊ emerging, but we need to test these options. This could include viral, versus exosomes, versusÊ nanoparticle delivery vehicles or differentÊÊ cargoes, such as DNA or mRNA or RNAi, or targetedÊ approaches, like CRISPR, to determine which worksÊÊ best for which tissue. This type of comparativeÊ work would be great for a failed fast approachÊÊ and would be broadly relevant, but let meÊ say that skin and muscle would be a greatÊÊ place to start testing these options. ARPA-HÊ can catalyze major advances in data scienceÊÊ by developing tools to accelerate interoperabilityÊ of data sets to enable machine learningÊÊ and artificial intelligence approachesÊ across the whole spectrum of data type. There is a particular urgency for toolsÊ to promote comparisons of omics acrossÊÊ diseases. Indeed, such comparative of big dataÊ science offers the possibility of a revolutionaryÊÊ new paradigm for medicine based on mechanisms, notÊ manifestations. So, I have provided some thoughts,ÊÊ but we know the NIAMS research committee willÊ have many creative ideas for new solutions. I want to thank our advocates for taking timeÊÊ to share your perspectivesÊ today about the challenges thatÊ may be solved by ARPA-H. Thank you,Ê and I will turn it back to Francis. Dr. Collins: Thank you RichardÊ and Bob for a very thoughtfulÊÊ input here to our discussion this morning.Ê If you have joined late, just to remind youÊÊ what our framework is going to be, there areÊ now 142 people, I see, that are now linked upÊÊ to the Zoom call. We are now going to hear fromÊ a series of five stakeholders who will express,ÊÊ each of them, in about four minutes,Ê comments that they have about ARPA-H. They have been asked a series ofÊ questions to think about in termsÊÊ of what kinds of opportunities could beÊ catalyzed by this approach to fundingÊÊ or to the systemic gaps in R&D enterprise that areÊ currently slowing, or, impeding progress, what areÊÊ the challenges of advancing research this way, allÊ the way to commercialization, implementation, andÊÊ are there partnership strategies or collaborationÊ strategies that should be incorporated as we areÊÊ thinking about the overall ARPA-H designÊ and any other ideas are welcome as well. So, I guess you can tell while we areÊ enthusiastic about the big picture highÊÊ level framework of ARPA-H, we're veryÊ interested in hearing from stakeholdersÊÊ about many of these unresolved issues andÊ particularly excited to hear about things thatÊÊ you believe ARPA-H could contribute to in termsÊ of specific projects that are currently difficultÊÊ to do and fall somewhere in the gap between whatÊ public and private are currently investing in. So, I’m going to introduce each ofÊ the stakeholders, extremely briefly,ÊÊ basically, by their name, and their connectionÊ to any organization if there is one. There willÊÊ be this bell that will ring when there's 30Ê seconds left in their four minutes and thatÊÊ will be a little clue to wind up because we wantÊ to be sure we leave plenty of time for discussion. Again, the discussion, after weÊ hear from these five stakeholders,ÊÊ will be open to everybody who is on the zoom callÊ and you can put a question for our considerationÊÊ into the Q&A box and we will start to figure out how to answer those. I seeÊÊ Teresa Barnes has already placed aÊ question in the Q&A to get us startedÊÊ but you can do that at any time. So, let's nowÊ go to stake holder comments. Our first stakeÊÊ holder presentation is going to be from ProfessorÊ Alison Moore of the American Geriatric Society. Dr. Moore. Thank you very much, Dr. Collins. So, I amÊ a Geriatrician and Chief of the Division ofÊÊ Geriatrics, Gerontology and Palliative CareÊ at the University of California, San Diego.ÊÊ I am honored to comment on behalf ofÊ the American Geriatric Society or AGSÊÊ where I serve on the board of directors. AGS members work to improve health, independence,Ê and quality of life of all elder adults and ensureÊÊ their access to high quality care, free ofÊ discrimination and bias. We would like toÊÊ thank Dr. Hodes and the NIA for their commitmentÊ to scientific advancements to advance the health,ÊÊ safety and independence of older Americans. WeÊ support the President’s proposal to establishÊÊ ARPA-H. Federal investments in research haveÊ led to discoveries that have helped to increaseÊÊ lifespan and delay onset of chronicÊ diseases. Despite these advances,ÊÊ over 65 percent of Medicare beneficiaries liveÊ with two or more chronic conditions and more thanÊÊ 35 percent, of four or more, often experiencingÊ changes in physical or cognitive functionÊÊ that negatively affect their daily activities,Ê independence, and ability to age in place. To be successful, ARPA-H must address age as aÊ shared risk factor for all diseases and infuseÊÊ attention into two key principles across theÊ research it funds. First, that fundamentalÊÊ aging mechanisms contribute to the conditions thatÊ drive the bulk of morbidity, mortality and healthÊÊ expenditures across the lifespan; and second,Ê that aging begins at conception, and fundamentalÊÊ aging processes can contribute to disablingÊ conditions and chronic diseases even in children. Further, ARPA-H must also ensure that the researchÊ supports include individuals with multi-morbidity,ÊÊ diversity, with no upper age limits, outcomesÊ aligning with what matters to patients,ÊÊ and aging is a shared risk factor forÊ multiple chronic diseases. Without attentionÊÊ to these issues, broad dissemination of newÊ therapies and technologies that are useful,ÊÊ safe and effective for all of usÊ as we age, will be jeopardized.ÊÊ A strong partnership between NIA and ARPA-HÊ that is nimble and undeterred by possibleÊÊ failure will accelerate research in twoÊ areas: geroscience and gerontechnology. Geroscience and the study of biological mechanismsÊ that drive aging and disease focuses on developingÊÊ interventions to delay the onset of multipleÊ chronic diseases and conditions such as arthritis,ÊÊ Alzheimer's disease and frailty. InterventionsÊ that slow aging processes have the potential toÊÊ dramatically lower health care costs whileÊ significantly improving quality of life.ÊÊ Currently there are eight types of interventionsÊ that target fundamental aging processes suchÊÊ as senolytic drugs, some of which delay,Ê prevent or alleviate over forty conditionsÊÊ across the age range in animal models and are now or will be in early-stage clinical trials. Gerontechnology seeks technological solutionsÊ that optimize independence in older adults;ÊÊ smart phones, wearables, robots, exoskeletonsÊ and a myriad of other technologies can enhanceÊÊ communication, reduce isolation, improve physicalÊ activity, support cognition, improve access toÊÊ healthcare, assist with personal caregiving needs.Ê Technologies such as those mentioned by Dr. HodesÊÊ and Dr. Carter also have promise to identifyÊ digital phenotypes and morbidity and disability. Gerontology integrates clinicians, engineers,Ê computer tech scientists and gerontologists withÊÊ older adults and their caregivers. This maximizedÊ the likelihood that the technology developed,ÊÊ is useful, effective, safe and preservesÊ privacy for a diversity of older adults.ÊÊ Finally, to be truly successful, AGS recommendsÊ additional investments in network capacityÊÊ so that investigators can work collaborativelyÊ using the same data across institutions. And second, developing the next generation ofÊ aging researchers by supporting geriatrics healthÊÊ professionals to embark on careers and researchÊ developing geroscientists and ensuring that allÊÊ researchers have the necessary training forÊ including complex older adults in research.ÊÊ Thank you for inviting the AmericanÊ Geriatric Society to present today. We see the proposed investment in ARPA-H asÊ an inflection point to ensure that researchÊÊ leads to innovations thatÊ supports all of us as we age. Thank you very much, Dr. Moore for thoseÊ excellent comments. Next, we will hear fromÊÊ Dr. James Appleby who is the Executive DirectorÊ of the Gerontological Society of America. Dr. Appleby. Yes, good morning, thank you, Dr. CollinsÊ and thank you for the opportunity toÊÊ provide comments on behalf of theÊ Gerological Society of America.ÊÊ GSA’s 5,000 members include gerontologists,Ê biologists, all of the health professions,ÊÊ behavioral and social scientists, demographers,Ê economists and many other disciplines. TheseÊÊ researchers, clinicians and educators study allÊ facets of aging with a life course perspective. GSA’s mission is to cultivate excellence andÊ interdisciplinary aging research and educationÊÊ to ultimately advance innovations in practice andÊ policy. Our vision of meaningful lives as we ageÊÊ reinforces the society its commitmentÊ to diversity equity and inclusion.ÊÊ GSA applauds the administration forÊ taking the bold step of creatingÊÊ ARPA-H and believes it will compliment theÊ established biomedical research community. We are pleased to see the recognition ofÊ the importance of a strong relationshipÊÊ between the current research ecosystem andÊ the enterprising opportunities that existÊÊ with ARPA-H. We're also pleased that NIH’s andÊ OSTP’s statements committing to ensuring thatÊÊ funding remains robust for the NIH centers. ARPA-HÊ is intended to develop breakthroughs to prevent,ÊÊ detect and treat diseases likeÊ Alzheimer’s, Diabetes and cancer. Yet the broader questionÊ posed in the recent ScienceÊÊ Policy Forum article was what more can we do toÊ accelerate the pace of breakthroughs to transformÊÊ medicine and health. That is a much broaderÊ framing in where prevention plays a larger role.ÊÊ As GSA matches the opportunities to catalyzeÊ new approaches to solve the vexing challengesÊÊ of today and tomorrow, we think of theÊ intersection of aging and chronic disease. Most biomedical research and practice focusesÊ on treating a single disease. While this diseaseÊÊ first approaches is important on a individualÊ level, it is inefficient on a population level.ÊÊ As noted in a recent issue of GSA'sÊ Public Policy and Aging Report,ÊÊ the impacts on life and health expectanciesÊ targeting aging are much greater than waitingÊÊ until people get sick and then trying toÊ cure or ameliorate their individual diseases. To truly transform health, GSA recommendsÊ ARPA-H embrace a Geroscience approach.ÊÊ Geroscience seeks to understand the fundamentalÊ aging process and how it contributes to manyÊÊ chronic diseases that accompany older ages. Age isÊ in fact, as I’ve stated the greatest risk factorÊÊ for most chronic diseases. Developing new insightsÊ into the biology of aging and developing relatedÊÊ applications holds the promise of preventing theÊ onset of multiple chronic diseases simultaneously. Fortunately, current geroscience research providesÊ many opportunities to be exploited. While ARPA-HÊÊ emphasizes biomedical breakthroughs, GSA believesÊ it is essential to be inclusive of opportunitiesÊÊ available through the behavioral sciences. GSA inÊ fact, recommends that ARPA-H embrace and pursueÊÊ solutions driven by new insights derivedÊ from the behavioral and social sciences. Transforming health throughÊ breakthroughs in these areas may provideÊÊ rapidly scalable innovationsÊ while advancing health equity.ÊÊ GSA commends NIH and OSTP for acknowledging theÊ importance of transparency and accountability.ÊÊ We are encouraged by the culture ofÊ collaboration and vision for ARPA-HÊÊ to include other government agencies and privateÊ sector partners to propel findings rapidly. Making the most of scientific breakthroughsÊ requires coordination across regulatory and policyÊÊ mechanisms, to speed application and ensure broadÊ access. This will enable society to realize itsÊÊ full benefit. GSA looks forward to participatingÊ in the discussion today and providing ongoingÊ feedback as ARPA-H advances.Ê Back to you, Dr. Collins. Thank you, Dr. Appleby for a really helpfulÊ statement. Let's now go to Dr. Lou BridgesÊ who is the board President of the FoundationÊ for the American College of Rheumatology. Dr. Bridges. Thank you, Dr. Collins for the opportunityÊ to speak today. I am the President of theÊÊ Rheumatology Research Foundation which is a 501C3Ê organization associated with American College ofÊÊ Rheumatology and I also serve as physician andÊ Chief at the hospital through special surgeryÊÊ in New York City. Many areas in arthritis andÊ rheumatic diseases can be transformed by ARPA-H. One is the vexing problem of quantifyingÊ the effects of environmental exposuresÊÊ in patients with chronic, complex diseasesÊ such as rheumatoid arthritis and Lupus.ÊÊ Genetic factors account for a minority ofÊ disease risks so technologies to rapidly,ÊÊ accurately and quantitatively characterizeÊ exposure to foreign substancesÊÊ through the lungs, the skin, mucosa and theÊ GI-tract and other routes will be game changing. Coupled with the use of genetics andÊ predictive biomarkers, detailed exposure dataÊÊ could lower disease incidence throughÊ prevention and mitigation strategiesÊÊ enacted through public health and legislativeÊ approaches. This knowledge would also enableÊÊ population screening to identify at riskÊ individuals or those with subclinical disease. People affected by poverty may benefit the mostÊ as they are most likely to have deleteriousÊÊ exposures. Another area of importance is advancingÊ predictive analytics which are critical to usingÊÊ large amounts of digital healthcare data. ImprovedÊ pipelines to integrate and analyze multipleÊÊ diverse data sets, clinical, genetic, immulogicÊ imaging, et cetera, can help individual patientsÊÊ receive medications that are the most efficaciousÊ and have the lowest risk of serious adverseÊÊ events. Another significant gap is the abilityÊ to analyze human blood, fluid, or tissue samplesÊÊ rapidly, accurately, inexpensively to improveÊ diagnostic accuracy and to help tailor treatments.ÊÊ Drugs with different mechanisms of action areÊ effective in specific diseases so rapid analysisÊÊ of biospecimens would facilitateÊ stratifying patients according toÊÊ which pathobiological pathway is mostÊ dominant at the time. This would alsoÊÊ minimize patient time on sub-optimally effectedÊ medications and help avoid disease flares. The ability to repetitively characterize complexÊ at biospecimens will also help us to understandÊÊ different long-term disease trajectories. Next,Ê many rhematic diseases disproportionately affectÊÊ African American, Hispanic, and Native AmericanÊ communities. To improve patient outcomes in theseÊÊ communities, ARPA-H could leverage existingÊ relationships between rheumatologists and NIHÊÊ infrastructure programs, such as, research centersÊ and minority institutions or Native AmericanÊÊ research centers for health. Communities withoutÊ access to rheumatologists could be the focusÊÊ of dissemination and implementation researchÊ using practice based research networks.ÊÊ Finally, there is a huge need forÊ effective treatments for osteoarthritis. ARPA-H is ideally positioned to fundÊ multidisciplinary teams to developÊÊ clinical trials using novel study designs,Ê biomarker driven patient selection and cuttingÊÊ edge imaging approaches to rapidly test novelÊ or repurpose therapeutics for OA. In terms ofÊÊ collaborative opportunities and other resourcesÊ that are available to ARPA-H to help with theseÊÊ ideas, the ACR and the Rheumatology ResearchÊ Foundation have a long history of innovativeÊÊ collaborations with industry partners to improveÊ the lives of patients with rheumatic diseases. For example, the American College ofÊ Rheumatology’s Rheumatology InformaticsÊÊ System for Effectiveness (RISE) is a qualifiedÊ clinical data registry. It is a nationalÊÊ digital network of more than 1,000 rheumatologyÊ practices that collects high quality clinicalÊÊ data. RISE could serve as a key resourceÊ for ARPA-H to support innovative approachesÊÊ to transform the health of patients with rheumaticÊ diseases. Thank you again for the opportunity toÊÊ make these remarks and we look forward toÊ participating with ARPA-H in the future. Thank you very much, Dr. Bridges. Next,Ê we are going to Dr. Suzanne Jan de Beur,ÊÊ who is President of the American SocietyÊ for Bone and Mineral Research. Dr. de Beur Morning, my name is Suzanne Jan de Beur andÊ I am President of the American Society ofÊÊ Bone and Mineral Research (ASBMR). I amÊ also Associate Professor of Medicine atÊÊ the Johns Hopkins School of Medicine andÊ Director of the Clinical Research UnitÊÊ Network for the Johns Hopkins InstituteÊ for Clinical and Translational Research.ÊÊ I would like to thank the NIH and the OSTPÊ for the privilege of sharing the ASBMRÊÊ feedback on the establishment of AdvanceÊ Research Projects Agency for Health or ARPA-H. As a physician scientist who treatsÊ patients with bone disorders,ÊÊ my words today reflect theÊ collective thoughts of ASBMR members.ÊÊ Nearly 3500 preeminent physicians and biomedicalÊ scientists comprise the ASBMR, which is theÊÊ world’s largest and most respected society forÊ bone, mineral, and musculoskeletal research. The NIH is a global standard for support ofÊ fundamental research and its tested methodsÊÊ have led to reductions in deaths fromÊ osteoporosis, heart disease, cancer, strokeÊÊ and many other chronic disorders over the decades.Ê ASBMR believes there is room for both advanced R&DÊÊ approaches like ARPA-H and foundationalÊ science that is core to NIH’s mission. However what cannot be lost isÊ the former depends on the latterÊÊ and that NIH will continue to support researchÊ that addresses the critical needs for cures,ÊÊ treatments, diagnostics andÊ preventive intervention. Thus it is important to ensure that investments inÊ ARPA-H are balanced with robust investment in NIHÊÊ supported foundation, investigator initiatedÊ research and that forms the bedrock of ourÊÊ nation's medical research ecosystem. The successÊ of ARPA-H depends on the continued robust supportÊÊ for fundamental biomedical researchÊ already within NIH’s purview. Furthermore, it is critical for ARPA-H to notÊ compromise the excellent work that it’s alreadyÊÊ conducted within the NIH intramural and extramuralÊ programs. Funding decisions at ARPA-H must avoidÊÊ excessive overlap with NIH projects and NIH ICsÊ should not be required to contribute significantÊÊ financial resources to ARPA-H projects inÊ order to preserve the investigator initiatedÊÊ basic and clinical research pipelineÊ that leads to biomedical advances. We expect that intramural and extramuralÊ researchers funded by NIH and other agencies willÊÊ be involved in many projects funded by ARPA-H.Ê However, there are features of the DARPA modelÊÊ which ARPA-H will adopt that may create barriersÊ to the effective recruitment and engagement ofÊÊ NIH funded researchers. Most notably the highÊ level of administrative oversight and reporting.ÊÊ Academic scientists and cliniciansÊ already bear significantÊÊ administrative workloads and the integrationÊ of a DARPA -like grant management system mayÊÊ be insurmountable for many academicÊ scientists and unintentionally limitÊÊ the pool of candidates to a select group ofÊ researchers at well resourced institutions. Program officials will be able toÊ better foster collaboration amongÊÊ experts in different settings if ARPA-HÊÊ implements more flexible compliance schemes withÊ funded support for administrative requirements. Also as existing academic tenure and promotionÊ processes for biomedical researchers is heavilyÊÊ biased towards standard NIH grant mechanisms,Ê academic institutions should be engaged so thatÊÊ they cannot only help reduce administrativeÊ burdens for researchers involved in ARPA-HÊÊ but also so that these projects areÊ recognized in tenure and promotion decisions. Finally, the process to prioritize and fundÊ projects must be carefully considered and groundedÊÊ in science with safeguards put in place to preventÊ undue influence from limited stakeholder groupsÊÊ as well as political influence.Ê ASBMR members, as stakeholders,ÊÊ thank you for involving us early in this process.Ê We are excited about the opportunities to advanceÊÊ biomedical research and address pressingÊ public health priorities through ARPA-H. We look forward to continuing to engage withÊ NIH, OSTP and Congress as this new initiativeÊÊ moves forward. Thank you very much for theÊ opportunity and back to you, Dr. Collins. Thank you very much, very thoughtful commentsÊ indeed. We have two more stakeholders who areÊ going to make statements. Next is Dr.Ê Rebecca Minnillo, who is the Chief ProgramÊÊ and Development Officer for the Society forÊ Investigative Dermatology, Dr. Minnillo. Hi, I am Becky Minnillo and thanks for theÊ opportunity to share our feedback. You willÊÊ see my group got a lot more specific butÊ there are some nice recurring themes.ÊÊ As Bob indicated, skin is a good place to start,Ê so what I did is it’s a thematic collection ofÊÊ the suggestions that our stakeholders gave.Ê So in health disparities digital imaging isÊÊ important in accurate diagnosis and treatmentÊ of skin of color to reduce health disparities. There is a lack of images of patientsÊ of color for skin conditions and skinÊÊ manifestations of systemic disease. ImagingÊ tools recognizing symptoms in skins of colorÊÊ need to be refined to eliminate bias. We needÊ more data on differences and disease severityÊÊ in black patients such as melanoma and why is itÊ patient awareness, delayed physician diagnosis,ÊÊ or does it depend on the location of the lesions. In terms of technology and potential opportunitiesÊ include microbiopsy, transdermal delivery of RNAÊÊ and DNA based vaccines, nanoparticulate drugÊ applications that can be applied to the skin,ÊÊ photodynamic therapy and CAR-TÊ therapies for autoimmune diseases,ÊÊ manufacturing of vector and cellularÊ therapies and GMP plasmid, using CRISPRÊÊ to develop topical applications of drugsÊ or cells that would lead to gene editing,ÊÊ and correction of severe genetic diseases suchÊ as sickle-cell disease and cystic fibrosis. Using long-term slow releaseÊ media may –improve the managementÊÊ of chronic disease by a consistentÊ dosing improving outcomes.ÊÊ Repurposing existing therapeutics for differentÊ skin and other disorders including [inaudible]. In terms of data, integration of single cell andÊ spatial technologies, transcriptome, epigenetic,ÊÊ genetic, metabolic with healthy and disease statesÊ and advancing method development systems biology,ÊÊ bioinformatics to facilitate data integration.Ê Synthesis of technology and biomedicine researchÊÊ gathering data that goes beyond traditionalÊ medical history to include information onÊÊ genomics, environmental exposures, diet andÊ microbiome to deliver personalized medicine.ÊÊ Incorporating common data priorities identifiedÊ across aging, arthritis, musculoskeletal and skinÊÊ into national data surveys such as NHANES. Funding and peer review,ÊÊ streamlining and shortening the peer reviewÊ process, a special emphasis panel or studyÊÊ section to cover a skin of color initiative couldÊ rapidly gain the attention of investigators whoÊÊ can help build solutions, including patientÊ representatives in study sections for clinicalÊÊ research to better define needs and acceptableÊ solutions. For commercialization, an NIH fundedÊÊ database that provides stepwise guidance throughÊ the commercialization rocess starting from benchÊÊ discovery to commercialization includingÊ collaborator teaming and FDA approval.ÊÊ Such information may then be adapted by eachÊ institution to provide clear guidance andÊÊ transparency in the process. IncentivizingÊ industry to conduct R&D on rare diseases.ÊÊ For partnership and collaboration, break downÊ silos. A national biobank for skin biopsy tissue,ÊÊ RNA and microbiome DNAÊ especially for rarer diseases. Encouraging collaboration with large AIÊ technology companies for discussion ofÊÊ ideas such as harnessing genomic or microbiomeÊ data for predictive and diagnostic algorithms.ÊÊ Expansion of SBIR and STTR programs to ensureÊ academic faculty competence in life science andÊÊ management. Foster collaboration between clinicalÊ departments and engineering and computer science. Offer thematic disease based program projects,ÊÊ provide support for multi-institutionalÊ data analysis centers accessible to fundedÊÊ investigators. Academic investigators know how toÊ generate data but may not know how to analyze it,ÊÊ or about all the analytic platforms available.Ê So obviously there is some excitement from ourÊÊ community and we look forward to workingÊ with everyone at the NIH and we appreciateÊÊ the opportunity to share this.Ê Back to you, Dr. Collins. Dr. Minnillo thank you very much and I doÊ appreciate your bringing specific ideasÊÊ for us to begin to chew on when we contemplateÊ what ARPA-H might be able to do. That’s reallyÊÊ kind of fun to imagine the kinds of projects weÊ currently might have trouble mounting but we wouldÊÊ fit within this particular framework. Our finalÊ stakeholder presentation will be from Dr. MariaÊÊ Carrillo who is the CEO, excuse me if I haveÊ got it wrong, of the Alzheimer's AssociationÊÊ and I may have also butchered your name, justÊ like I did earlier, so you are welcome to speak. Thank you very much, Dr. Collins it is actuallyÊ Carrillo, but not everyone can roll that R so I asÊÊ answer to anything. But its great to be with allÊ of you today. Thank you very much and on behalfÊÊ of all of those living with Alzheimer’s Disease,Ê their caregivers, and their families, I want toÊÊ thank you all for the opportunity to address theÊ Advanced Research Projects Agency for Health,ÊÊ ARPA-H. We're really glad to see Alzheimer'sÊ as listed as one of the disease areas of focus. We respectively urge the administrationÊ to ensure that it does not duplicate orÊÊ supplant current Alzheimer’s research efforts atÊ the National Institutes of Health and primarilyÊÊ at the National InstituteÊ on Aging. But there are manyÊÊ important unfunded targets that I know that NIHÊ and ARPA-H could fund much of this is outlinedÊÊ in the NIH Professional Judgement BudgetÊ for Alzheimer Disease and related dementiasÊÊ for fiscal year 2023. Which of course we thankÊ Richard Hodes and Dr. Hodes’ team for leading. Examples of Alzheimer’s related projectsÊ that ARPA-H could be undertake in ourÊÊ point of view is certainly accelerating theÊ discovery of brain imaging, eye imaging andÊÊ blood or fluid biomarkers, that are capable ofÊ really measuring semantic loss neuronal health,ÊÊ glial and inflammatory pathways as meansÊ of tracking response for Alzheimer's andÊÊ for other disease therapeutics. TheseÊ are very specific but I think you haveÊÊ heard specifics from others as wellÊ and there are recurring themes here. A current example, of course ofÊ collaborative work already takes placeÊÊ with Alzheimer's and other diseasesÊ through the accelerated medicinesÊÊ partnership which we are very pleasedÊ to be a part of. In specific forÊÊ funding of the Alzheimer’s Disease arm. It is aÊ precompetitive partnership that is I think veryÊÊ innovative and it includes government industryÊ nonprofit organizations such as ourselves and itÊÊ focuses on novel clinically relevant therapeuticÊ targets and developing biomarkers as well. These are targets that we desperately need, weÊ know we need to go beyond amyloid and tau toÊÊ address dementia more broadly and we needÊ a diverse pipeline that goes beyond this.ÊÊ But how do we take that program that’s alreadyÊ very successfully funded and established to theÊÊ next level? Partnership strategies that shouldÊ be incorporated into an overall ARPA-H design IÊÊ think could include those types of partnershipsÊ with nontraditional partners. Towards a pathwayÊÊ with thinking about earlier collaboration,Ê guidance from the beginning with regulatoryÊÊ agencies that support therapeutic or diagnosticÊ packaged development. These need funding andÊÊ infrastructure that create a funnel to funnelÊ validated targets that could be used by industry,ÊÊ academia or through some very again innovativeÊ partnership that brings them altogether. And it would also bring in of course SBIR andÊ STTR mechanisms that already take place so weÊÊ do want to recreate the wheel but ifÊ this could happen in a one-stop shopÊÊ imagine the time and resources saved along thatÊ pipeline pathway. In our own funding programs,ÊÊ we have the intention to createÊ not only pipeline enabling projectsÊÊ but these types of projects that can run intoÊ trials are a challenge as well as very costlyÊÊ and the investment level discussed in regard toÊ ARPA-H has incredible potential to promote thoseÊÊ types of breakthroughs not only in Alzheimer’sÊ but in related dementia and aging broadly.ÊÊ And non-traditional partners could includeÊ community advisory boards that could weigh in onÊÊ more local and culturally sensitive guidanceÊ which we know we need more input on. And we can contribute through that to theÊ reduction of health disparities from theÊÊ inception of the planning, not trying to fix itÊ after we have gone down the road quite a way.ÊÊ But there is this huge potential to advanceÊ health equity in creative and new ways,ÊÊ which I know you have also heard from others.Ê There are lots of opportunities to explore digitalÊÊ technologies for diagnosis, assessment and disease monitoring, novel ways to measureÊÊ and evaluate cognition and function and developÊ tools for voice recognition and other passive waysÊÊ that may measure changes in the brain and inÊ diseases of course that include Alzheimer'sÊÊ but others. In addition, opportunities that canÊ enable complex modeling of contributions to riskÊÊ are so important. Risks as we age thatÊ contribute to cognitive decline and thenÊ ultimately dementia. These are ripeÊ opportunities for investment, but need sortÊÊ of big picture and big thinking assessmentsÊ and they will include of course genetic,ÊÊ biological and other clinical measures but weÊ urge ARPA-H to engage in activities that provideÊÊ validated algorithms for diseaseÊ risk using that big availableÊÊ big data like biomarker digital and emergingÊ technologies to help translate these resourcesÊÊ for clinicians and drug discovery experts broadlyÊ not only within the ARPA-H model and consortium. ARPA-H can fill a very important role byÊ complimenting the current work at the NIH,ÊÊ NIA, NINDS by driving, transformationalÊ innovation and research and speedingÊÊ the application and innovationÊ of cutting edge breakthroughsÊÊ which we know occur today through traditionalÊ pathways and requirements that are important andÊÊ implemented for good reasons but now we haveÊ an opportunity to create something that won'tÊÊ be held back by a longer timeline because ofÊ progress and to procedure that we must respect. And we caution of course that ARPA-H shouldÊ not operate in silos or in isolation,ÊÊ transparency surrounding these activities is key,ÊÊ and data sharing through open resources willÊ be important as well to ensure that we can getÊÊ that data out there as soon as possibleÊ to others and not hold it inside ARPA-H.Ê Those resources are already available throughÊ other things that NIH and NIA does. InfrastructureÊÊ and data sharing like the AD Knowledge portalÊ add a portal link to it through an open-sourceÊÊ platform called Agora, clinical resources areÊ also linked there through AMP-AD, like the GlobalÊÊ Alzheimer’s Association’s interactive network,Ê GAAIN for clinical data and we would be pleasedÊÊ to partner with ARPA-H, with the NIH to assist inÊ any of these efforts as an organization. So thankÊÊ you very much for the opportunity to comment andÊ for considering all these important processes. Well thank you very much and thanks to all ofÊ our stakeholder presenters who did a great job ofÊÊ answering of these questionsÊ that we hoped you would addressÊÊ and even manage to do it within fourÊ minutes which I know is asking a lotÊÊ when there is a very large amountÊ of things we can say about this. Well we can now we can move into ourÊ discussion and as I said at the outsetÊÊ and, I can see some people haveÊ already started to act upon it,ÊÊ those of you listening in can participate byÊ submitting questions to the Q&A box and Dr. TaraÊÊ Schwetz is going to serve as our moderator andÊ orchestrator of this part so yes thank you forÊÊ turning on her image and Tara do you want to startÊ right in with the questions that you see thereÊÊ and we can kind of figure out who is in the bestÊ position to answer them once we see what they are. Sure, so one question I think that might beÊ good to start with is one on when ARPA-H fundingÊÊ would start, and just talk a little bit aboutÊ the level of funding and then there is aÊÊ follow up question about the reviewÊ but maybe just start with the funding. Well, I guess I could try toÊ see what I could say about that. Again, the way we are currently seeing thisÊ take place, we hope, the President has proposedÊÊ funding for ARPA-H in the FY22 budget and proposedÊ this bold idea of six and a half billion dollarsÊÊ to be available over three years but this goesÊ into the base for NIH which means in FY2023,ÊÊ there would be another $6.5 billion dollars and soÊÊ on in out years and that’s a substantialÊ amount of funding. We are really pleasedÊÊ the President has put this forward as beingÊ spendable over three years because it might beÊÊ pretty challenging to go from a standing startÊ to that kind of expenditure and do it wisely.ÊÊ Now how does that actually translate into reality? Well most of you know, the PresidentÊ proposes, and then the Congress disposes soÊÊ Congress now has to decide what they thinkÊ of this proposal. The House has alreadyÊÊ indicated they are strongly supportive. The HouseÊ Appropriations process, chaired by Rosa DeLauro,ÊÊ has basically put out their mark for the FY22Ê budget and in that is included $3 billion dollarsÊÊ for ARPA-H, its not six and a half, its three andÊ we of course hope that over time that could growÊÊ to a larger number but that wasÊ what they thought was reasonable. I should also point out because it was mentionedÊ by several of you that the House was also worriedÊÊ that nothing be done in terms of starting upÊ ARPA-H that would detract from the importanceÊÊ of supporting the NIH institutesÊ and the long tradition of successÊÊ with R01’s and other investigator drivenÊ initiatives. And so they gave a recommendationÊÊ that the rest of NIH should have an increaseÊ in FY22 of $3.5 billion dollars which wouldÊÊ be a very nice thing indeed to try toÊ support all the rest of what we to. So that’s three and a half plus three, they’reÊ proposing a six and a half billion dollarÊÊ increase for FY22. The Senate has yet toÊ weigh-in about where they are in termsÊÊ of the appropriation process. There are someÊ wrinkles here in that ARPA-H needs both moneyÊÊ and it needs authorities andÊ so the authorizing committeesÊÊ are now looking at that and trying toÊ figure out what they could do to make sureÊÊ that some of the things we are going to need toÊ achieve the kind of flexibility and nimblenessÊÊ that ARPA-H will require can be provided.Ê Things about how to hire the director, andÊÊ the program managers and some of the contractingÊ that we’ll want to do in a very rapid turnaround. So we're optimistic about that andÊ certainly getting lots of questions.ÊÊ Now those of you who have been around for a whileÊ know that while the fiscal year officially startsÊÊ on October 1st, it almost never getsÊ funded by then. There is generally aÊÊ period of gnashing of teeth and arguing aboutÊ details until eventually the budget emerges onÊÊ a good year maybe November or December, inÊ a bad year, could be even longer than that. And meanwhile, we have what’s called aÊ continuing resolution, We can't start ARPA-HÊÊ until there is actually funding for it.ÊÊ So it seems unlikely that we will be able to hitÊ the start button before about December and thatÊÊ is something to keep in mind. And, again thatÊ means really wanting to be ready to go quickly. So Dr. Schwetz working with Dr. Tabak at NIH withÊ a whole team of other people have been reallyÊÊ trying to lay out all the things that we can doÊ ahead of time to be ready if we get to hit thatÊÊ start button in around December so that we don'tÊ have a long delay built in at that point. So IÊÊ thought that might be useful to put on the tableÊ and Tara, let me ask back to you, because I alsoÊÊ heard questions about how projects are going toÊ be chosen and how the review is going to be done. Could you just outline for theÊ people listening how that is goingÊÊ to work because it is very different than theÊ traditional NIH study sections and councils.ÊÊ This is much more along the lines of theÊ DARPA model but maybe you could explain that? Yeah, I will start by sort of explainingÊ the ARPA-approach generally and with theÊÊ recognition that they're still obviouslyÊ working through some of the details so howÊÊ exactly the process for ARPA-H might vary aÊ little bit, but this is kind of the backbone. DARPA in particular sort of gets its ideas throughÊ the folks that they hire so they bring on theseÊÊ program managers who have really incredible ideas.Ê And actually a part of their interview process isÊÊ actually to pitch ideas. And they come to theÊ organization and are able to work on them andÊÊ kind of, if they get the green light, to go aheadÊ then are able to develop an actual full program. That’s one main mechanismÊ that this model uses to gatherÊÊ information for developing programs. Now sometimesÊ programs kind of bubble up naturally throughÊÊ other conversations with the leadership mightÊ have an idea that they ask them to explore,ÊÊ and we could foresee somethingÊ like that here with ARPA-H. And I will also add that I think it willÊ also be important to have multiple mechanismsÊÊ of feedback and input. So if you think forÊ example about the NIH IC’s, I mean there is aÊÊ wealth of knowledge and information andÊ expertise there. You could imagine ideas couldÊÊ come to ARPA-H from folks within the ICs orÊ what they are hearing within the community. There could be mechanisms to discussÊ with stakeholders and I use that termÊÊ broadly so folks in patient advocacy groups,Ê industry, academia, professional societies,ÊÊ et cetera that may be able to put forth ideas.Ê There's also as part of the sort of DARPA model,ÊÊ one of the mechanisms they use they do have a kindÊ of what NIH would call an investigator initiatedÊÊ mechanism to apply for opportunities soÊ that is another way where ideas come about. And then they are reviewed internally byÊ a group of federal experts from across theÊÊ federal government and decisions are made basedÊ on the feedback that they get but they don't doÊÊ a ranking system. It is an actual sort of yes orÊ no, is this supportable is this not supportable,ÊÊ does it meet the goals of whatÊ we're trying to accomplish or not. And that’s how they are kind of bucketed andÊ then the program manager puts forth a portfolioÊÊ of projects that can help to address the challengeÊ that’s trying to be tackled. So that is sort ofÊÊ the high-level overview and of course the directorÊ of the organization signed off on everything. Ê Which means it’s going to be reallyÊ important to get the right person for that.ÊÊ We envision somebody who is a real entrepreneur,Ê who’s had some experience in the private sector,ÊÊ that would be ideal, who is not unfamiliar withÊ taking big risks and even occasionally failingÊÊ because if ARPA-H doesn't fail sometimes, it’sÊ probably not jumped into this risky zone thatÊÊ we want it to try to tackle, taking onÊ things that otherwise wouldn’t happen. Also, this person will need to be somebody whoÊ could share that vision and excitement and doÊÊ the recruiting of these program managersÊ that Tara just mentioned who are going toÊÊ be critical for the success of the enterprise andÊ convince them come and spend three to five yearsÊÊ doing something that might notÊ have been part of their life plan. So somebody who’s not quite walking on water butÊÊ coming pretty close and we can imagine thereÊ are some people who have those skills and weÊÊ hope they would see this as probably the bestÊ job in biomedical research for a decade or more,ÊÊ to be able to steer this kind of a ship with allÊ of its potential to do really amazing things. So Tara, you are looking at the Q&AÊ and I am too but maybe you want toÊÊ pick a question that we think wouldÊ be good for the group discussion? Yeah, there was a question,Ê well there’s actually been aÊÊ couple of questions and this relates toÊ some of the statements we heard earlierÊÊ about just ensuring diversity of staff andÊ addressing health equity issues at ARPA-H. Well, we totally agree that that’s gotÊ to be included in everything ARPA-H does. Certainly, NIH has come strongly around toÊ that perspective especially in the courseÊÊ of the last year as we have recognized our roleÊÊ in what unfortunately is a long historyÊ of structural racism and the need toÊÊ address health disparities in new ways andÊ that is going to have to be by facing ourÊÊ lack of diversity sometimes in our own workforceÊ and also in the way in which we approach problems. So that’s going to be integrated into all theseÊ decisions. If you had a chance to read the paperÊÊ in science that Tara and Eric Lander and LarryÊ Tabak and I wrote we tried to document justÊÊ exactly how that was going to be an essentialÊ issue. Even gave some examples of the kinds ofÊÊ projects that ARPA-H might undertake. You allÊ have proposed some wonderful ones this morning,ÊÊ stakeholders. One of the ones I amÊ enamored of, I’ll just put it out there,ÊÊ is the idea of having ARPA-H mount a projectÊ to see just what could be accomplishedÊÊ if we took the model of community health workers,ÊÊ which is adopted in some other countries,Ê many of them low and middle income countriesÊÊ and saw what we could accomplish in terms ofÊ prevention of illness, as well as managementÊÊ of chronic disease. Particularly in communitiesÊ where health disparities have hit them hard. The promontories model that the Latino communitiesÊ use, I think there is a lot of promise there butÊÊ it has never really been put to a test. So thatÊ would be a hypothetical ARPA-H program if somebodyÊÊ could sell it to the director as something that isÊ likely to have results that would be meaningful,ÊÊ which means it’d have to have milestones you’dÊ have to be sure that you knew it wasn’t tappingÊÊ into territory that some other organization couldÊ do but yeah, I think that’s a really good thing. You know, let me ask you, Tara, becauseÊ it came up I think in a comment from ourÊÊ friends at the ASBMR was the sense, and I thinkÊ we heard this in another session yesterday thatÊÊ DARPA has a pretty heavy –bureaucratic well,Ê maybe that’s not fair, pretty heavy oversightÊÊ process that people are worriedÊ is going to be really burdensomeÊÊ on those who take part in ARPA-H projects.Ê I’m not sure I was aware of that before, soÊÊ is that something since you have been doing aÊ lot of comparing of notes with DARPA and ARPA-E,ÊÊ is that something that is going to requiredÊ or something that we could come up with a wayÊÊ to be a bit more streamlined and efficient asÊ long as we’re doing the oversight responsibility. Yeah, I think what’s being referenced and thisÊ is me trying to [inaudible] it a little bit, butÊÊ I think what’s being referenced is the activeÊ project management that they play with all ofÊÊ their programs and projects. And I think the mostÊ similar sort of parallel at NIH, I guess, would beÊÊ the cooperative agreements that, that weÊ have. So, it would be a little bit likeÊÊ cooperative agreements but maybeÊ with even more active engagement. They do touch base with the performers asÊ they call them on a generally from whatÊÊ I am gathering on a either bi-weekly so everyÊ other week or monthly basis, and have, you know,ÊÊ milestones and metrics by which the performers areÊ held. And you know there’s some wiggle room there. They are not necessarily hard and fastÊ but they do stick to them pretty wellÊÊ and can make the program managers, just sortÊ of speaking to the autonomy that they have,ÊÊ they do have some flexibility to make adjustmentsÊ to the program as it is moving along. So asÊÊ things evolve as the science continues to advance, they might find that they need toÊÊ combine two separate teams into one team becauseÊ they’re working on something that’s actuallyÊÊ merging into something that would actuallyÊ be better served to be done together. So there’s flexibility there as well andÊ I think that’s maybe the kind of activeÊÊ management that folks are referring to. Yeah, I can understand that especially for peopleÊ who are used to somewhat of a low-touch approachÊÊ from traditional NIH research where you gotÊ to send in your annual progress report butÊÊ people aren't asking you month after month,Ê okay have you done this, have you done that. Again, ARPA-H, because it’s gotÊ to be milestone driven is goingÊÊ to be asking more of those questions.Ê That sort of comes with the package. So one of the questions that we’ve also gottenÊ is about just how ARPA-H will interact withÊÊ the existing programs and infrastructureÊ at NIH and we touched on this a littleÊÊ bit earlier but I wonder if you couldÊ elaborate on that a little bit more. Well again, we want to be sureÊ that ARPA-H has its autonomy veryÊÊ clearly defined because this is notÊ intended to be the 28th institute andÊÊ to function the way the other institutes do.Ê This is supposed to be a different entity. The director should have ultimate authorityÊ in deciding which projects to fund after theyÊÊ are pitched to the director by those programÊ managers, the director will have a budget lineÊÊ from the Congress. We'll of course be expectedÊ to be open-minded to all kinds of great ideasÊÊ coming from many different directions butÊ specifically most of them from the programÊÊ managers who will outline not just here’sÊ an idea, but here’s how we could pursue it. So you would want therefore thereÊ to be a clear porous interactionÊÊ with ARPA-H about exciting science ideas with allÊ the institutes but you would not want it to be aÊÊ circumstance where any specific institute could basically demand you’ve got to workÊÊ on this project because I said so.Ê It is going to have to be a caseÊÊ where the director has the ability to look atÊ the whole landscape of opportunities and chooseÊÊ those projects that are most likely to yieldÊ results that are going to benefit patients. This has to be use-driven. That can beÊ contrasted with curiosity-driven whichÊÊ is good science as well but ARPA-H needs to haveÊ a project in its portfolio that has clearly someÊÊ potential implications for clinical benefit. ThatÊ could be of course something that is a platformÊÊ that if you developed it, could be appliedÊ to lots of applications but you ought to beÊÊ able to see a path forward from that project toÊ clinical benefit for it to fit within ARPA-H. So my view is it’s a great opportunity for thisÊ to live within the scientific environment of theÊÊ National Institutes of Health because all of theÊ amazing scientific things that are happening. YouÊÊ wouldn't want I think this to be off inÊ some isolated part of the government. YouÊÊ would lose those connections and you mightÊ very well find that the resources of ARPA-HÊÊ were not then really being targeted to theÊ places of most potential. but at the same timeÊÊ we have to be sure that the decision processÊ is insulated from undue influences otherwise,ÊÊ this basically will fall into a trapÊ that we don't want it to. It does needÊÊ to basically build on the success of DARPA whichÊ has very much followed that model and not run theÊÊ risk of reducing the chances of taking on thingsÊ that are truly high-risk, high-reward which aren’tÊÊ always popular in traditional review processesÊ that can sometimes tend to be a bit conservative. There are a couple of questions onÊ partnerships and transitioning projectsÊÊ so for instance, the reference to DARPA, having a customerÊÊ in the DOD and different service branchesÊ of the DOD, and just how could envisionÊÊ those partnerships being developed andÊ things transferring to other entities. Tara, why don't you take that one. Sure, so I mean the short answer is, isÊ obviously we would want this organizationÊÊ to partner very closely with multiple differentÊ stakeholders and partners, right? So that includesÊÊ not just industry but those across theÊ federal government and in terms of,ÊÊ you know, the customer base, right, and how those,Ê outputs that would be developed could transitionÊÊ potentially to move out to market and get to the broader public, you know, if we couldÊÊ envision that through multiple different channelsÊ and some could be through partnering with industryÊÊ and providing incentives for them to do so ifÊ there isn’t much incentive that already exists. Other mechanisms as I indicated, could beÊ with partnering with the federal agencies,ÊÊ so you know for example the FDA, CMS, VA, andÊ there are lots of others, so not to just singleÊÊ those out, but those are those are, some thatÊ you could envision either working towardsÊÊ decreasing some of the regulatory hurdles or toÊ actually having a customer base to transitionÊÊ the intervention of products orÊ whatever is being developed too. Yeah, that’s a good summary of the kinds ofÊ things that we will very much want to catalyze. There is a question about how it is and maybe itÊ would be great if we had a DARPA program managerÊÊ on this panel that could sort of describe how theyÊ pick projects. But I gotta quote you something,ÊÊ there is if you go to the DARPA buildingÊ you will see much of their wall hangingsÊÊ seem to be devoted to a particular set ofÊ questions called the Heilmeier catechismÊÊ which was put forward by George HeilmeierÊ who was the DARPA Director in the 1970sÊÊ to help agency officials think throughÊ and evaluate a proposed research program. Listen to these, they are veryÊ simple and straightforward butÊÊ actually they make a lot of sense. There are just eight of them. First of all,Ê what are you trying to do, articulate yourÊÊ objectives using absolutely no jargon. Okay. IfÊ you can't do that there is probably a problem. Second, how’s it done today? And whatÊ are the limits of current practice? Third, what is new in your approach andÊ why do you think it will be successful. Next, who cares if you are successful,Ê what difference will it make. Next, what are the risks and then how muchÊ will it cost, then how long will it take. And last one, what are theÊ mid-term and final examsÊÊ to check for success, in other words,Ê what are your metrics going to be. So pretty simple set of questions,ÊÊ but I suspect we’ll adopt someÊ version of that, or the Director willÊÊ in trying to assess whether a particular project aÊ program manager is pitching will be successful isÊÊ worth investing in. And that will be, thoseÊ will be interesting discussions to be sure. You mentioned the director and there areÊ some questions about how the director andÊÊ the program managers might be selected and theÊ types of characteristics of those individuals. Well, there is no current decisionÊ about whether the director needs toÊÊ be appointed by the President or shouldÊ be appointed by the Secretary. That is anÊÊ active topic of discussion. I thinkÊ the President cares a lot about ARPA-HÊÊ and so you might say well this would be a goodÊ thing to have the President do the appointment. The anxiety about that relates to sortÊ of political implications that mightÊÊ apply in future years so that hasn’tÊ quite been settled but it will be aÊÊ very high-level appointment that’sÊ for sure. And then program managers,ÊÊ we would expect the director would play theÊ major role in hiring because this is goingÊÊ to be the team that he or she oversees andÊ is in many ways going to shape the program. Those program managers will be invited to comeÊ not for life but for a 3-year appointment withÊÊ a possible extension to five years if that seemsÊ reasonable and then they are expected to move on.ÊÊ That probably means this won't be an appealingÊ job for somebody who is in a stable and long-termÊÊ tenure or tenure track academic position unlessÊ they expect their gonna move on to something elseÊÊ after this but it might be very appealing to a lotÊ of people in the private sector who tend to haveÊÊ a lot of job changes anyway, to come andÊ spend three to five years in the midst ofÊÊ this exciting effort and to be in charge definingÊ and then managing projects, that’s going to beÊÊ a really exciting opportunity. I would want toÊ do that if I was a little earlier in my career. So, we have gotten a lot of questions aboutÊ different diseases and conditions and whetherÊÊ or not they could be within scope of ARPA-HÊ so if we could just talk a little bit aboutÊÊ the focus, I guess, theÊ scientific focus areas of ARPA-H. Yeah, you know, maybe it would be good toÊ talk about a specific example in terms ofÊÊ how we can think this through.Ê The very first question we gotÊÊ was about a condition, mainly fibrosis whichÊ is common in a lot of diseases, but whichÊÊ has not been, I think, identified so muchÊ as a specific topic so the questionerÊÊ is asking whether in fact that’s something thatÊ we might want to consider as a ARPA-H project. If Bob Carter is still on andÊ wants to weigh in here? So, Bob,ÊÊ what do you think of that kind of an idea? Let's just sort of talk about it in realÊÊ time here without of course being able toÊ make any commitments but what do you think? Oh no, I think it is a great idea.Ê In fact we're having roundtableÊÊ on methods for resolution of inflammation,Ê specifically to think of that as a way toÊÊ prevent fibrosis. I think most of us see that asÊ sort of a fork in the road and we should be ableÊÊ to manipulate it. It certainly covers a wholeÊ lot of territories the participants suggested. So I do think it is right, I do thinkÊ it could be very specific deliverables,ÊÊ starting with some models and building up fromÊ there it would be again, try this, fail fast,ÊÊ move on, get the right answer and I think it’sÊ a perfectly viable approach that we’d support. I like the idea that this could apply toÊ multiple different disorders as well soÊÊ you could say studying the mechanisms of fibrosisÊÊ provides you sort of a platform upon whichÊ you could build interventions for a number ofÊÊ conditions. So yeah it’s the kind of idea that IÊ think will be appropriate to start kicking around. And that’s the key part of this model,Ê right is that you mentioned Francis, thatÊÊ it would be a platform, right and I thinkÊ one of the things as we are thinking aboutÊÊ ARPA-H that we want to think about is howÊ it can build capabilities in platforms,ÊÊ things that could be broadly applicable acrossÊ a wide range of diseases and conditions. And a sort of the approach that is,ÊÊ ARPA-H could be an enabler, and a catalystÊ of certain areas and that would be appliedÊÊ to a broad range of different diseaseÊ types, as we are speaking of now. So Tara I think, looking at a couple of theÊ questions, I think people are also wonderingÊÊ if they’re out there in the biomedical researchÊ community and academia, or maybe in the privateÊÊ sector and ARPA -H happens, how will they have aÊ chance to take part? What should they be lookingÊÊ for as a signal that there’s a projectÊ getting generated that they might want toÊÊ be a part of? How is that going to work? Well, as we mentioned previously, thereÊ likely will be a sort of just broad openÊÊ announcement that can be applied to. That’sÊ the sort of approach of investigator-initiated,ÊÊ send us your bold audaciousÊ ideas and we'll go through them. The other thing, as these programs areÊ being developed, right, as we mentioned,ÊÊ there would be a fair amount of communityÊ engagement, right. There is a level of,ÊÊ for lack of maybe a better term, market researchÊ or just research that needs to be done toÊÊ understand the landscape, to be able toÊ answer the Heilmeier questions, right? And so, with that there will be opportunities toÊÊ really gather information and connectÊ with people in the community and thatÊÊ will be in some ways a signal of whatÊ the agency is interested in exploring. And then if a program manager gets all thatÊ information, makes a pitch to the ARPA-H directorÊÊ and gets a green light, and they now have a prettyÊ good idea of what components they need to bringÊÊ together to make the project happen, how does thatÊ then get started? What kind of outreach occurs? What kind of opportunities do people haveÊ to learn about that at that point that theyÊ might want to raise their hand and say hey IÊ can do something useful to contribute to this. Yeah, once the announcement wouldÊ go out and that would go outÊÊ broadly and publicly, you know there’s oftenÊ things that can be done and their going toÊÊ sound familiar to what NIH sometimesÊ leverages and these are things likeÊÊ really program days to bolster knowledge andÊ information about the program that is tryingÊÊ to be put forth that allows the potentialÊ applicants to ask program staff questions. As part of the process, this is something that allÊ of the ARPA’s use, they have a kind of abstractÊÊ that’s submitted first, it’s a very short documentÊ and that’s used as a way to kind of get someÊÊ insight from the field and also to kind of signalÊ to the field what the program manager and whatÊÊ the organization is interested in supporting byÊ asking for full applications from some of these. So, they undergo a review process on that as well. Francis, you are muted. Well, I have to do that at least onceÊ a day so I will now check the box.ÊÊ I think we have come to the end of our time though, folks. Tara, and I should have also said a thank youÊ earlier on to Dr. Rachael Fleurence who’s helpedÊÊ a lot with organizing these sessions. Could we tryÊ to provide brief answers to the things that wereÊÊ in the Q&A that we didn’t get to, just sendingÊ them afterwards in some kind of quick response? I am not quite sure the mechanicsÊ because it is the first time we haveÊÊ tried to do this with the Q&A. Is thatÊ something that’s going to be feasible? Let's just say we’ll try? [laughter] Because some of these I am not sureÊ quite how we would get back to people,ÊÊ like the anonymous attendee, whoever thatÊ is. We will do our best. I think we managedÊÊ to cover most of the major themes here, andÊ what we didn’t get into, were some of the more,ÊÊ very specifics about a particular kindÊ of approach, like for instance usingÊÊ machine virtual reality for early detection ofÊ Alzheimer's which sounds like an interesting idea. So I would just want to then say thankÊ you again to all of the 150 or so of youÊÊ who were part of this 75-minute session.Ê Your interest in ARPA-H, is most welcome. I guess I heard from our stakeholders strongÊ interest and enthusiasm for this but with a lot ofÊÊ questions about how it’s gonna will play out andÊ a strong exhortation that this must not be doneÊÊ in a way that does harm to the rest ofÊ NIH and believe me I would not want toÊÊ see that happen either as the NIHÊ director over now almost 12 years. We’re really grateful Richard Hodes and Bob CarterÊ for your input and for our wonderful stakeholders,ÊÊ all six of you, who brought us I thinkÊ really interesting perspectives and ideas.ÊÊ This is just one way to engage with us so beforeÊ I close, there’s several other opportunities thatÊÊ you might want to take advantage of. NIH andÊ OSTP will be holding more listening sessionsÊÊ like this over the next week, that will beÊ publicly broadcast. You can find informationÊÊ on those on the NIH webpage about ARPA-H. There’sÊ also an ARPA-H comments box, which remainsÊÊ open. And we look forward as we try to shape thisÊ to hearing all the great ideas from the communityÊÊ about how ARPA-H could take a placeÊ that really needs to be filled inÊÊ and accelerate the progress of bringingÊ scientific advances to clinical benefits. So with that, with many thanks and especially TaraÊ to you for all of the hard work you’re doing andÊÊ everybody else who took part in planning for this,Ê I think we can say good morning, we are adjourned.