Departments of Labor, Health and Human Services, and Education, and Related Agencies Appropriations for Fiscal Year 2018

DEPARTMENTS OF LABOR, HEALTH AND HUMAN SERVICES, AND EDUCATION, AND RELATED AGENCIES APPROPRIATIONS FOR FISCAL YEAR 2018

THURSDAY, JUNE 22, 2017

U.S. SENATE, SUBCOMMITTEE OF THE COMMITTEE ON APPROPRIATIONS, Washington, DC. The subcommittee met at 10 a.m. in room SD–138, Dirksen Sen- ate Office Building, Hon. Roy Blunt (chairman) presiding. Present: Senators Blunt, Cochran, Shelby, Alexander, Moran, Lankford, Kennedy, Murray, Durbin, Shaheen, Murphy, Manchin, and Leahy. DEPARTMENT OF HEALTH AND HUMAN SERVICES

NATIONAL INSTITUTES OF HEALTH STATEMENT OF FRANCIS S. COLLINS, M.D., Ph.D., DIRECTOR ACCOMPANIED BY: DOUGLAS LOWY, M.D., ACTING DIRECTOR, NATIONAL CANCER IN- STITUTE GARY GIBBONS, M.D., DIRECTOR, NATIONAL HEART, LUNG, AND BLOOD INSTITUTE ANTHONY FAUCI, M.D., DIRECTOR, NATIONAL INSTITUTE OF AL- LERGY AND INFECTIOUS DISEASES RICHARD HODES, DIRECTOR, NATIONAL INSTITUTE ON AGING NORA VOLKOW, M.D., DIRECTOR, NATIONAL INSTITUTE ON DRUG ABUSE JOSHUA GORDON, M.D., Ph.D., DIRECTOR, NATIONAL INSTITUTE OF MENTAL HEALTH

OPENING STATEMENT OF SENATOR ROY BLUNT Senator BLUNT. The committee will come to order. The Appro- priations Subcommittee on Labor, Health and Human Services, Education, and Related Agencies will come to order. Before my opening statement, I want to recognize Melinda Bachini, who we had a chance, nine of us did, to meet and talk to about her cancer fight and the success she’s made there when we were out at NIH (National Institutes of Health) a few days ago. And we are glad you’re here, and I was just told that the young- est of your six children just got their driver’s license, so good luck with that. [Laughter.] (1) 2

Senator BLUNT. Good luck with all of that. And we were glad to have a chance to meet with her. We’re glad to have Dr. Collins and the other Institute Directors here today. The budget, of course, proposes cuts that I think that you can rest assured the committee will find unacceptable. The $7.5 billion cut from NIH would, according to analysts, cost nearly 90,000 jobs nationwide, result in $15.3 billion of lost economic activity. In my home State of Missouri, that equates to a loss of nearly 1,700 jobs and $292 million in economic activity. The cut is one that I think you can rest assured this committee will not take. I certainly fundamentally disagree with the proposed funding reduction. However, this isn’t the first President to propose a reduction. President Obama proposed a $1 billion cut in his budget last year. We went $3 billion above his proposal. I’m not sure we could do anything like that this year, but I also mentioned in a hearing earlier this week that when his budget was submitted to the Senate, 98 Senators voted against it, and 1 Senator voted for it. So we have a long history of the Congress asserting itself on issues of how to allocate money. I believe this committee will do the same thing this year. In the last 2 years we were able to increase funding by $4 billion, with significant encouragement from the whole committee, and particularly from Senator Murray, Senator Alexander, Senator Durbin, and really the whole committee, we had nine of our committee out at NIH recently. I think it was the biggest Senate dele- gation to ever go to NIH. We spent most of the afternoon. I hope you, Dr. Collins, and your Institute Directors, know how much your work is appreciated. In the last 2 years, we have increased NIH funding by a little more than 13 percent, and we’re going to be listening carefully to your presentations today. But before that, I would like to turn to Senator Murray for her opening comments. [The statement follows:]

PREPARED STATEMENT OF SENATOR ROY BLUNT Good morning. Thank you, Dr. Collins and the other Institute Directors, for ap- pearing before the Subcommittee today to discuss the National Institutes of Health’s fiscal year 2018 budget request. The budget request proposes to cut $7.5 billion from the NIH. According to analysis from United for Medical Research, this funding reduction could cost nearly 90,000 jobs nationwide and result in a $15.3 billion loss in economic activity. In my home State of Missouri, that equates to a loss of nearly 1,700 jobs and $292 million. A cut to NIH is not a cut to Washington bureaucracy; it is a cut to life-saving treatments and cures, affecting research performed all across the country. I fundamentally disagree with the proposed funding reduction for NIH. However, this is not the first President’s budget to propose reducing NIH funding. Just last year, the Obama Administration proposed cutting $1 billion in discretionary funding from NIH. This Committee and Congress did not agree, instead, appropriating a $2 billion increase for a second year in a row. Yet, simply proposing a drastic reduction to medical research is the wrong message to send. It’s the wrong message for the millions of Americans suffering from life-threatening diseases; it’s the wrong message to the medical research community tirelessly working to develop new treatments and cures; and it’s the wrong message to the young scientists deciding whether medical research is the career path they should pursue. When I became Chairman of the Labor/HHS Appropriations Subcommittee 2 years ago, I worked with colleagues on both sides of the aisle, including Senators Murray, Alexander, and Durbin, to realign the priorities of this bill, putting a renewed focus back on medical research funding. 3

For over a decade, funding for the National Institutes of Health remained stag- nant, its purchasing power decreased by 22 percent since 2003, and grant success rates, in some NIH Institutes, fell to as low as 9 percent. This had to change and, over the past 2 years, it has. We have increased funding in the past 2 years by $4 billion, an increase of 13.3 percent. This is a larger increase for NIH in 2 years than in the previous 10 years combined. In the last 2 years, we have more than doubled the amount of research funding for Alzheimer’s disease and started directly funding precision medicine programs. Together, these initiatives could transform the way healthcare is delivered and help stabilize the long-term viability of Medicare. But under the proposed budget, these programs may not move forward as envisioned. In fact, Alzheimer’s disease funding is cut by $549 million and the National Cancer Institute cannot even provide a Precision Medicine funding level. I am also deeply concerned about several of the specific proposals in the budget request, including capping indirect costs and eliminating the Fogarty International Center. The funding cut to NIH is so deep that it is difficult to determine if these proposals are recommended because you truly believe they will gain efficiencies for the agency, or if they are proposed because the topline funding levels forced you to do so. I know each of the witnesses today remains committed to biomedical research, just like I do. And, I know we all want to ensure that our researchers have the support and funding they need to make the life-saving breakthroughs that could change so many Americans’ lives. I know this is a budget they do not want to defend. It’s a request no one should have to defend. Thank you for being here today.

STATEMENT OF SENATOR PATTY MURRAY Senator MURRAY. Well, thank you very much, Mr. Chairman. Dr. Collins, thank you to you and all of your team for being here today. We appreciate all that you do to champion the critical work of NIH. You’ve been a great partner, and I really appreciate your leadership and all your teams. And I, too, welcome Ms. Bakini. It’s good to see you again up from Montana. And I look forward to having a discussion today about really the devastating impact that President Trump’s budget would have on NIH. As you all know, President Trump has proposed cutting NIH by 22 percent, most of it by arbitrarily capping indirect costs, resulting in the lowest funding level for biomedical research since 2002. Three months after releasing this proposal, we still do not have basic information from the administration about how NIH would implement a $7.5 billion reduction without severe consequences for thousands of research facilities and tens of thousands of scientists that rely on its grants to support their work, facilities like Fred Hutchinson Institute in my home State of Washington, just to cite one example, where scientists have pioneered bone marrow trans- plants and today are searching for cures to cancer and an HIV vaccine, but because of this proposal, could be forced to dramatically scale back their efforts to develop cures for patients. So these cuts are deeply concerning, which is why I’ve said repeatedly I really hope that both parties will once again reject Presi- dent Trump’s budget proposal and continue to work together, as we have, to ensure NIH is able to carry out its vital work that gives hope to those living with chronic and life-threatening disease and bolster economic growth and competitiveness. But before this discussion can happen, however, I have to note that today’s hearing takes place in the midst of a very pivotal moment for our healthcare system as a whole. As we have heard all 4 week, our Republican colleagues appear to be dead set on jamming their version of Trumpcare through the Senate in just a matter of days. This is a bill that has been subject to no hearings, no public debate, and no expert testimony. It’s a bill so secret that apparently until just moments ago many Republican Senators were telling press and constituents they couldn’t say what was in the bill. It was a bill so secret even President Trump’s top healthcare advisor, Secretary of Health and Human Services, told us last week that he didn’t know what was in it. It has been so secret and closely guard- ed that not even the 13 male Senators who made up the so-called working group could comment with certainty on what was in that or when it would be brought up or by what procedure. And in fact, it’s a bill so secret that even the White House Press Secretary couldn’t confirm whether President Trump or anybody in the White House, for that matter, had seen the bill, which begs the question, as I have said this week, what are Republican leaders so ashamed of? Well, it is becoming very clear now that those who wrote the Trumpcare bill knew they wouldn’t be able to go back home and defend it because based on what we are now learning, this bill is going to be the same kind of Trumpcare bill that went in the House, and it will have tremendous impact on patients and families, higher cost for families, especially seniors and people with pre- existing conditions. Insurance companies no longer will be required to cover basic healthcare, like maternity care or mental health services and more. Women would lose access to their doctors and to the care they need at Planned Parenthood. And tens of millions of people across the country would see their Medicaid coverage taken away. That means people nationwide who are finally getting treatment for substance use disorders like opioid addiction or mental healthcare or access to a primary care doctor under Medicaid are going to lose that access. So as many of my Democratic colleagues have said, this is not a healthcare bill, it’s an attack on families’ health and financial security. So, again, I just want to reiterate my message to Republican leadership: it is not too late to dump this Trumpcare bill, it’s not too late to make the right choices and work with us, as Democrats, to fix our healthcare system. As the Chairman and others on this committee should know by now, Democrats stand ready, as we always have, to work together to actually make healthcare more affordable and accessible for patients and families across the country, but we cannot begin that conversation until Republican leadership reverses course. And lastly I do have to say that after hearing this week about so many of my Republican colleagues feeling frustrated about this bill’s process, who are angered about being shut out of this process, are receiving conflicting information, or who may be even shocked at the text that was just released, well, you have the power to do something about it, not just to complain. You can insist on full hearings, open debate, increased transparency, because let’s be very clear, people across the country are really worried about the approach that’s being taken. They are watching. They’re going to 5 be paying close attention. And we need to get this right, not what is being jammed through the Senate. And with that, Mr. Chairman, I’ll turn it back to you. Senator BLUNT. Thank you, Senator Murray. We are pleased to have both the Chairman of the full committee and the Ranking Member of the full committee with us today. I think Chairman Cochran does not have a statement, but I think you may, Senator Leahy. Senator COCHRAN. Mr. Chairman, I ask that my statement be printed in the record. [The statement follows:]

PREPARED STATEMENT OF SENATOR THAD COCHRAN Mr. Chairman, I am pleased to join you to review the fiscal year 2018 budget request for the National Institutes of Health (NIH). A good example of the work funded by the NIH is the Jackson Heart Study in my state of Mississippi. Over the past 20 years, this study has yielded insight into the causes of and potential treatments for cardiovascular disease in African Ameri- cans. We are proud of this landmark study, and I am hopeful this good work can be expanded when the contract is reconsidered later this year. I am concerned that the 22 percent funding cut proposed for NIH could negatively affect longstanding research endeavors like the Jackson Heart Study. I look forward to hearing from Dr. Collins and his colleagues about how the NIH can continue its robust support of medical research. Senator BLUNT. Good. Thank you. STATEMENT OF SENATOR PATRICK J. LEAHY Senator LEAHY. Thank you, Chairman Blunt, Chairman Cochran, glad to be here with you, and of course, with Senator Murray. And I completely agree with her statement. I think this is an important meeting. And Dr. Collins, it’s good to have you here and your whole team. Just for a personal note, my mother, when she was still with us, she was first-generation Italian American, and when she saw my schedule, that Dr. Fauci was going to be here, she would say, ‘‘Say hello to that nice young man.’’ [Laughter.] Senator LEAHY. Or as you say, ‘‘Say buon giorno.’’ [Laughter.] Senator LEAHY. But I am worried about the budget. You know, this affects all of us. It ignores the fact that you have to support the middle class, you have to lift up the most vulnerable, and you have to serve our values and interests as a Nation. And NIH has been a shining example of serving our Nation, but sequestration has had devastating consequences for both defense and non-defense programs. I think those consequences are going to last for a generation, it will affect my children and my grandchildren. And this budget makes it even worse, deep budget cuts. Those that have drawn the most bipartisan opposition, you heard what Senator Blunt said, and others have, about such budgets, the most bipartisan criticism has been reductions for the National In- stitutes of Health. And I want to commend Chairman Blunt and Ranking Member Murray for their efforts to bolster the NIH budget in recent years. But this one, this budget that we’ve been given by the White House 6 turns that progress upside-down. It slashes NIH resources by $7.2 billion, 21 percent, the lowest NIH budget since 2002. Well, you know far better than I do that you can’t—in medical research, you can’t say, ‘‘Okay, we’ll just turn off for a few years those studies and trials and all, but we’ll come back 5 years from now and pick it back up again.’’ You just can’t do it. You don’t hit Pause on studies. You can’t have ups and downs based on the whims of an anti-science group. That hurts the medical research field. I think not only what it would do to you, but there’s a cap on research that’s being done around the Nation at universities and other entities. I’m not being parochial, but I mention the University of Vermont. They receive millions of dollars of NIH grants each year. They wrote recently to Director Mulvaney and Secretary Price and noted it’s unlikely that they could continue their research on this budget, and they’ve been doing cutting edge research in cancer, among other things. And I would ask for a full copy of the University of Vermont’s letter be placed in the record, Mr. Chairman. Senator BLUNT. Without objection. [The letter follows:] 7 8

Senator LEAHY. Thank you. So I think, as vice chairman of the overall committee, I’m committed to try to get money back in. This science, this is where we can excel, where we can lead the world. But not only that, we can make life so much better for our own people and people around the world. So I will fight for every dollar to get it back that I can. And thank you very much, Mr. Chairman. Senator BLUNT. Thank you, Senator Leahy. Director Collins, we’re pleased you’re here and look forward to your opening statement. And when you’re through with that, we’ll go to questions. SUMMARY STATEMENT OF DR. FRANCIS S. COLLINS Dr. COLLINS. Well, thank you. Let me introduce the folks at the panel table with me. Over on my left, your right, is Dr. Richard Hodes, the Director of the National Institute on Aging. Next to him, Dr. Nora Volkow, the Director of the National Institute on Drug Abuse. And next to me, Doug Lowy, who is the Acting Direc- tor of the National Cancer Institute. To my right, your left, Joshua Gordon, who is the Director of the National Institute of Mental Health, and you’ve already recognized in one comment at least, Dr. Tony Fauci, the Director of the National Institute of Allergy and Infectious Diseases. And at the far left, on your side, Gary Gibbons, who is the Director of the National Heart, Lung, and Blood Insti- tute. We brought the ‘‘A Team’’ today. [Laughter.] Dr. COLLINS. So it’s a pleasure and an honor that we were able to host many of you on our campus earlier this month, and it’s a 9 great honor to be here with you today, and I’m privileged to continue in this role as NIH Director. I want to thank all of you for your sustained commitment to NIH, a commitment that will ensure that our Nation remains the global leader in biomedical research, with all that it means for human health. Today, I would like to highlight several areas of exceptional scientific opportunity, introduce you to a few patients, and also talk about some young researchers who are working hard to make these dreams come true, and I’ll show a few images over there on the screen. [The graphic follows:]

Dr. COLLINS. Let’s start with an opportunity that shows the transformational power of investing in NIH basic science. So imagine that you could determine the precise molecular structures of proteins like what you see here, proteins targeted by pharmaceuticals, and see exactly how they interact with each drug. This is starting to happen thanks to a new technology called cryo-EM. [The graphic follows:] 10

Dr. COLLINS. This image shows the structure of a protein channel, which is indicated in gray mesh, that’s the channel part, that regulates salt and water balance in the lungs. This very protein is misfolded in cystic fibrosis (CF), our Nation’s most common fatal genetic disease. The genetic mutation that causes cystic fibrosis was discovered in my own research lab many years ago, but only now is new structural information allowing us to design better drugs to help cystic fibrosis patients like little Avalyn Mahoney, who will be celebrating her second birthday next week. Avalyn’s life has not been easy. She required surgery for an intestinal blockage shortly after birth, but she’s doing pretty well now. Just a few decades ago, she probably wouldn’t have made it beyond her teens. No longer. Today, we have two targeted drugs for CF, and more to come, all building on NIH-support basic research. And we’re not done. The goal is to turn CF into a 100 percent curable disease. For that, we need the next generation of scientific talent. Among the early stage investigators tackling this challenge is Stephen Aller, of the University of Alabama at Birmingham. Trained in both computer science and biology, Stephen plans to transform in fundamental ways how we design and deliver drugs for all kinds of conditions. In fact, we need that. Treatments only exist today for about 500 of the 7,000 diseases for which a molecular cause is now known. [The graphic follows:] 11

Dr. COLLINS. Among those in desperate need of a breakthrough is sickle cell disease, a life-threatening disorder in which red blood cells are deformed in a way that clogs small blood vessels. Sickle cell disease is caused by a genetic misspelling, and that was essentially understood 60 years ago, yet even today the only way it can be cured is by a bone marrow transplant from an unaffected donor. That can work really well for some patients, like Chris Sweet, shown here with his family. Chris received a transplant at the NIH Clinical Center 6 years ago and is now essentially cured. But unfortunately most don’t have a well-matched bone marrow donor. So what if we could actually correct that sickle misspelling in the patient’s own blood cells? A few years ago, I would have said that’s pretty unlikely, but that’s all changing. NIH’s Courtney Fitzhugh is seeking to use a new gene editing system called CRISPR to modify bone marrow stem cells in people with sickle cell disease. The goal is to fix the underlying genetic defect and make the patient’s own cells healthy. If Courtney and other young scientists can get this to work for sickle cell disease, just think about what they might do for thousands of others still awaiting a cure. [The graphic follows:] 12

Dr. COLLINS. Now imagine you could develop a detailed understanding of the 86 billion neurons in the human brain. That’s what our BRAIN Initiative aims to do. I know that each member of this subcommittee is aware of the enormous toll that brain disorders are taking upon our Nation’s health and economy. Alzheimer’s disease alone has an estimated economic cost of $259 billion this year, and it’s projected to exceed $1.1 trillion by 2050. Let’s imagine that using tools and technologies created by the BRAIN Initiative you could easily identify someone at risk for Alz- heimer’s and use such advanced warning to apply effective ways of preventing this disease that’s touched so many, including singer Glen Campbell, who was here on the Hill with his family just a few years ago to advocate for Alzheimer’s disease research. Well, young investigator Yaki Oki Rose, of Massachusetts Gen- eral Hospital, is among those taking on this challenge. Her work is focused on the largest known group of people in the world with inherited Alzheimer’s, an extended family living in the mountains of Colombia. In an effort to uncover subtle changes in the brain years before symptoms appear, her team is using PET scans to compare the brains of family members who carry the Alzheimer’s gene mutation with those who do not. Clearly, finding Alzheimer’s won’t be easy, but Yaki and other young researchers have the talent and drive to make it happen, and you all are part of this. Your emphasis on Alzheimer’s and related dementias research in fiscal 2016 and 2017 is enabling progress toward our mutual goal of preventing and effectively treating these devastating conditions. [The graphic follows:] 13

Dr. COLLINS. So all of us here are motivated today by a sense of urgency to help patients in need of breakthroughs. The next generation of innovative and passionate young researchers will be the most critical part of achieving that bright future. Two weeks ago, NIH announced the Next Generation Researchers Initiative, a focused approach to bolster support to early- and mid-career investigators like the three you see here. Our Nation’s health and well- being depend on your strong support for them. [The graphic follows:]

Dr. COLLINS. So thank you, Mr. Chairman. My colleagues and I welcome your questions. [The statement follows:] 14

PREPARED STATEMENT OF FRANCIS S. COLLINS, M.D., PH.D. Good morning, Chairman Blunt, Ranking Member Murray, and distinguished Members of the Subcommittee. I am Francis S. Collins, M.D., Ph.D., and I have served as the Director of the National Institutes of Health (NIH) since 2009. It is an honor to appear before you today, and it was a pleasure to host many of you at NIH earlier this month. Before I discuss NIH’s diverse investments in biomedical research and some of the exciting scientific opportunities on the horizon, I want to thank this Subcommittee for your fiscal year 2017 commitment to NIH. As the Nation’s premier biomedical research agency, NIH’s mission is to seek fundamental knowledge about the nature and behavior of living systems, and to apply that knowledge to enhance human health, lengthen life, and reduce illness and disability. As some of you have witnessed first-hand on your visits to NIH, our leadership and employees believe passionately in our mission. This extends equally to the tens of thousands of individuals whose research and training we support, located in every State of this great country, and where 81 percent of our budget is distributed. I would like to provide just a few examples of the depth and breadth of the amazing research being supported across the Institutes and Centers of NIH. The core of our mission remains basic biomedical science. Given the exploratory and, hence, unpredictable nature of fundamental discovery, basic science is generally not supported in the private sector—but it provides the critical foundation for advances in disease diagnosis, treatment, and prevention through future clinical applications. Virtually none of the substantial gains in reducing human suffering and extending longevity over the last century would have happened without basic science. NIH’s emphasis on fostering innovation to understand fundamental biological processes has led to no fewer than 149 Nobel Prizes to our grantees, and is leading year by year to new and more effective ways to treat complex medical conditions. As a current example, the emergence of ‘‘cryo-EM,’’ a new form of electron micros- copy, has dramatically sped up the time needed to visualize the exquisite details of biological structures including protein-protein and protein-drug complexes. This is a major revolution in structural biology that already is transforming drug design. Basic research is also fueling new advances in our understanding of the brain, which will be critically important for treating diseases such as Alzheimer’s disease, Parkinson’s disease, autism, epilepsy, traumatic brain injury, and others. Through the Accelerating Medicines Partnership (AMP), a public-private partnership between NIH, the Food and Drug Administration (FDA), 10 biotechnology companies, and nonprofit organizations, we have joined ranks across sectors to expand our understanding of Alzheimer’s disease. In one component of AMP, researchers are ana- lyzing large-scale molecular data from thousands of affected and unaffected human brain samples, including genomic, gene expression, and protein measures. With this information, NIH and our partners are building new molecular pathways to understand the cause of Alzheimer’s, and charting a course for entirely new ways to detect and treat this devastating disease that go beyond the previous understanding of the amyloid and tau proteins. By working with industry and sharing data widely in the scientific community, NIH aims to shorten the time between these discoveries and the development of new strategies for Alzheimer’s disease treatment and prevention. Rare diseases also represent an area of great need and great opportunity, one which NIH continues to be uniquely positioned to address. Though such diseases are individually rare, collectively an estimated 25 to 30 million Americans are affected. Great advances have been made through genomic science in uncovering the cause of rare diseases, and that has led to dramatic improvements in diagnosis. But of the 6,500 identified rare and neglected diseases for which the molecular cause is now known, only about 500 have approved treatments. The private sector generally finds it difficult to mount expensive initiatives for such small markets—the risks are too high. Finding new treatments thus requires NIH to play a lead role—by investing in the early stage of therapeutic development to ‘‘de-risk’’ such projects. While almost all Institutes and Centers at NIH work on rare diseases, the National Center for Advancing Translational Sciences (NCATS) has a particular focus on this area of opportunity. As an example, autoimmune pulmonary alveolar proteinosis (aPAP) is a rare, potentially fatal disease marked by a build-up of lipids and proteins in the lungs, and leads to respiratory failure. The current treatment for severe aPAP is whole-lung lavage, whereby both lungs are repeatedly filled and washed with a salt solution. This procedure is complicated, dangerous, and must be repeated throughout a pa- 15 tient’s entire life. NCATS has supported efforts to develop an inhaled treatment for aPAP, providing support and expertise to the basic research, pre-clinical research and testing, and early-phase clinical trials. Other transformative technologies are offering dramatic new approaches to achieving a truly molecular cure of rare diseases. For example, experts are now testing genetic therapy in bone marrow stem cells as a curative treatment for sickle cell disease, the first human disease understood at the molecular level and the most common inherited blood disorder in the United States, affecting over one hundred thousand Americans at a yearly cost of hundreds of millions of dollars. As a final example, consider how fundamental research over many years now promises to transform medicine for patients with advanced cancer: immunotherapy. For decades, basic scientists have worked to understand how the immune system functions at the molecular level. Now, thanks to a series of dramatic advances, we can not only watch the immune system at work, we can instruct it—‘‘send it to school.’’ In a recent breathtaking example, a young woman with widely metastatic breast cancer, whose cancer had failed to respond to several rounds of chemotherapy, enrolled in an experimental protocol at the NIH Clinical Center as a last hope. Her tumor genome was sequenced, and rare immune cells in her body with the potential to seek and destroy those cancer cells were identified. After those immune cells were massively expanded in the laboratory, and then unleashed to go after the cancer, her tumors started to recede within days. Now more than a year later, there is no evidence of any remaining cancer in her body. She is part of a revolution in cancer treatment, all made possible by years of dedicated basic research in fields like immunology and genomics. So the future has never been brighter for advances in biomedical research than right now. Imagine what this feels like for a talented and curious new investigator. Early-stage investigators are responsible for many of the advances I’ve told you about today, and our future depends on them and their bright ideas. Those young men and women are thrilled by the prospect of exploration, and driven to help people. NIH is responsible for training these scientists, and for making sure that our investment in their careers, and the potential advances they will bring to patients, are sustained into the next stage. They are our most important resource. If advances in medical research are to continue, if research is to lead to breakthroughs that can reduce healthcare costs, if the considerable economic return on research is to continue, and if America is to continue its global leadership in biomedicine, we need to be sure this next generation has the confidence that there will be support for them. This is a priority for me. Two weeks ago, NIH announced the Next Generation Researchers Initiative, a focused approach to bolster support to early- and mid-career investigators comprised of four components. First, we are repurposing funds from NIH’s base budget, beginning this fiscal year with about $210 million, and ramping to approximately $1.1 billion per year after 5 years to support additional meritorious early-stage investigators, as well as mid-career investigators (those with less than or equal to 10 years as a principal investigator who are about to lose all NIH funding or are seeking a second award for highly meritorious research). Second, we will track the impact of NIH Institute and Center funding decisions for early- and mid-career investigators with fundable scores to ensure this new strategy is effectively implemented in all areas of research. Third, we will place greater emphasis on current NIH funding mechanisms aimed at early- and mid-career investigators, such as the NIH Common Fund New Innovator Awards the National Institute of General Medicine Sciences Maximizing Investigators’ Research Award (MIRA), the National Institute of Dental and Craniofacial Research Sustaining Outstanding Achievement in Research (SOAR) Award, and other special awards from specific institutes, with an aim of funding most early-career investigators with applications that score in the top 25th percentile. Fourth, we will encourage multiple approaches to develop and test metrics that can be used to assess the impact of NIH grant support on scientific progress. I have provided you with examples of how investments in bright new ideas in biomedical research are advancing human health, spurring innovations in science and technology, stimulating economic growth, and laying the groundwork for the future of the United States biomedical research enterprise. We have never witnessed a time of greater promise for advances in medicine than right now. Your support has been critical, and will continue to be. The fiscal year 2018 Budget provides $26.9 billion for NIH, which is $7.4 billion below the fiscal year 2017 enacted level. The fiscal year 2018 Budget eliminates the Fogarty International Center while retaining a total of $25 million in mission-critical international research and research related activities within the Office of Direc- tor. It includes $272 million in discretionary budget authority within NIH to pre- 16 serve key research activities previously carried out by the Agency for Healthcare Re- search and Quality (AHRQ), including critical survey activities, support for the U.S. Preventive Services Task Force, evidence-based practice centers, patient safety, investigator-initiated grants, and researcher training grants. NIH is engaged in many efforts to encourage good stewardship practices across all levels of the biomedical research enterprise. These include ways to streamline administrative processes for investigators, efforts to support new and early stage investigators, and a focus on cultivating a world-class biomedical research workforce. The fiscal year 2018 Budget includes an indirect cost rate for NIH grants that will be capped at 10 percent of total cost (currently NIH expends approximately 28 percent of its extramural budget on indirect costs). This approach would be applied to all types of grants with a rate higher than 10 percent. In addition, Federal research requirements for grantees will be streamlined to reduce grantee burden through targeted approaches as proposed by NIH. This concludes my testimony, and I look forward to answering your questions.

FOGARTY INTERNATIONAL CENTER Senator BLUNT. Well, Dr. Collins, again, we’re glad you’re here. I was pleased with the President’s decision to continue your leadership at NIH, and many of us had advocated for that, and we’re pleased to see it happen. Your team and what your team does is inspiring to all of us. We’ll have a 5-minute round of questions. I think there are a lot of competing things going on today, so we’ll try to keep that as close to 5 minutes as we can starting with me. A couple of areas I want to ask specifically about in the Presi- dent’s proposal, one was to eliminate the Fogarty International Center. I think particularly with the Zika virus response we’re going through and have gone through, that Center was pretty actively involved. Your thoughts about what the Center does as op- posed to commenting on necessarily the President’s view of this. Dr. COLLINS. I appreciate the question. I’m going to ask Dr. Fauci to say something about this. Senator BLUNT. Great. Dr. FAUCI. Thank very much, Mr. Chairman. The Fogarty Inter- national Center is truly integral to all that we do both directly and indirectly internationally and domestically particularly in the arena of infectious diseases, because as we know and have testified before this committee so often, infectious diseases know no borders. There are some cogent examples of how the training of international scientific colleagues supported by the Fogarty Inter- national Center has benefited the United States of America, and the two that are most recent are the Ebola outbreak and the Zika outbreak, not to mention the long-standing commitment to HIV/ AIDS and the clinical trials that are being done in Sub-Saharan Af- rica. Almost all of these trials are led by international scientists who were trained by Fogarty grants. Now, with regard to Ebola, you might recall that in West Africa, in Liberia, Guinea, and Sierra Leone, they had 28,000 cases and 11,000 deaths. If the Ebola outbreak had gone beyond those borders to places like Mali or Nigeria, it could have been even a greater catastrophe than it was. When Ebola infected individuals went to Mali and to Nigeria, it didn’t make much press because it was a success in that the investigators in those countries were able to handle, identify, isolate, contact, trace, and stop Ebola in those countries before it started to spread, particularly in Nigeria, which is the most populous country in Africa. Each of those investigators 17 who helped control Ebola were people who were trained by the Fogarty International Center. We look upon Fogarty-trained scientists as our true colleagues. I refer to them, and I mean that sincerely, as our brothers and sis- ters in the battle against infectious diseases. If this were a military metaphor, they would be our closest allies. They might wear a different uniform, but they are our allies. So the impact of the training that Fogarty supports has been extraordinary, and we really need to continue. AGENCY FOR HEALTHCARE RESEARCH AND QUALITY INTEGRATION INTO NIH Senator BLUNT. Another area, the establishment of the National Institute for Research on Safety and Quality,—the Agency for Healthcare Research and Quality would be consolidated into a new—I believe they propose a new institute in your organization. One, if you want to comment on that generally; and two, if that was going to happen, are there alternative ways for those things to be moved into NIH without creating a new institute? Dr. COLLINS. So the Agency for Health Research Quality does complementary research to NIH particularly focused on health safety and health quality, for instance, looking at how to prevent health problems such as hospital readmissions, such as infections from intravenous catheters. We have strong interest in the research they do, and vice versa, and we have close connections with them. And we regularly look at our portfolios to make sure that we’re being complementary and not duplicative. So if it were the case that AHRQ (Agency for Healthcare Re- search and Quality) was moved into NIH, as is proposed in the President’s budget, we would figure out how it is that we could make the best of that circumstance in order to keep that important research going forward. Your other question is, would there be other models to achieve this other than a new institute? Certainly we could consider other models, such as having the portfolio that’s in AHRQ distributed around amongst the existing institutes who do similar research and incorporating the staff that’s part of AHRQ into the NIH staff without having them set up as a separate entity. That would be another option. Senator BLUNT. I might point out in my last 30 seconds here to something I should have mentioned earlier, and it follows up on Senator Murray’s view that we’ve tried hard to work together. You know, what we’ve done at NIH in the last 2 years, there was no new money to do that, so it was truly a prioritization that elimi- nated programs and consolidated programs. And these were programs we had to determine weren’t doing everything we had hoped they would do so that priority could be placed on what you’re doing. And this is one of those times when Congress really has chosen to make decisions that for a lot of Members were really hard and for some Members were almost impossible to make, but the case you’re making is an important case for us to be able to understand and talk about. Senator Murray. 18

INDIRECT COSTS/FACILITIES AND ADMINISTRATION

Senator MURRAY. Thank you. And thank you again, Dr. Collins, to you and all your team. As you have been hearing, there is tremendous concern among the research community about President Trump’s proposal to cap indirect costs. What can you tell us about the status of efforts to replace the existing long-standing practice for calculating indirect costs with a 10 percent flat fee? Are your staff participating in those discussions? Dr. COLLINS. So ‘‘indirect costs’’ maybe is a somewhat unfortu- nate term because it’s a little hard to know what’s being referred to. Another alternative is ‘‘facilities and administration’’ or ‘‘F&A.’’ Those indirect costs, which on the average right now for NIH are about 28 percent of the grant awards in the extramural community, but it varies from institution to institution, go to cover such things as the facilities, the building, the utilities, the supply of light and water, the operations of various administrative services, such as human subjects oversight, animal care oversight, and so on. Those are not things that can be ascribed to a single grant, but they are basically necessary for the institution to be able to conduct research. Certainly, the proposal to reduce the amount that would go from NIH to indirect costs from 28 percent roughly on the average to 10 percent has attracted a lot of attention in the community because universities who do this work see that as potentially quite dangerous for their ability to keep going forward. We are looking at every possible way that we might be able to assist in this conversation by identifying areas in which various administrative burdens that we ask institutions to follow could be reduced because maybe they’re not as necessary as they are. So we’re looking at our current regulations, for instance, about conflict of interest, about animal care, about effort reporting. We might in that process be able to identify a way to reduce somewhat the burden, but frankly, I don’t think it would add up to an enormous difference in what we’re currently asking our grantee institutions to do, and they are the ones who do the work. We depend on them.

INTRAMURAL RESEARCH PROGRAM

Senator MURRAY. Well, what would happen to your intramural research program if the costs were kept at 10 percent? Dr. COLLINS. Our intramural program, which you visited recently, much of it on the NIH campus, is about 11 percent of the overall budget. Calculating indirect costs is a little complicated. It’s a purely government facility. When that was recently looked at, but not that recently, it was about 30 percent. It was similar to what we would see happening in the extramural community. For that intramural program, there would be no other potential source of funds. It would make it rather hard for me or anyone at this table I think to imagine what we would do if that was required to drop to 10 percent given that we have the buildings and the electric power and so on. 19

IMPACT OF ADMINISTRATIVE COST TO EXTRAMURAL RESEARCH

Senator MURRAY. So it would be pretty devastating. Dr. COLLINS. I’m having a hard time imagining how we would manage that. Senator MURRAY. Okay. Dr. Lowy, this proposal assumes that States or some other benefactor will somehow step in to cover the lion’s share of indirect costs once NIH abandons that responsibility. It’s a lot to assume that our States are going to pick up what’s long been a Federal responsibility, but many private institutions don’t have access to State resources or large trust funds that could cover the difference. What would likely happen to those research—places like Fred Hutch or SOC or Scripps if they are forced to result their indirect costs to 10 percent of their grant? Dr. LOWY. Senator Murray, it’s difficult to speculate exactly what would happen, but institutions such as the Fred Hutchinson Can- cer Research Center have been central to the advances that we have made in cancer research. For example, Donnall Thomas received a Nobel Prize for the research that he conducted with his colleagues at the Fred Hutch- inson. More recently, Paul Nghiem led the effort to do research on the use of immunotherapy for patients with Merkel cell cancer, and this has led to a breakthrough for those patients who have this disease. It’s not as common as melanoma, but it is the skin cancer that has the highest mortality rate. And recently the FDA approved a cancer immune checkpoint inhibitor for treatment of this disease, the first advance in many years. At the Scripps Institute, for example, they’re performing breakthrough research on trying to inhibit a particular oncogene called Myc that is involved in at least 50 percent of human cancer, but we don’t yet have interventions that are successful for that. So these are just some examples of the breakthrough treatments that are being developed at these institutions. Senator MURRAY. That would have an impact if the direct impact was cut, it would be hard for them to continue that. Dr. LOWY. Yes. Certainly they would have difficulty to continue their rate of progress. Senator MURRAY. Okay. Thank you very much, Mr. Chairman. Senator BLUNT. Thank you, Senator Murray. Chairman Cochran. MINORITY REPRESENTATION IN ALZHEIMER’S RESEARCH Senator COCHRAN. Mr. Chairman, let me join you in congratu- lating our panel here and the participation you’re bringing to this challenge. Dr. Collins, how is the NIH working to ensure that minorities are represented at Alzheimer’s research activities? Dr. COLLINS. So we are very interested in making sure that the resources Congress gives us are utilized in an optimum way for health disparities research across all of the fields represented by people at this table. You specifically asked about Alzheimer’s. I’m going to ask Dr. Hodes, who is our key person for Alzheimer’s research, to address that. 20

Dr. HODES. Thank you very much for the question. In fact, in our efforts at Alzheimer’s research, very prominent among them is attention to disparities, both because all Americans have a right to the fruits of research, but also because the best understanding of what underlies the processes behind Alzheimer’s is going to come by understanding how it affects individuals of different racial, ethnic, social backgrounds. And in fact, a great deal of discovery has shown that even the genetic risk factors differ across groups. Now, to ensure that we included these populations in research, we have active recruitment efforts that are broad. We also work through collaboration with some of the existing resources. For example, some of the populations who have been studied through NHLBI (National Heart, Lung, and Blood Institute), including those in your own State, are being harmonized with other studies. So we can look across all of these, do comparisons about risk factors, causes, and ultimately identify interventions that will target on a personalized basis across dispersed disparate populations. Senator COCHRAN. Thank you. Senator BLUNT. Thank you, Chairman. Senator Durbin. Senator DURBIN. Let me first acknowledge, Dr. Lowy, thank you for coming to Chicago last October and meeting with the directors of Illinois’ two NCI (National Cancer Institute)-Designated Com- prehensive Cancer Centers, Lurie Comprehensive Cancer Center of Northwestern and University of Chicago Medicine Comprehensive Cancer Center. And thanks for your years of service as the Acting Director of the NCI. I understand you’re going to be stepping aside to allow Ned Sharpless to take over. Your work personally has helped to develop a vaccine against cervical cancer, which is a leading cause of cancer death among women. It has saved and will continue to save countless lives. Our Nation and beyond are forever indebted to you for your dedication to research. I hope reports that you are going to continue on at NIH in another capacity are true. And I just want to thank you on behalf of this committee and the people who have been benefited by your great work over the years. Thank you, Dr. Lowy. Dr. LOWY. Thank you, Senator Durbin. INFORMING THE PUBLIC OF NIH’S CONTRIBUTIONS TO RESEARCH DEVELOPMENT Senator DURBIN. Let me ask you a question, Dr. Collins. If I were to ask you whether or not NIH research was part of the development of a certain pharmaceutical drug or part of the development of a certain medical device, could you trace the lineage of the research so that you could tell me a yes or a no if NIH was involved? Dr. COLLINS. I think usually we could, and in about 75 percent or so, the questions of that sort you would ask, the answer would be yes, NIH played a role, not necessarily a direct proximal role to the ultimate product, but discoveries that happened at an earlier point leading to ideas about mechanisms, leading to ideas about possible therapeutics, yes, you can connect those dots, and those dots almost always involve NIH research in some way. Senator DURBIN. Well, let me tell you why I ask you that question. We’re all sitting here wearing clothing and suits and such, 21 and somewhere there’s a label inside, where it’s made. And we go out to the market and we buy products, and we have an identity of the producer and contents. And I think it’s about time that the NIH had a label that is applied to pharmaceuticals and medical devices and other things where you can connect the dots. I think it’s time the American people came to hear the National Institutes of Health being referred to on a regular basis as part of the sourcing of the great things that are happening. You have so many miraculous stories to tell. And I don’t know if you did a survey across America how many people would be able to identify what the letters ‘‘NIH’’ stand for. I think it’s time we do something about it. We pass laws about the labels on my suit and the labels on products, and I’d like to ask the Chairman and others to think about joining me in a bipartisan effort to make sure that credit is given where it’s due so that Americans come to appreciate how you’re at the heart of basic research that really makes their lives an awful lot better. And so I’m going to work on something and I’m going to work with you to make sure we do it in the right way. Dr. COLLINS. Well, Senator, I really appreciate your emphasizing the importance of this being more widely recognized. It is true if you ask people on the streets, ‘‘Do you know what NIH is?’’ I think the last survey it was less than 20 percent. A much higher recognition for NASA (National Aeronautics and Space Administration) than there is for NIH, and yet obviously a lot of the taxpayers’ dollars going into what we’re trying to do here. I would give a quick plug that in August there is a series on Dis- covery called First in Human, which follows a series of families that have been treated at the NIH Clinical Center, which you all just visited a couple of weeks ago. It is powerful. It is three subsequent weeks, 2-hour segments, and you will follow and see what happens to these patients and their families as they go through what are clearly circumstances that are quite desperate. And that’s how people come to us, because all other options have been ruled out. That would be a very good way for America to get a sense about what we do and why it matters so much. Senator DURBIN. Thank you. OPIOID—HEROIN CRISIS Dr. Volkow, we’re in the midst of an opioid-heroin crisis, some places hit harder than others, including the home State of my col- league, Senator Shaheen. It is an incredible crisis generated by the production of 14 billion opioid tablets a year in the United States of America, enough for every adult, every adult, to have a 1-month prescription to opioids. That production number is approved by the Federal Government each year, the Department of Drug Enforce- ment Administration. And then, of course, it gets into the general population through scripts written by doctors. CDC (Centers for Disease Control and Prevention) has warned these doctors, ‘‘Don’t overdue it except in extreme cases.’’ I know you’re looking closely at this and couldn’t join us when we visited, but would you comment on the fact that at least at this 22 moment the United States Government is complicit in the over- production of opioids? Dr. VOLKOW. Well, I think that in the healthcare system we have to recognize our involvement in creating the opioid crisis, and it was the result of a well-intentioned initiative to treat those patients that were suffering from chronic pain, but without the prop- er education or understanding about the tools that we’re using to actually treat those patients, which was predominantly relying on opioid medications. And as a result of that, there was an over- prescription that we’re currently leading. That led to diversion, abuse, and then transfer into heroin and synthetic opioids. What we are doing from the NIH perspective is taking a multipronged approach to address it. Recognizing that the need of pain patients was the initial driver, we are aiming to actually create public-private partnerships, and this is encompassed by the whole NIH, for energizing the development of alternative analgesics that are not going to be addictive. So that’s one of them. The other one is again incentivizing the pharmaceuticals through these public-private partnerships to the development of alternative formulations for the medications that we currently have for treating opioid use disorders as well as to developing alternative targets for the treatment of addiction of opioids. And finally, again, through public-private partnership with industry, to develop prevention interventions for overdose as well as to develop even more efficient reversal medications such as Narcan to address the opioid crisis. Senator DURBIN. Thank you. Senator BLUNT. Thank you, Senator Durbin. Senator Moran. NIH GRANT DOLLARS FOR RESEARCH COMPARED VS SALARIES PAID Senator MORAN. Chairman, thank you very much. Dr. Collins, welcome to you and your fellow Directors at NIH. Such a pleasure to hear from you. And I join my colleagues in ex- pressing our gratitude for the work that occurs at NIH and across the country on behalf of improving the lives and health and well- being of millions of Americans and people around the globe as well as helping us. While we have this healthcare debate going on, it’s always been my belief that if we can devote additional resources into finding cures and delays in treatments of diseases, it’s one of the suggestions I’ve made for a long time, we can do a significant benefit to the cost of healthcare in the United States. And as we have a debate going on about how to pay for healthcare, I hope we never forget the opportunity to look at why healthcare costs so much in the first place. Who pays? Is the different question. That’s a challenge for lots of folks. But if we can reduce the cost to everyone, all will benefit, and I hope that we can spend a lot of attention on that, including the continued support for NIH and its mission. Let me ask a process question I guess to Dr. Collins. One of the things that has been brought to my attention is the way that NIH spending occurs in grant support. And I raised this with Secretary Price when he was in front of our committee last week, but it’s my understanding that some research institutions make, and particu- 23 larly universities, make the salaries of their researchers contingent upon receiving an NIH grant, and instances in which some researchers receive up to 80 percent of their salaries as a result of a grant. And the question I raise is, is there thought about trying to focus the NIH grant dollars on the research as compared to the salaries of the researchers such that more money goes into—I know you can’t have research without the scientists, but I also know that universities and other institutions, in my view, should be supporting those individuals more or grant dollars go to the research. Am I missing something, Dr. Collins? Dr. COLLINS. No, I think you’ve accurately stated the facts of the situation. Since World War II, the government, through NIH and other funding agencies for science, has sought to try to encourage institutions to do scientific research and has basically then con- tracted with those universities to provide the full cost of that research being done, and that has included in that calculation then the percentage of time of a faculty member that’s going towards a research project as an allowable request when the grant application is submitted. And many of the times in some places where faculty are essentially doing almost all of their work in research, their percent effort over various grants then can climb up to be in the neighborhood of 50 or 60 or even 80 percent, although in reality on the average it’s generally much less than that because most researchers have other activities as well. And again, we do not pay for other activities of faculty, such as teaching or running committees for their institutions. It looks as if roughly something between 5 and 10 percent of the NIH budget currently goes to pay the salaries for those faculty members who are our grantees who are doing that research. Insti- tutions would obviously be alarmed at the idea that that would no longer be allowable. I would point out that there are caps on the level of salary that we will pay. A salary cap has been applied by the Congress in most of the last many years. But in terms of an actual effort to reduce the total percentage, that has not previously been tried. I would also say, of course, that we are willing to pay the salaries of the postdoctoral fellows, the technicians, who are working in projects, and some of those would be at 100 percent level because that’s all they’re doing, is doing the research. If you add up all the salary coverage, well, it’s probably in the neighborhood of 35 to 40 percent of our grant extramural funding. But in a way, that’s our most critical resource, those are the people doing the work. They’re the ones we have the hopes and dreams are going to make that next discovery. So, again, hearkening back to the arrangement made after World War II, this has seemed so far consistent. Senator MORAN. Thank you for your answer. I may explore with you additional thoughts I have on this topic outside the hearing. Dr. COLLINS. I’d be happy to. 24

VETERAN’S AND MENTAL HEALTH RESEARCH Senator MORAN. Let me ask Dr. Gordon. I chair the subcommittee that funds the Department of Veterans Affairs. It’s a new assignment to me in the appropriations process. What’s the relationship, I mean—and one of the things I think in which the VA (Veterans Affairs) faces some of its greatest challenges is in the care and treatment for those who served in our military and the consequential effects upon their mental health. Too many veterans slip through the cracks, and often it’s, in my view, it’s in the mental health arena. What is it that takes place in research at the De- partment of Veterans Affairs that is different or in addition? How is there coordination between what happens at NIH and at the VA? Dr. GORDON. Thank you very much for the question, Senator Moran. We have at the NIMH (National Institute of Mental Health), like the NIH in general, a long-standing relationship of collaboration with our colleagues at the VA. Many of our investigators work with the VA investigators, and many VA investigators work with us. Specific programs we’ve focused on over recent times include programs in suicide prevention and in PTSD (Post Traumatic Stress Disorder) research. In suicide prevention, we played an integral part in helping the VA develop research to identify those veterans who are at highest risk of suicide so that we can help them get into treatment and reduce the suicide rates among veterans. That’s an ongoing program now that’s being implemented throughout the Veterans Administration that will hopefully help save lives in the near future. We also are engaged in research programs, as I mentioned, particularly around PTSD, but in general around the mental health of veterans. One resource that the Veterans Administration has con- structed, the Million Veterans Program, is an area of active interest which we’re engaged with them in trying to help our extramural investigators that we fund to use that data to better the health of veterans and really all Americans. Senator MORAN. Thank you, Doctor. Thank you, Mr. Chairman. Senator BLUNT. Thank you, Senator Moran. Senator Shaheen. SOLVING THE OPIOID CRISIS Senator SHAHEEN. Thank you, Mr. Chairman. And Dr. Collins, thank you very much for hosting the members of the committee who came to NIH 2 weeks ago. And thank you to Chairman Blunt for arranging that visit. I certainly learned a lot. It was very impressive to see your work firsthand at NIH, and we appreciate everything that you all do. Dr. Volkow, thank you for coming to New Hampshire and for seeing the challenge that we face with the heroin and opioid epidemic. You joined me at Catholic Medical Center, and we heard a very compelling presentation about how they were dealing with seven patients all with an overdose of carfentanil at one time in the emergency room and what kind of challenges that presented. And certainly as we look at what’s happening in New Hampshire, we 25 have got to do more, we have got to provide more resources, more help. And I know you responded to Senator Durbin about some of the things that you’re working on. But is there something that you think holds the most promise that we ought to be focused on, or is this trying to better coordinate everything that we’re doing? Dr. VOLKOW. I mean, in order to solve the crisis, we need an integrated approach working with the other agencies and multipronged strategy. So the one that I was describing was specifically targeted towards development of medications or new therapeutics. But in the meantime, we need to actually act rapidly. And one of the big challenges, particularly certainly in New Hampshire, but not unique to New Hampshire, is the lack of treatment programs that can accommodate for patients with substance use disorders or opioid use disorders. So in the area of implementation research, one of our priorities has been to take advantage of the fact that there are healthcare systems throughout the whole United States. So how do we integrate the healthcare system into being actively involved in the screening, treatment, and follow-up of patients with opioid use disorder? So in New Hampshire, we were very interested in addressing, for example, involvement of emergency departments on treatment, involvement of neonatologists on treatments. And many of these models are starting to emerge in the States like New Hampshire, and we’re trying to evaluate them so we can translate it into other places. So this area of implementation research, new models for treatment of opioid use disorders, is fundamental. BREAKTHROUGHS IN DIABETES TREATMENT Senator SHAHEEN. Absolutely. And I’ve visited many hospitals in New Hampshire, and one of the things that everyone cites as being critical to how to respond has been the expansion of Medicaid and the ability to get Medicaid dollars, and we have many hospitals, community mental health centers, that have been able to hire people that are looking at expanding and expanding treatment because they’re able to count on those Medicaid dollars that are available through the Affordable Care Act. So as we look at what happens with healthcare here, that’s one of the real challenges I think we face. I want to go, and I’m not sure, Dr. Collins, who to direct this to, but one of the real chronic diseases that we are challenged with in this country is diabetes. I have both a personal and a policy interest in Type 1 diabetes. And I think there are many people in the country that don’t understand there is a difference between Type 1 and Type 2 diabetes, that Type 1 has nothing to do with lifestyle, it has nothing to do with what you’ve eaten, it has nothing to do with where you live, sadly, but it also is increasing at rates that will make it hard in the future to afford treatment to make sure we can address this disease by—I think the statistic is by 2050, 1 in 3 Americans will have diabetes either Type 1 or Type 2. So can you talk about what research is happening at NIH to address Type 1 diabetes and Type 2? 26

Dr. COLLINS. I’d be happy to do that myself because my own research laboratory on the NIH campus is primarily focused on Type 2 diabetes. We’re learning a lot about both Type 1 and Type 2 in terms of what the risk factors are, particularly using the tools of genomics to identify the pathways that seem to be conferring susceptibility. For Type 2, the type that’s generally coming on later in life, although not that late anymore with so much of a problem with juvenile obesity, that’s pointing us towards new ideas about therapeutics. A particularly exciting program we have is a partnership with industry called the Accelerating Medicines Partnership, or AMP, which has focused one of its components on Type 2 diabetes, and has brought both sectors together in a way that didn’t happen before with a whole lot of really interesting ideas about new drug targets. For Type 1 diabetes, again, we’re learning more about the genetic susceptibility. We still don’t quite know what the environmental trigger is, and we presume there must be one because not everybody with a susceptibility gets the disease. But a particularly exciting advance is the development of an artificial pancreas that would make it possible for kids and adults with diabetes to have a way of managing their glucose and insulin without having these fre- quent finger sticks and injections of insulin, which frankly don’t work as nicely as one would like. Just last year when I spoke to this panel, I predicted that we might actually find in the next 10 years an artificial pancreas reaching FDA (Food and Drug Administration) approval. Well, it actually happened 6 months later, so that’s—— Senator SHAHEEN. I was going to say it’s going to happen a lot sooner than 10 years. Dr. COLLINS. Well, there you go. In November 2016, FDA approved the first one of these. It’s basically a feedback loop that samples glucose and then delivers the appropriate dose of insulin without the individual having to do the calculation or stick their finger. Ultimately, we believe this kind of artificial pancreas could be even better if it was made not from this kind of machinery, but from your own cells using the opportunities we’re learning about with stem cells, to take your skin cells and turn them into those cells that make insulin that maybe aren’t doing that anymore for someone with Type 1 diabetes but could be convinced to do so. It’s a very exciting area. Senator SHAHEEN. Well, it is. And thank you very much for the work that’s ongoing. Thank you, Mr. Chairman. PRECISION MEDICINE AND CANCER TREATMENT Senator BLUNT. Thank you, Senator Shaheen. I think we may have a few more of our colleagues come, but if we don’t, Senator Cochran, Senator Moran, and I might have a second, third, and fourth round of questions while you’re all here, and we’re fortunate to have that. Dr. Lowy, in March, we had a hearing on funding and cancer. One of our witnesses, Dr. Tim Eberlein, runs the Siteman Cancer Center in St. Louis, and he was talking about the importance of 27 precision medicine. One of the things he thought might be possible to determine was whether 80 percent of the women that currently have chemotherapy after breast cancer surgery would have to have that. I think there is some active discussion that probably only about 2 out of 10 women benefit from that, but how to define that. On that topic and generally your immunotherapy advances, would you talk a little bit about individual cancers and individual people and how they fight those cancers, and how you’re working to find ways to define what treatment they need, and also ways to figure out how they can better, from their own unique makeup, fight that cancer? Dr. LOWY. Thank you, Senator Blunt. I had the pleasure of vis- iting Dr. Eberlein and his colleagues at Siteman Cancer Center last year, and they and many other NCI-Designated Cancer Centers are at the forefront of this area of precision medicine. The overall goal, as you point out, is to deliver the right medication for the right patient at the right time and not to overtreat people because we know that overtreatment can sometimes actually have serious side effects. Recently, for example, with NCI-supported research, it was reported at the ASCO meeting that giving people with colorectal cancer less treatment, they actually did better than people with more treatment. An important part of the Precision Medicine Initiative, which, thanks to your committee and Congress, has been strongly supported, we have been conducting research that is trying to understand better how the molecular abnormalities with breast cancer and other kinds of cancers can have implications for what treatments should different patients be obtaining as we try progres- sively to refine those opportunities and those interventions. DEMENTIA AND STROKE RISK Senator BLUNT. Dr. Gibbons, I think there is some new research out that would suggest that having a stroke more than doubles the risk of dementia. Could you talk about that a little bit? And also in that area, you might further define, as people get older, a stroke may not even be apparent, but what’s the cumulative impact of that? I guess my question is stroke as it relates to dementia. Dr. GIBBONS. Sure. Well, it’s an important question you raise, Senator, and we now appreciate that there are many forms and pathways that promote dementia. You all are very familiar with Alzheimer’s, but there is another category called vascular dementia that can affect maybe one in five of individuals affected by that debilitating condition. And indeed, vascular dementia can be insid- ious, as you implied. It may be the cumulative effects of vascular disease over time and risk factors such as high blood pressure that lead not only to heart disease, but also to compromised brain health. And so this is an active area of investigation. It is actually one area where women as well as African Ameri- cans appear to be particularly predisposed in terms of the cause of dementia. And again it relates to an earlier question by Senator Cochran as to why in the Jackson Heart Study we are particularly interested in looking at African Americans and the causes of dementia, both vascular and Alzheimer’s disease. 28 In collaboration with our colleagues at the National Institute on Aging, and Neurological Disorders and Stroke, we are engaged in the SPRINT-MIND trial, which looks at the effect of lowering blood pressure in terms of preserving cognitive function. So this is an active area of research. Senator BLUNT. You know, I would think also that’s another verification of generally my view, and I think the Committee’s view, that while prescribing funding in some areas is frankly helpful to get these funds increased and to make the case, as in Alz- heimer’s, we’ve gone from I think $631 million to $1.4 billion in 2 years. But, one, you’re better at knowing where the pathways are than we are; and two, there’s a more than even chance, I believe, that you will find something somewhere differently than you’re looking for it, and there is lots of research that suggests that’s the case. Senator Moran. ALZHEIMER DISEASE AND DEMENTIA PREVENTION Senator MORAN. Chairman, thank you. Doctors, perhaps this is for Dr. Hodes, and we’ve had a number of Senators raise the topics about dementia and Alzheimer’s. What is the current state? One of the things I think, and I’ve told Chair- man Blunt this, and we’re in agreement, that one of the opportunities this subcommittee has is to highlight to Americans ways in which they can change their lifestyle, dietary intake. What’s the status of the research in regard to dementia and Alzheimer’s today that we would want every American to know in regard to their activities, behavior, and nutrition and diet? Dr. HODES. Well, it’s a very important question. Obviously all of us, both individually and societally, want to make sure that we’re doing all that we can to decrease the risk of dementia and cognitive decline. And in fact, it’s an important enough question that NIH recently commissioned a study on just this to ask what the level of evidence is for the kinds of interventions which might have that desired effect in reducing risk. It was released today, and I think some of your staff may have been briefed as recently as yesterday about it. The key words were that there is a great deal of encouraging, but in most cases inconclusive, evidence for what we can do. I can identify three critical areas and the implications for what we know now and what we need to do. One of them just alluded to was control of hypertension. So there is very strong association between hypertension and its control and the risk of Alzheimer’s disease and dementia. As Dr. Gibbons mentioned, one study, SPRINT, was designed to look at the impact of aggressive control of blood pressure on multiple outcomes. And this is a case where, just as described, our In- stitutes, working together and using some of the Alzheimer’s funding, have supplemented that study to look at its impact on dementia. Those studies are ongoing. So it’s an area of great promise where clinical trials such as SPRINT may give us conclusive evidence. But again I would have to point out that the evidence for the importance of controlling blood pressure and decreasing stroke and cardiovascular disease is 29 so critical that it must be a part of our public health imperatives as we communicate. Another area is that of physical activity and exercise, once again shown to decrease the risk of death, cardiovascular disease, and where again there is suggestive evidence that it may play a role in decreasing risk of dementia. There are a number of studies, including some going on, as you know, at the University of Kansas— we had a chance to discuss last year there—that are looking directly in randomized clinical trials to see what forms of physical activity may make a difference in lowering the risk of cognitive decline or dementia. The other area is that of cognitive training. And one study supported by NIH some years ago showed that cognitive training was actually able to induce sustained improvements in cognitive function in particular areas as individuals age. That kind of study needs to be extended further to see if it actually will have an impact on dementia. Senator MORAN. What’s the example of cognitive training? What is it that the study suggests one ought to be doing? Dr. HODES. There was a specific study called ACTIVE, that’s its acronym, that looked at older Americans, men and women, who had normal cognitive function and trained them in either speed, reasoning, or memory, and then studied them over years to see the impact of that training. And it was an extremely positive outcome. And it’s those individuals who were trained in those areas did have improved function over 5 and up to 10 years in that domain. What this recent National Academies report stresses, however, is that there is not yet compelling evidence for any of the other activities, including the computer-driven games, to identify whether they provide similar outcomes. So there are a good number of studies. Currently supported, another area where, thanks to the increased funding for Alzheimer’s research, we’re able to look to see what kind of cognitive interventions as well as these others may play a long-term role in decreasing cognitive decline and dementia. RELATIONSHIP BETWEEN DOWN SYNDROME AND ALZHEIMER’S Senator MORAN. Doctor, thank you. In response to Senator Dur- bin’s suggestion that NIH ought to receive more credit for its work, I certainly want that to occur. One of the ways that Americans would really relate to NIH is, ‘‘Here are the things that if you do, the chances of your health improving or being maintained, there’s a consequence to this behavior,’’ and it is a way that I think you can tie NIH to everyday Americans and their lives, their worry about themselves and their families. Let me tie another topic that I care a lot about, Down syndrome. We’ve had conversations in the past in which Down syndrome and Alzheimer’s, perhaps there’s a connection. What’s the status of our research in Down syndrome? I don’t know who I should be looking at. I’ll keep looking to my right. What’s the status of that research, and what do we know about the relationship between Down syndrome and Alzheimer’s? Dr. HODES. Well, it’s a very important area of research that probably begins with a genetic basis, is the fact that, as you know, 30 Down syndrome is associated with a trisomy. There is an extra copy of one chromosome, chromosome 21, which happens to be the chromosome on which the gene-encoding amyloid protein and peptide lie. And reflective of that is in fact that, as we have seen an increase in life expectancy with Down syndrome, it’s a remarkable accomplishment, over 30 years now an average life expectancy, not 30, but 50 and 60, that individuals at a relatively early age in high proportion are developing Alzheimer’s-like dementia both in terms of symptoms and in terms of brain function and structure. So both because this population now is one at a special high risk that is deserving of attention and because studying this population is likely to inform all we know about Alzheimer’s research, we have, in collaboration with the Child Health Institute, and, again, using some of the funding that has been provided over the last fiscal years, initiated longitudinal studies in individuals over a range of age with Down syndrome to study what is happening in the brain through imaging biomarkers to better understand and have a basis for ultimately intervening in these people, a highly vulnerable population, as well as learning more about the more general problems surrounding Alzheimer’s type dementia. Senator MORAN. Thank you very much. Thank you all for being so capable of speaking in language and terms that are reasonably understandable to me. [Laughter.] Senator BLUNT. Thank you, Senator Moran. Senator Alexander. JOB CREATION AND RESEARCH CENTERS Senator ALEXANDER. Thank you, Mr. Chairman. First let me thank you, Dr. Collins, for what you do for our country. We’re all excited about the future of the National Institutes of Hope, as you call it. We’re delighted the President has asked you to lead that. And we look forward to your implementation of the 21st Century Cures Act, which we all worked on, voted for, and even in effect asked NIH, what could we put in there to make it easier for you to succeed? And I want to salute Senator Blunt, Senator Murray, Senator Cochran, Senator Durbin, and Senator Moran for their bipartisan support of increasing biomedical research. There is very little that’s happened in terms of technological change in our country since World War II that hasn’t had some government research as a part of it. We’re obviously leading the world in biomedical research, and we want to accelerate it, not slow it down. Dr. Collins, am I correct that it’s a goal of the Trump administration to keep more American jobs in the United States? Dr. COLLINS. Yes, that’s my understanding as well. Senator ALEXANDER. Yes. And we have about 50 major research universities, 17 national laboratories, no other country in the world has anything like them. Is it true that around those—and we spend a lot of money on them. The Office of Science supports $5.3 billion for the national laboratories; approximately $28 billion goes through your agency to universities for research. Is it true that around these universities, like Stanford, the University of Okla- homa, the Universities of Kansas, Tennessee, Missouri, grow com- 31 plexes of industries who are attracted by the research and who, as a result, create jobs around these centers of research? Dr. COLLINS. That’s absolutely true. If you look at the geography of where those places have sprung up, it is very much attached oftentimes to a university that’s a generator of a lot of interesting ideas and a critical mass of visionary scientists. LOWERING INDIRECT COSTS Senator ALEXANDER. Is it also true that China is making an extraordinary investment in new research, and even though they have one-fourth our gross domestic product, they may exceed us soon in the amount of total funding for research, and that as a result, a number of the Chinese scholars at our graduate schools and universities are being attracted back home? Dr. COLLINS. That’s also true. A recent paper published in the JCI pointed out that in 2000, China spent only 12 percent of what the U.S. does on biomedical research. By 2015, it was 75 percent. And I’m not talking about percent of GDP (gross domestic product), about actual spendable dollars, and they’re on track to surpass us in the next 3 or 4 years if those—— Senator ALEXANDER. Well, this leads me to one of the more hair- brained recommendations in the budget that came up to us, which is that we lower the amount of indirect costs that are allowable for research grants from an average of 28 percent to 10 percent. This came up when I was Education Secretary 25 years ago and it produced a huge uproar. Most universities and colleges said to us at the time, ‘‘Look, we spend a lot more than the average 28 percent on research, and the net effect of taking that from 28 to 10 or anything like it would be less research, and less research, we’ve just reminded ourselves, means more jobs moving overseas to cluster around the research wherever it is in the world.’’ I just did a quick look. The University of Tennessee could lose nearly $10 million if that new policy went into place; the Univer- sity of Missouri, $15 million; Kansas, $4 million. People think of Harvard and Stanford when they think of indirect costs. ‘‘Well, they’re rich enough to handle it,’’ people say. Well, Tennessee, Mis- souri, Kansas might not be. The only way I can think of to make that money up is either higher tuition or less research, and less research is not our goal because less research means to me more jobs overseas. Now, I understand that you may be asked, because of the $27 or $28 billion that goes through your agency to the universities for the kind of research that we’re trying to increase, not decrease, to report to Secretary Price and to the Office of Management and Budg- et, where I have great suspicions that ideas like this originate, of what the effect of this would be. So may I ask that you put in your report the following? Number one, if there is to be any change to this, Congress wants to be involved. And I’m going to get in the middle of that, and I’ll bet I can get a bipartisan group up to make sure we are. Number two, will you please ask the universities, especially the State universities, how much they would lose in funding, how much they contribute to their own administrative and facilities costs, outside of the funding you give them, and whether there would be more or 32 less research as a result of this policy. Include that all in your report, and if it’s appropriate, let us know about that as well? I hope we can nip this idea in the bud. I hope it’s one of those ideas in the President’s budget that’s just out there to stir up conversation. But it is a thoroughly awful idea, bad policy. It would not do what I know the President wants to do, which is to create more American jobs, not fewer, more research, not less, and this policy would be less. And my time is up, but if you want a constructive way to get more money out of NIH, look at the National Academies. May I take 60 seconds just to finish up? Senator BLUNT. Yes. Senator ALEXANDER. The National Academies has done two reports that says more than 40 percent of a researcher’s time is spent on administrative tasks. My guess is most of those come from the Office of Management and Budget, too. So if we want to reduce some of those administrative tasks and free up more money for research grants that would be a good area to work on. So maybe I could ask you to be prepared to talk to us about that at some time in the future. I don’t want to put you on the spot now, my time is up, but I wanted to register my strong concern about the indirect cost policy and ask that you be very specific in polling universities around the country about, ‘‘How much money would you lose? How much do you put into research yourself? And would there be more or less research as a result of this policy?’’ Thank you, Mr. Chairman, for your courtesy. Dr. COLLINS. Senator, I’ll be happy to work with you on that. Senator ALEXANDER. Thank you. Senator BLUNT. Senator Lankford. REDUCTION OF ADMINISTRATIVE BURDEN/COST Senator LANKFORD. Thank you. For Senator Alexander as well, your extra 60 seconds bled right into my first 60. How about that? Because that’s actually where I was beginning. Let me say first I appreciated all your hospitality in the time we could spend at NIH to get a chance to be able to see what’s going on. We’re all looking forward to quite a bit of what we saw in research in initial levels and in clinicals actually moving out to the general population, getting a chance to be able to see that. Every- one would benefit from things like universal flu vaccines, the Zika vaccine that is obviously progressing, and the AIDS vaccine, which has been progressing for a long time and getting closer and closer. Those are remarkable discoveries and will help a tremendous number of people. What’s happening in cancer, mental health, and everything else. We very much appreciate the ongoing research as it benefits families all over the country and all over the world. Let me tap into what Senator Alexander was mentioning before about administrative costs because I want to zero in on just a couple areas. Many areas have already been addressed. One is how grants are done and how they’re approved. And I want to talk specifically between coordination. When I talk to grant recipients, they will tell me, ‘‘I go apply at NSF and I apply at NIH and I apply anywhere else where I think it’s close,’’ and they’re just going after money wherever they can get 33 it to be able to do their research. It is up to the entities to be able to determine, ‘‘We’ve got this one. You shouldn’t take this one. This is closer to what we’re going to do.’’ And the example I would give you is when we do a law enforcement, they can tell you the lane that DEA has, that ATF has, and that FBI have. They know, ‘‘That’s not ours, that’s theirs.’’ In the research area, that’s a little tougher to do. So what I’m trying to figure out, not from the grant recipients, they’re eager to go get the grant money wherever they can get it; from our end, how do we help coordinate that to make sure that we do have good coordination that we’re not doubling up on research in other areas, but that we’re prioritizing that? And then how do we actually get more research done by reducing the administrative costs? If 40 percent of the costs of what’s happening with the research dollars are just paperwork that’s being completed, that’s not helping us get to greater discovery. So what can we do to simplify the process on the research and reduce the burden for the researcher, but also make sure that we’re coordinating this from a Federal level and being strategic? Dr. COLLINS. Senator, those are two great questions. So first of all, just in terms of reducing the administrative burden, we’re very intensely interested in looking at ways that that might be achieved. Senator Alexander already mentioned this 42 percent number that came out of that National Academy study. I should point out that 22 percent of that may be the part that we really want the investigators to do because that’s writing the grant proposal and making sure they’ve got great science ideas and they’re putting them forward plus giving us annual progress reports so we know what they’re actually doing. Senator LANKFORD. I totally agree. Dr. COLLINS. But that still leaves a whole lot of other time. And we have some levers that we can pull at NIH to try to reduce some of those things, effort reporting, for instance, or some of the oversight of conflict of interest, although we need to pay attention to that. But some of those levers we don’t hold, and that would require sort of other discussions to see if there are ways systemati- cally to do those reductions. Senator LANKFORD. How do we discover those so we can help in that? Dr. COLLINS. I think it would be fine for you all to ask us to give you kind of a summary of what the current administrative respon- sibilities are and where those are decided. We have a pretty good list of those, if that would be useful. Senator LANKFORD. Terrific. I think that would be very useful and it would be helpful not only to this committee, but to others, HELP included. Dr. COLLINS. And the National Academy recently published a report on this, you’ve referred to it already, that goes through a good deal of that information as well, but it’s a bit lengthy. We could consolidate it if that would be helpful. 34

COORDINATION OF RESEARCH EFFORTS BETWEEN AGENCIES

Senator LANKFORD. Right. Not to increase your administrative burden while we increase others, but we need the help. [Laughter.] Dr. COLLINS. And in terms of the very real concern about not having duplication between different funding agencies, we are worried about that and do everything we can to try to nip it in the bud if it’s starting to happen. We also have much better tools now for doing analytics of what’s in our portfolio and what’s in the portfolio of the National Science Foundation (NSF) or the Department of De- fense’s medical research efforts, or the Department of Energy’s efforts, and we are looking at those with increasing intensity now to be able to identify if there are unintended duplications. Sometimes it’s good to have some efforts going on in different ways. Certainly, with NSF, we have a lot of areas where we specifically coordinate. The BRAIN Initiative, for instance, is one where NSF, NIH, and DARPA, and a few other organizations have a big role, and we are meeting regularly with them to be sure that’s going the way it’s supposed to. In some other areas, we have a pretty good swim lane definition. Take genomics. NSF does plants, and the USDA does agricultural plants and animals. NIH does those that are relevant to human health, and we pretty good tabs on those things. But we do ask every investigator, when they send us a grant, they have to list their other support. And if we’re going to give them the grant, we have to look at that and make sure that what they put there doesn’t sound awfully familiar to what they’re asking us to do, and we will go and ask them very carefully if that’s the case. So I think for the most part we don’t have a lot of unintended overlaps. But I think these new tools that we’ve developed may be an opportunity to do an even better job of that, and I would love to follow up with you on how we can do that. Senator LANKFORD. Yes. And I understand the grant recipients have to list where they’re getting other fundings, but if they’re si- multaneously applying for other areas, that’s the area that I see as the weak spot in that, and there has to be some way to be able to coordinate to say, ‘‘We’ve got this part of it. You’ve got this part of it. And we’ve got to figure out who’s got what lane because we need all the research done and need it done efficiently.’’ Dr. COLLINS. I’m with you. Senator LANKFORD. Thank you. Senator BLUNT. Thank you, Senator Lankford. Senator Shelby. GOVERNMENT AND PRIVATE SECTOR COLLABORATION IN BIOMEDICAL RESEARCH Senator SHELBY. Thank you, Mr. Chairman. I’ve been in another committee. I’m very sorry. Dr. Collins, how much money overall in the U.S., not just NIH, but all the governmental agencies, VA, you name it, is spent on biomedical research? And how much is spent out of the private sector? Whatever it is, it’s not enough, I know that. 35

Dr. COLLINS. So the NIH budget, which you all have overseen, and thank you for your strong support in a very bipartisan way over many decades, this has now led us to $34 billion for fiscal year 2017. The VA part of this, I don’t have the number in front of me. It is probably in the neighborhood of a billion or two—— Senator SHELBY. Can you furnish some of that for the record? Dr. COLLINS. Yes, I would be happy to do that. [The information follows:]

GOVERNMENT AND PRIVATE SECTOR COLLABORATIONS IN BIOMEDICAL RESEARCH (1) JAMA | The Anatomy of Medical Research: US and International Comparisons by Hamilton Moses et al January 13, 2015 (see Figure 2 and Figure 3). (2) Research!America | U.S. Investments in Medical and Health Research and De- velopment 2013–2015 Fall 2016 (see Sector by Sector Analysis on page 4 and Estimated U.S. Medical and Health Research Expenditures table on page 8). (3) National Science Board Science & Engineering Indicators 2016 https:// www.nsf.gov/statistics/2016/nsb20161/#/ (see Chapter 4. Research & Develop- ment: National Trends and International Comparisons Figure 4–13). (4) FY18 Presidents Budget Analytics Perspective 18 Research and Development. Dr. COLLINS. The private sector actually outspends government- supported biomedical research by a factor of two or maybe a little bit more than two. You put it all together and we’re talking about—— Senator SHELBY. Maybe three to one? Dr. COLLINS. Two to one, three to one, in that space. So we’re talking about an overall spend in the neighborhood of $100 billion a year. Senator SHELBY. And how much of that is complementary? In other words, do you coordinate to some degree the investigators in the private sector and NIH and other government? Because there’s a lot of overlap there. Dr. COLLINS. I’m glad you ask, because this has been a personal priority of mine to try to identify ways that we could avoid the overlap, but also encourage the appropriate collaborative projects. Senator SHELBY. That’s important. Dr. COLLINS. And this project—— Senator SHELBY. And how do we do that? How do we do that? Dr. COLLINS. Well, we have a model that’s working pretty well, which is called the Accelerating Medicines Partnership. And this gets the scientists and the scientific leaders from the public sector, mostly funded by NIH, and the private sector, heads of R&D of Big Pharma, and we get around the table and say, ‘‘What are the needs that neither of us can do ourselves that would speed up getting treatments to patients?’’ So those need to be in the precompetitive space; otherwise, the industry people get nervous. They don’t want to have competition finding its way in there. But there’s a lot of that. So we now have a project on diabetes, we have a project on Alz- heimer’s disease, we have a project on rheumatoid arthritis and lupus, and we just started a new one on Parkinson’s disease, all part of this AMP effort, which is joint industry at NIH, and we put money into it from both places. There’s money on the table and skin in the game, and these projects are actually I think turning out to be very successful. And we’re talking about hundreds of millions of dollars going into this. 36

Senator SHELBY. How much coordination is it regarding investigating various challenges we have internationally with our international friends or competitors and so forth, in the private and public sector? Dr. COLLINS. Well, I’m happy to say—— Senator SHELBY. What you’re looking for is a cure for this and this, aren’t you? Dr. COLLINS. Yes. Yes, indeed. Well, I’m happy that science has always been a pretty international enterprise, and most scientists have collaborators that are all over the world. Certainly when it comes to this industry interaction, Europe has a similar kind of effort called IMI, the Innovative Medicines Initiative. We work closely with IMI, which is now IMI 2, to make sure that what we’re doing is complementary with what they are doing. Until recently, I’ve served as the chair of the heads of international research organizations, which brings together all of the funders in the public sector of the world, about 95 percent of those dollars, to be sure that we are not stepping on each other’s toes and actually being able to work better with each other. UPDATE ON CYSTIC FIBROSIS RESEARCH Senator SHELBY. Well, that’s good to hear. Dr. Collins, we’ve discussed research, I have with you privately in here many times, involving cystic fibrosis and some autoimmune disease, such as lupus, several times. I know NIH has been involved in research in a lot of this. You’ve made a lot of progress. Could you bring us up to date first on cystic fibrosis, where we are? We’ve made progress. Where are we going? Of course, we’re looking for a cure, I know that. Dr. COLLINS. We are, and I think we’re bold enough to say we’re on the path towards getting there, Senator. You know, the cystic fibrosis cause, the genetic glitch, was discovered in my own laboratory when I was at Michigan in 1989, but now we are here at this moment in history seeing the development of very effective targeted drugs. The first one only treated about 5 percent of patients with cystic fibrosis who had a particular misspelling in that gene. But the next one brought us up to about 50 percent of patients who can be qualified for that. And when you look at what’s happening now—and this is a wonderful example of academic research leading to advances in the private sector now in a company called Vertex. Jeff Leiden, who is the CEO of Vertex, was bold enough to say when I saw him a couple of weeks ago, ‘‘We’re on the path towards curing 100 percent of patients with cystic fibrosis, and we’re not talking 20 years from now either.’’ Senator SHELBY. Well, you’ve extended the life of a lot of children—— Dr. COLLINS. Oh, yes. Senator SHELBY [continuing]. In the last year, so that’s a mile- stone in itself. Dr. COLLINS. And a hat tip of the biggest sort to the Cystic Fibro- sis Foundation, who have been incredible supporters of this effort from a philanthropic perspective. Those folks have just been awe- some. 37

Senator SHELBY. Absolutely. How many children, or people you should say, because they become adults more and more, are affected by cystic fibrosis? Dr. COLLINS. In the U.S., it’s about 30,000 people. Senator SHELBY. Worldwide, what is it? Dr. COLLINS. Worldwide, again it’s primarily in people of North- ern European backgrounds, so worldwide it’s probably about 100,000. UPDATE ON LUPUS RESEARCH Senator SHELBY. Okay. What about lupus? Let’s talk about that. It’s difficult, I know. Dr. COLLINS. It’s difficult. This AMP project I just mentioned has a focus on lupus, and what they’ve been doing, which is really very advanced technologically, is to look at kidney biopsies from patients with lupus because, as you know, that’s one of the major consequences of this disease, is affecting the kidney. And what they’re doing is looking at the immune cells that are in those kidneys to see what’s going on, not just as a whole bunch of cells together, but one cell at a time. Senator SHELBY. Is this new? This is—— Dr. COLLINS. This is brand-new. This is single-cell biology applied to lupus in the kidney. And they’re discovering there are types of immune cells in the kidney that we didn’t really know were playing a role because they’re rather rare, but if you look at one cell at a time, you can find them. Now, where that’s going to take us in terms of new therapeutics, right now I can’t tell you, but this is another example where industry working with academia doing this project has gotten everybody pretty excited about what this could lead to. DISCOVERY IN BASIC RESEARCH—AUTOIMMUNE DISEASE Senator SHELBY. Is the money spent overall for all autoimmune, so many things related to our autoimmune system, is it over- lapped? Do you discover things in basic research? Dr. COLLINS. I should ask Dr. Fauci to quickly jump in here as the person who’s the immunologist at the table. Senator SHELBY. Yes, sir. I know him. Dr. COLLINS. Because I think the answer is absolutely yes. But, please, Tony. Dr. FAUCI. There is a major effort on autoimmune diseases coming from multiple institutes. NIAID is the lead institute on this, but there are other institutes that also are pursing the concept of the induction of immune tolerance. Autoimmune disease is an inappropriate reaction of your own body’s immune system against your own tissues, and different disease occur depending upon what the tissue is, such as lupus, rheumatoid arthritis, or autoimmune thy- roiditis. What we’re trying to do is to essentially go back in the development of an individual and try to target the cells that normally would have been either deleted or suppressed from the time you were developing as a fetus. When you develop as a fetus, you have cells that have the capability of attacking all of your tissues. 38 What happens in normal development is that those cells that can attack your tissues either get suppressed, deleted, or they get tolerized, namely, they don’t recognize or they don’t respond inap- propriately to your own tissues. NIAID supports research through its Immune Tolerance Network, which is working by a number of mechanisms to determine how you can shut off the inappropriate immune response without suppressing your appropriate immune response. Today, the crude approach to autoimmunity is to suppress the entire immune system, which unfortunately leads to complications like infections and other types of adverse events. We’d like to be more precise in targeting autoimmunity disease. Senator SHELBY. And generate a different thing. Dr. FAUCI. Exactly. GENETICS AND LUPUS Senator SHELBY. Is kidney failure one of the big things dealing with lupus? There are other things, but that’s the big one? Dr. COLLINS. It’s a multisystem disease, as you well know, and Senator, you’ve shared your wife’s struggle with this, and I hope she’s doing well now. Senator SHELBY. She’s doing well, thanks to medical research. Dr. COLLINS. That’s wonderful. As you know, it affects the joints, it affects the kidneys, and it can certainly affect other parts of the body, including causing difficulties with the brain. So we need to get on top of this and figure out what is the best way to intervene and maybe to prevent it altogether. Senator SHELBY. What role does DNA play in this? A lot, I guess. Dr. COLLINS. Well, of course, I’m going to say DNA plays an important role in absolutely everything—— [Laughter.] Dr. COLLINS [continuing]. But it would happen to be true in this case. Senator SHELBY. That’s why I asked you that question. [Laughter.] Senator SHELBY. You’re the father. Dr. COLLINS. So clearly there are genetic susceptibilities to lupus. Again, they’re not at the present time sufficient for us to understand exactly why some people get it and some don’t. You can see some people are susceptible, but there must be some other trigger that happens on top of that. We know that lupus, for instance, is particularly common in African American women, and we don’t entirely understand that. Some of that may be genetic, but some of that may be environmental. Dr. FAUCI. It is likely both genetic and environmental, which is often the case when you have diseases that have a genetic predisposition. That’s one of the things that we see in all diseases of autoimmunity, that they have some sort of either very strong or maybe a little bit more modest genetic predisposition. Senator SHELBY. There is some link there, isn’t it? Dr. FAUCI. It is a link. It isn’t as strong as one gene, one disease, but it’s certainly a genetic link. Senator BLUNT. Senator Shelby officially took his two 5-minute rounds all at once. 39 [Laughter.] Senator SHELBY. I thank the chairman for his indulgence. Senator BLUNT. No, no, we’re getting a chance to ask multiple questions. Senator SHELBY. I think the chairman might have been asking those same questions. Senator BLUNT. No, no. Those were good questions asked. Senator Moran. Senator MORAN. Mr. Chairman, thank you. Senator Shelby, while the chairman realized you did that, I didn’t even notice. [Laughter.] PEDIATRIC CLINICAL RESEARCH Senator MORAN. Perhaps my final question is this, and I don’t think we have the Director here for this topic particularly, but let me hear from you. I’ve heard from parents, advocates of children’s hospital directors, the difficulties in improving pediatric care. Treatments and new drugs are often developed with adults rather than children in mind. Establishing pediatric clinical trials is a challenge. So I’d like to ask these questions. Considering the difficulties facing this patient population, what work is NIH doing in research on pediatric issues? And what’s standing between NIH and pediatric research that might restrict your capacity to have greater results and achieve what we’re looking for? Dr. COLLINS. Well, thanks. You’re correct, that the Director of the National Institute for Child Health and Human Development, Dr. Diana Bianchi, is not at the table, although it would be great for you to have a chance to meet her. She was recently recruited from Tufts in Boston and is just a terrific leader in this space. But every Institute at this table has some investments in pediatric research because of the way in which little kids become grown-up adults, but we also recognize that they’re not the same as miniature adults, and they need special kinds of attention. The focus on pediatrics certainly has been a long tradition of what NIH has done. I might just ask two of the folks at the table to say something about this, maybe Dr. Lowy about pediatric cancer, and Dr. Gordon about autism. Dr. LOWY. Thank you, Senator Moran. I would like to highlight three new programs which the NCI is initiating to support pediatric cancer research. As you may know, in the last 15-year period, there has been a 20 percent decrease in mortality rates from children with cancer, but there are two serious problems. First, some children who get cancer aren’t helped. And second, the long-term side effects for children who are successfully treated can be devastating. So one program that we are initiating is part of the use of the Cancer Moonshot funds from the 21st Century Cures bill, which is to develop new treatments for children with cancer. And as Dr. Col- lins mentioned, children—childhood cancer is not just adult cancer in the small sense, but it’s qualitatively different, and so it requires a separate kind of research effort, et cetera. So that’s number one. 40 Number two, with our regular appropriation that Congress has been generous in giving to NCI, we are also doing what we are calling the Provocative Questions Initiative, and that is to deal with vexing problems in pediatric cancer research. And number three, again, this is with the Precision Medicine Ini- tiative, in oncology, developing the pediatric MATCH trial, which will be opening in the next few weeks, and building on the success of the adult MATCH trial. It’s a paradigm-shifting trial which first brings the treatment to the patient rather than the patient to the treatment. And second, based on the molecular abnormalities of the patient rather than the kind of cancer that they have. Dr. COLLINS. I just realized I should have also put into my quick response something about the ECHO program, which is a new initiative at NIH that we’re very excited about. So ECHO stands for Environmental Influences on Child Health Outcomes. This is a trans-NIH effort to try to collect information on more than 50,000 children in terms of environmental exposures, in terms of genetic risk factors, following them over the course of time, bringing together cohorts that had previously been established but hadn’t been connected or subjected to this kind of very careful scrutiny and standardized assays. Because there are still many things we don’t understand about the role of the environment maybe even in the prenatal arena, maybe especially in the prenatal arena, as well as in early childhood in terms of how that affects such things as asthma, obesity, neurological development, including autism, and basically how it affects whether that child is healthy or not. We want to not just study illness, but also health. So ECHO, which is now just about a year on, which is involving a very large number of components, including IDeA States Pedi- atric Research Network to basically be able to do clinical research, is our big investment that’s new on the scene here to try to answer this kind of a question. If you want to very quickly say something about autism. I’m sorry I went on too long. Dr. GORDON. No, that’s okay. So autism is really not just a trans- NIH initiative, but it’s actually a trans-governmental initiative. I chair the Interagency Autism Coordinating Committee that involves colleagues from really across the government, from the DOD, from Department of Education, of course from the NIH and NSF. And our goal is to really try to understand and formulate a strategic plan for research around autism. I would say there are three really exciting ongoing things that we’re trying to do. First, we’re really trying to understand what makes a difference in terms of interventions during childhood and how that translates into long-term outcome. The second, we’re trying to get a better handle on screening, particularly the younger and younger that we can identify people at high risk for autism so that we can intervene earlier and also so that we can learn more about what happens in these early ages. And the third is really recent developments in both genetics and environmental influences that really suggests things are going on actually in the womb, that’s really where things are starting. So we’re learning that we really have to understand early neuronal 41 development so that we can really understand the risks for autism and do something about them. Senator MORAN. Thank you for answering that question in a timely fashion such that Senator Shelby still owes me. [Laughter.] Senator MORAN. I would conclude, Mr. Chairman, thank you, by saying this: one of the light bulbs that went off as you were describing this new initiative such as ECHO, one of the things that it suggests to me that increasing funding for NIH research, science brings new knowledge, which then causes us to look in a new area, and a new initiative arises, which suggests the resources are growing, the need for resources continue to grow. Very few things do we get to put the check in the box and say we no longer need to look at this, but research allows us to say, oh, here’s a new way, a new place, a new opportunity for us to find information through research and science that otherwise didn’t exist. And so there are lots of reasons I have advocated for increased funding of NIH that never occurred to me that just your success in finding information breeds the need for more resources to find more information. ADOLESCENT BRAIN COGNITIVE DEVELOPMENT STUDY Senator BLUNT. So, Dr. Gordon, before we go to Senator Ken- nedy, there are 19 places, including Washington University that are looking at the adolescent brain cognitive development. And I wonder if you would give us a little update on what we’re seeing in those 19 locations. Dr. GORDON. I’d be happy to, but that’s an initiative that Dr. Volkow really spearheaded. We contribute funds and intellectual opportunities and also the database, but Dr. Volkow might be in a better—— Senator BLUNT. That would be great. Dr. Volkow. Dr. VOLKOW. Yes, thanks very much, and thanks, Josh. The idea of the ABCD study, the Adolescent Brain Cognitive De- velopment, was a concept that now we have the technologies that allow us non-invasively to actually image the human brain in its structure and its function. And this is a non-invasive technology that is widely available across different health science centers in the country. And we wanted to—so we now have the capabilities to actually monitor how the human brain develops from childhood through adolescence through adulthood. And the idea is if you can get the standards, then like we currently do in pediatrics, where you have a norm that tells you whether a child is growing faster or slower, we should be able to get what are the normal distribution of human brain development. So when a parent comes to the physi- cian with a child complaining that the child has problems, you can actually determine the extent to which the brain is changing. This will allow us to understand, for example, the effects of early exposure to drugs in brain development, very relevant as States are legalizing marijuana, the concept this is not harmful. It will allow us to understand, for example, how mental illness emerges. 42 Can we detect that early on, on the basis of these brain changes? It will allow us to understand how physical trauma, like during sports, may negatively influence the development of the brain. How alcohol, how tobacco, how genes influence the diversity on how our brain works. This will be a prospective study. It will follow 10,000 children from ages, 9, 10, until they reach adulthood. And we will evaluate not just their brain periodically, but also their cognitive performance, their performance at schools, their social networks. It will be an open access study, so any investigator will be able to analyze and extract data and information from that study. Senator BLUNT. Thank you. Senator Kennedy. TECHNOLOGY TRANSFER AND POTENTIAL DISCOVERIES Senator KENNEDY. Thank you, Mr. Chairman. And thanks to all of you doctors. I have two brothers in the medical field. I’ve heard them talk for years with respect and admira- tion about NIH, and so I was especially pleased to be able to attend the meetings that we had at NIH a few weeks ago that Senator Blunt organized. Very, very, very impressed. Here’s my question. Let’s suppose, as you often do, that NIH or one of the Institutes develops a new pharmaceutical drug or a new vaccine, and obviously it’s developed with your creativity and intelligence and experience, but the money comes from the American taxpayer. And you develop it, it’s successful, it works. At some point that vaccine or that new pharmaceutical drug is turned over to the private sector to develop further and market. When that happens, how much in terms of royalty or shared compensation does NIH and, more to the point, the American taxpayer get? Dr. COLLINS. So the connection between NIH research and the development of successful drugs, vaccines, and devices is very strong. You can certainly point to NIH-funded discoveries in the majority of such instances, upon which the research track was traveled. In some instances, the NIH funding was for very basic science, but it made a light bulb go on that then led a company to figure out how to turn that into a treatment. In other instances, NIH car- ries the discoveries further down the line to something that is even patentable and then can be licensed out to a company to develop a product. If that is done by one of our grantees in one of those institutions that we support, 2,500 of them out there in this country, because of the Bayh-Dole Act, that institution then holds the intellectual property, and if there are royalties that come forward, they return back to that institution—— Senator KENNEDY. Pardon me for interrupting—— Dr. COLLINS. Please. Senator KENNEDY [continuing]. But as you know, we’re limited by time. I’m talking about when it’s not one of our grantees, it’s the NIH itself. Dr. COLLINS. Yes. Senator KENNEDY. Who negotiates the deal? Do you have a law firm you use? Do you use in-house counsel? What is the standard royalty? How do we know—how do you know you’re getting a good 43 deal? I’m not suggesting you’re not. Give me the details about how you do it. Dr. COLLINS. Sure. So if it’s a discovery made by one of our own intramural investigators, we have an Office of Technology Transfer, which regularly is looking around to see if people have made such discoveries, to make sure that they claim them appropriately if they have. And then a patent gets filed if it seems like it’s legiti- mate that it might ultimately be worth something. Once that patent is filed, then our Office of Technology Transfer, working with the scientists, try to figure out, who would be interested in licensing that? And so they put it out there. And an industry that steps forward and said, ‘‘We’re interested,’’ then a negotia- tion begins. I think our negotiators are pretty good in terms of fig- uring out what—— Senator KENNEDY. Are they in-house? Dr. COLLINS. Yes. Senator KENNEDY. Or do you use outside legal counsel? Dr. COLLINS. Yes, we have our own legal staff in-house. We do, I will tell you, employ also consultants, contractors, to help us if we have a special area of legal expertise that’s needed, but we have very strong intramural staff. That has resulted roughly each year in the return of about $90 million to the NIH from those discoveries that did get licensed and for which royalties are now flowing back. Senator KENNEDY. And again I’m sorry to interrupt you. Dr. COLLINS. No, please. Senator KENNEDY. I’m down to 1:06, and I want to keep within my time. Have you ever had—— Senator BLUNT. Senator Kennedy, you can take a little extra time. Senator KENNEDY. Okay. Thank you. Senator BLUNT. Everybody else has had—— Dr. COLLINS. You’re being much more disciplined than your colleagues, I think. [Laughter.]

DRUG DEVELOPMENT

Senator KENNEDY. Thank you. Have any of you ever had the development of a pharmaceutical drug or a procedure or a vaccine that you looked at and you said, ‘‘This works, it’s a lead-pipe cinch’’? I know maybe you haven’t completed all the different phases that you need to do to convince the FDA, but based on your intelligence, which is considerable, and your experience, ‘‘I know this is it,’’ have you ever had one of those? Dr. COLLINS. Oh, yes, all the time. Senator KENNEDY. Okay. [Laughter.] Senator KENNEDY. Have we ever thought in those instances, I’ll call them lead-pipe cinches, I don’t know where that phrase came from, but a certainty—that might be more senatorial—you’ve got a certainty, have you ever given thought instead of farming it out to someone, ‘‘Let’s do it ourselves’’? 44

Dr. COLLINS. Yes. The trick there, Senator, is whether the manu- facturing process is something that we want to take on. We don’t make pills in general except in very small amounts for—— Senator KENNEDY. Could you sub that out? Dr. COLLINS. You mean instead of to a pharmaceutical company, just contract it out. I suppose that’s a theoretical possibility. I’m going to ask Tony Fauci whether he knows of an example where that has been done. The times where we might do that would be if it’s a rare disease or a neglected disease where there just isn’t industry interest. Let me say we try very hard not to step into the territory where the private sector naturally is most capable, and we don’t want to mess with their success in those circumstances where they’re willing to take something on, but if they’re not, well, Tony, can you think? Dr. FAUCI. We have discussed this, Senator. It’s an excellent question and something that has crossed our minds multiple times. For example—I deal mostly with vaccines. Senator KENNEDY. Yes, sir. Dr. FAUCI. To get a vaccine production capability outside of the already established pharmaceutical industry is almost impossible to do. It’s just not out there. And our experience has been that it just makes sense in the scenario that you described, if we develop the very early stages of a vaccine, which we’re in the process of doing right now with Zika, and we did it with Ebola. In these cases, where you do the concept development, you do animal preclinical testing, you do a Phase 1 trial, and as you say, you’re never sure that it’s going to work until you do the trial, but there are some that you just have a feeling is going to work. At that stage, you have to develop a relationship with a pharmaceutical company because our experience in the past is that when we try to get into the pharmaceutical expertise at the end of the day, it’s much more economical to license the product to them, get the kinds of royalties that Dr. Collins has spoken about, and let them use their expertise. We certainly have considered your model, but it just doesn’t work. Senator KENNEDY. Okay. Well, I want to thank you. I don’t doubt for a moment that any one of you could go into the private sector and quadruple your income, and you know, money is not everything, and I think you live that, you don’t just talk it, and I just want to thank you. I was so impressed with the tour and talking to your researchers and your physicians and to the patients who were willing to talk to us, and I just want to thank all of you. Dr. COLLINS. Thank you, Senator. Senator KENNEDY. Thank you, Mr. Chairman. Senator BLUNT. Thank you, Senator Kennedy. Senator Shelby. Senator SHELBY. I will try to take some more time. Senator BLUNT. This will be your third round. [Laughter.] CYSTIC FIBROSIS DRUGS Senator SHELBY. Leveraging—this slide here, ‘‘Leveraging Basic Science,’’ can you put that back up there? Where it’s ‘‘Cystic Fibro- 45 sis Drugs Are Working’’? It shows outside the cell, inside the cell, you know? Dr. COLLINS. I’m afraid I can’t—— Senator SHELBY. You can’t do it. But this is—you’re very familiar with that. Dr. COLLINS. Yes. We showed that in the opening statement. Senator SHELBY. Is this the lung? Dr. COLLINS. Well, that diagram on the left, what is that? That is actually a photograph at a very high magnification using a technique called cryo-EM. It’s a protein. That is the protein that is responsible for CF. It’s there in the lining cells of the lung as a channel that moves chloride and salt around. And until a few months ago, we didn’t really quite know what it looks like, and now we do. Senator SHELBY. And this is where you’re talking about targeting things rather than perhaps rather than just do the shotgun approach. Dr. COLLINS. Exactly. It gives you the opportunity to be much more sophisticated in your drug design than just hoping you were going to hit something that was going to work. Senator SHELBY. Dr. Gibbons, you’re involved in the lung—heart, lung, and blood. Do you overlap into cystic fibrosis in dealing with the lungs there? Dr. GIBBONS. Yes, we do, Senator, and—— Senator SHELBY. Would you like to comment on this? I hadn’t given you a chance, but—— Dr. GIBBONS. Well, certainly, again, Dr. Collins clearly is a pioneer in this area. But there are other critical elements of the research. For example, he alluded to the fact that certain misspellings change how that protein traffics in the cell, and a lot of that involved basic cell biology research of the lung epithelial cells. Determining where the proteins got stuck inside the cells and why was very instrumental in understanding how to target them and correct the trajectory of that trafficking. So there’s always this back-and-forth between not only understanding the mutation, but how it affects the cell, the cell function, and therefore the organ’s function and the effect on the patient. Moreover, there are other elements of the disease. Microbial agents, such as Pseudomonas bacteria, can invade and affect the generation of the mucus in the lungs that’s so important as a bar- rier function. And so there are other treatment strategies—— Senator SHELBY. The accumulation of mucus in the lungs, isn’t it? Dr. GIBBONS. That’s correct, sir. Senator SHELBY. And how do you prevent it? Is that correct, Doc- tor? Dr. GIBBONS. Exactly. And so understanding that in addition to influencing how the channel works, there are other strategies that can be taken to help the patient. Senator SHELBY. And as you target the cells there you’re talking about, what are you—I guess you’re trying to suppress the mucus some way or get rid of it, I don’t know what you do. But—— Dr. COLLINS. It’s a great question. You try every tack you can. I mean, one of the drugs that’s turned out to be most useful in cystic fibrosis, but now 15 years ago, is actually something called 46 DNase, which makes that mucus more able to be removed, it’s not so thick and sticky when you have DNase there basically making it more fluid. So that’s one approach. And of course, there are infections that happen in cystic fibrosis, so antibiotics are critical, including those that can be inhaled as an aerosol and go right to where the problem is. But I think all of us primarily are looking to the time where you have a drug that’s not just treating the symptoms, not just treating the consequences, but actually treating the fundamental problem, which is—— Senator SHELBY. The underlying cause. Dr. COLLINS. That’s exactly right. And when I talked about this, I have to point out that the investigator that I highlighted in my conversation briefly about CF was from the University of Alabama at Birmingham who is one of those folks who is doing this amazing work to look at the structure of the protein at the atomic level. Senator KENNEDY. I think he went to med school at LSU, though. [Laughter.] Dr. COLLINS. It might be, I don’t know. Senator SHELBY. Dr. Gibbons, what kind of timeline do you see as far as—I know it’s hard to say it’s going to be in 3 years, 2 years, or what, but you’ve made so many breakthroughs in cystic fibrosis. Now you’ve made a big one, you think, right? Going to the fundamental thing? And if you can target that, that will change the game, would it not? Dr. GIBBONS. Oh, absolutely. Senator SHELBY. Change the lives, we should say, of so many promising young people. Dr. GIBBONS. Absolutely. It also is perhaps a forerunner for other rare diseases that we understand the genetic cause of. One that is a high priority for us is sickle cell disease. We are excited about the emerging new gene-editing technologies that exist where we can actually modify that genetic misspelling and turn it back into the correct spelling. This kind of therapy was only just a glimmer before, but now I think we’re on the threshold of bringing it to patients. So we are looking forward to rapid advances related to cor- recting these genetic disorders at a fundamental level. Senator SHELBY. Thank you. Thank you, Mr. Chairman. Senator BLUNT. Thank you, Senator Shelby. Well, you can see lots of continued interest in everything you’re doing, and we’re glad you’re here. Do you have a final comment, Dr. Collins? Dr. COLLINS. I just wanted to say thank you, Mr. Chairman, to you and the Members of this committee for your support of what all of my colleagues and I believe is at a remarkable moment in history. And I also wanted to take the moment, if you’ll forgive me, to allow me to introduce to you the future Senator from Michigan, my granddaughter, Bailey Fraker, who is sitting back there. So, Bailey, stand up. Senator BLUNT. Wonderful. [Applause.] 47

Dr. COLLINS. I dream of a day where she doesn’t have to worry about the health of herself or her children or maybe even of her grandfather, if he’s still interested in playing his guitar and riding his motorcycle 20 years from now. [Laughter.] Dr. COLLINS. But I just want to say thank you to all of you for your support. ADDITIONAL COMMITTEE QUESTIONS Senator BLUNT. Well, thank you for being here. And we hope you’re still playing your guitar and riding your motorcycle with en- thusiasm 20 years from now. Thanks to the Directors for also joining us today. The record will stay open for one week for additional comments. [The following questions were not asked at the hearing, but were submitted to the Department for response subsequent to the hearing:]

QUESTIONS SUBMITTED TO FRANCIS S. COLLINS, M.D., PH.D.

QUESTIONS SUBMITTED BY SENATOR ROY BLUNT

INDIRECT COSTS Question. There is significant concern in the research community about the proposal to cap indirect costs at 10 percent. First, I think the term ‘‘indirect’’ is a mis- nomer—these expenses are part of the cost of doing research in America—buying lab equipment, paying salaries, and having facilities to work in. Dr. Collins, if we accept the proposal to cap indirect costs at 10 percent, what would happen to the research system in the United States? Answer. The effect on grantees will vary by institution, depending on the current indirect cost rate and a variety of other factors. The impact will be greater on institutions that have a higher percentage of NIH funding compared to total funding from other sources, or a lower ability to cover indirect costs from other sources (e.g., donations, endowment income, state government, tuition). The Department continues to work on specific details of the NIH indirect cost policy for fiscal year 2018 and will assess the impact on grantees once the policy is finalized. Question. Washington University in St. Louis receives over $390 million a year in NIH-funded research. Under your proposal, they would lose $90 million a year in research funding, laying off 1,000 people. What discussions did you have with the research community before proposing this cap? Answer. The extramural NIH research community has provided extensive feedback since the Budget release through conferences and meetings with professional associations such as the National Council of University Research Administrators (NCURA), the Federal Demonstration Partnership (FDP), and the Council on Gov- ernmental Relations (COGR), as well as by email and phone call discussions. In- creasing efficiencies within NIH remains a priority of the Administration. NIH is working with the Department and OMB to identify strategies to streamline processes and increase efficiencies within NIH. These strategies to reduce grantee administrative burden are informed by direct feedback from grant recipients. Question. I understand that many nonprofits have caps on indirect costs, but they are likely able to do that because: (1) they fund a relatively small percentage of research; and (2) NIH’s indirect costs help offset the cost of their research. I also know the Secretary has cited the Gates Foundation’s indirect cost rates as an example, yet note, that recently Bill Gates issued a statement distancing his Foundation’s policies from the Administration’s. What type of reviews of the program did NIH do to come up with the 10 percent cap? Answer. The fiscal year 2018 Budget presents an opportunity to reexamine how to optimize Federal investment in a way that best serves the American people. The Department assessed opportunities within the NIH to determine where greater efficiencies may be possible within the research project grant mechanism. In addition, HHS also assessed strategies used by other non- Federal entities such as founda- tions and private sector organizations to understand how funds for direct and indirect research costs are allocated. 48

PEDIATRIC RESEARCH Question. Many Institutes at the NIH support pediatric research. What are your thoughts on how the NIH can better coordinate and support pediatric research across all Institutes and Centers? Specifically, I would be interested in your thoughts on the value of a coordinating committee and an office on child research to help manage and coordinate pediatric research activities trans-NIH similar to offices on women’s health, sexual and gender minority health and tribal health. Answer. Pediatric research continues to be a high NIH priority. The NIH’s strong basic research portfolio provides the foundation for pediatric research in a variety of scientific areas, including neurodevelopment, cardiology, lung development, cancer, and behavioral and social sciences. In fiscal year 2016, the NIH funded nearly $4 billion of research grants and projects directed specifically at pediatric research. Although the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) funds the largest proportion of pediatric research within NIH (18 percent) and takes a leadership role in many pediatric research efforts that involve trans-NIH collaborations, all NIH Institutes and Centers (ICs) support various aspects of pediatric research. Each year, NICHD coordinates the annual pediatric research report, required by the Children’s Health Act of 2000 (Public Law 106–310); this report provides an annual update on the most significant pediatric research advances across the NIH. NIH also publishes annually its Report on Collaborations with Other HHS Agencies, which includes several pediatric initiatives.1 In addition, NIH hosts many internal working groups with representatives from different ICs that are focused on coordinating research efforts on specific conditions, such as Down syndrome, muscular dystrophy, autism and mitochondrial diseases. The formation of an internal NIH pediatric research working group might improve coordination and encourage expanded child health research collaborations among the ICs without discouraging investigator-initiated ideas.

ALZHEIMER’S DISEASE Question. Dr. Collins and Dr. Hodes, recent clinical trial results for both disease- modifying and symptomatic treatments for Alzheimer’s disease have once again been disappointing. In July 2015, the U.S. Food and Drug Administration (FDA) released a report on targeted drug therapy that highlighted the lack of success to date in bringing transformative therapies to market for Alzheimer’s disease. The report identified basic research gaps that have contributed to subsequent failures in clinical development. Additionally, a February 2017 piece in The Atlantic explored whether the longstanding ‘‘amyloid hypothesis’’ is on the brink of success or failure. With more than 5 million patients waiting for a breakthrough, and millions more estimated to be diagnosed in the coming decades, what is the NIH doing to connect the dots from the clinical development failures back to its basic and clinical research priorities? Answer. We share your disappointment and frustration regarding the recent reports of failures of promising interventions in clinical trials. A major issue, and one that we are now addressing, is that previous trials may have been intervening too late in the disease process to be effective. Recent breakthroughs in biomedical imaging are enabling us to identify and track the earliest pathological stages of the disease process, long before clinical symptoms are apparent. These discoveries, in addition to discovery of other early biomarkers of the Alzheimer’s disease process, have opened a ‘‘window of opportunity’’ for us to target and potentially reverse the disease’s underlying pathology before cognitive, behavioral, and emotional symptoms appear. For example, the Accelerating Medicines Partnership (AMP) was established in 2014 to identify and validate novel, clinically-relevant therapeutic targets, thereby accelerating the process of bringing new medicines to patients. Alzheimer’s disease (AD) is one of the first conditions on which AMP is focusing. AMP–AD consists of two projects: 1) a Biomarkers Project that explores the utility of tau imaging (another suspected disease-causing agent) and novel fluid biomarkers for tracking re- sponsiveness to treatment and/or disease progression, and 2) a Target Discovery and Preclinical Validation Project, which integrates analysis of large-scale molecular data from human brain samples with network modeling approaches and experimental validation, with the ultimate goal of shortening the time between discovery of potential drug targets and development of new drugs. AMP investigators have al-

1 Https://report.nih.gov/crs. 49 ready identified over 100 novel candidate targets, which are currently being evaluated in collaboration with industry partners. With respect to the report in The Atlantic specifically questioning the amyloid hypothesis, it is important to note that, while amyloid remains a viable and dynamic area of study, NIH’s Alzheimer’s Research Funding Database indicates that in fiscal year 2016, NIH’s investment in amyloid and tau research accounted for only one- third of funded projects focused on increasing our understanding of the molecular and physiological processes underlying AD pathogenesis. Other funded areas of basic research include understanding how brain circuit and synaptic dysfunction, immunity and inflammation, and vascular/metabolic factors contribute to the development of AD and AD-related dementias. Earlier investments in amyloid and tau have resulted in their significant representation throughout the drug discovery, preclinical development, and clinical research pipeline. However, research funding currently covers an extensive and diverse range of additional therapeutic targets including ApoE and lipids, metabolism and bioenergetics, neurotransmitter receptors, and inflammation. NIH has also boosted the non-pharmacological portfolio to assess the role of diet, exercise, and cognitive training in preventing and alleviating dementia.

QUESTIONS SUBMITTED BY SENATOR THAD COCHRAN

INSTITUTIONAL DEVELOPMENT AWARD PROGRAM Question. Earlier this year, Dr. Jennifer Sasser of the University of Mississippi Medical Center testified before this Committee about how important the Institu- tional Development Award program has been to ensuring institutions in states like Mississippi can compete on an equal playing field for NIH grants. Dr. Sasser is a promising scientist still in the early stages of her career. How can the NIH leverage the IDEA program toward its new Next Generation Researchers Initiative? Answer. NIH has launched the Next Generation Researchers Initiative to bolster support for early-stage and mid-career investigators to address longstanding challenges faced by researchers trying to embark upon and sustain independent research careers. Consistent with this objective, the Institutional Development Award (IDeA) program has always placed significant emphasis, with corresponding investments, toward the professional and scientific development of early- stage investigators to facilitate their independence and sustainability as biomedical researchers. All four current IDeA Program initiatives have an objective of targeting early-stage and/or mid- career investigators: (1) Centers of Biomedical Research Excellence (COBRE—Phases I, II, and III). The goal of the COBRE initiative is to strengthen institutional biomedical research capabilities in IDeA states through three competitive, 5-year phases of infrastructure and faculty development of thematic and multidisciplinary research centers. COBRE specifically provides for the development of new and early-stage investigators in Phase I/II and mid- career investigators in Phase II. The Phase III awards are expressly targeted for developing the sustainability of scientific/technical core resources with some funds for pilot projects of early- stage and/or mid-career investigators. Of note, receipt of an independent investigator research program grant (RPG) is recognized explicitly by this initiative as a metric of success that results in the ‘graduation’ of a junior investigator from COBRE support. In fiscal year 2016, the NIGMS supported 112 COBRE awards, for a total of 122 active COBRE awards. (2) IDeA Networks of Biomedical Research Excellence (INBRE). The INBRE initiative enhances, extends, and strengthens the research capabilities of biomedical research faculty in IDeA states through a statewide program that links a research-intensive institution with primarily undergraduate institutions (PUIs). INBRE supports institutional research and infrastructure development; research primarily by junior faculty, postdoctoral scientists, and students at PUIs; and outreach to build science and technology knowledge in the states’ workforces. In fiscal year 2016, the NIGMS supported 24 INBRE awards. (3) IDeA Program Infrastructure for Clinical and Translational Research (IDeA–CTR). The IDeA–CTR initiative develops network infrastructure and capacity in IDeA-eligible states to conduct clinical and translational research focused on health concerns that affect medically underserved populations and/or that are prevalent in IDeA states. IDeA–CTR awards support mentoring and professional development activities for clinically oriented early-stage investigators and mid-career investigators newly embarking on clinical and translational 50

projects. The IDeA–CTR initiative provides for a pilot projects program for supporting research projects of mostly early-stage investigators. In fiscal year 2016, the NIGMS supported seven IDeA–CTR awards, for a total of nine active IDeA– CTR awards. (4) Research Co-Funding. IDeA co-funding is provided to eligible applications that have already been judged meritorious by NIH peer-review committees and national advisory councils but are outside the range of applications under consideration for funding by all of the NIH Institutes/Centers (I/Cs). Priority for co-funding is given to new and early- stage investigators. In fiscal year 2016, IDeA co-funded 58 research project grant awards at 17 NIH I/Cs.

PRECISION MEDICINE INITIATIVE—ROLE OF PHYSIOLOGY Question. The NIH Precision Medicine Initiative has focused primarily on genetic analysis. However, physiology that may not show up in genetics is also an important determinant of a patient’s reaction to treatment and overall health. The University of Mississippi Medical Center, as you know, has long been a national leader in physiology, dating back to the famous Dr. Arthur Guyton. How will the Precision Medi- cine Initiative look at the role of physiology in patients’ unique medical needs? Answer. There are four important ways that the All of Us Research Program, the patient cohort for the Precision Medicine Initiative, plans to look at physiology in the participants: (1) Electronic Health Records. We will ask for access to participants’ electronic health records (EHRs) to determine if they have any diseases or conditions, or early signs of certain conditions (e.g., heart disease), based on lab tests that have been recorded in the EHR (e.g., cholesterol levels). (2) Participant-Provided Information. We will ask participants to fill out sur- veys with questions that address their lifestyle and habits (e.g., do they smoke) and personal and family medical history. With this information we will be able to identify relationships between certain behaviors that may indicate healthier physiology or more pathologic physiology. We will also compare this information to participants’ EHR data to gain greater insight into how diseases manifest and progress, or what kinds of behaviors or lifestyles indicate healthier physiology. (3) Physical Measurements and Biospecimens. We will ask participants to visit a clinic to get their physical measurements (i.e., height, weight, waist and hip circumference, blood pressure, and heart rate) as well as collect biosamples (i.e., blood, saliva, and urine). We are in the planning stages to use the biosamples for selected clinical assays that will serve as biomarkers of basic physiology of most organ systems. A few examples of the kinds of tests we are planning to use include cholesterol tests for heart function, creatinine and microalbumin for kidney function, enzymes for liver function, and vitamin D for immune function. (4) Digital Health Technologies (mobile Health). Lastly, we will ask participants, over time, to provide personal information based on digital health technologies. For example, if participants have a fitness tracking device, we may ask them for the data to understand how physical activity affects physiologic function. We are also developing new apps that will allow participants to complete cognitive and movement tests and share information about their general well- being by answering questions about their mood or if they experience headaches. Importantly, the collective data from all of these sources can be integrated to gain a deeper understanding of how this information is interrelated, and may provide new ways to identify what factors are important for preventing certain conditions.

PRECISION MEDICINE INITIATIVE—FEDERALLY QUALIFIED HEALTH CENTERS Question. The NIH selected a number of federally Qualified Health Centers (FQHCs) to serve as collection sites for the Precision Medicine Initiative’s million- person research cohort. It is my understanding that these FQHCs will each contract with an outside group to provide technical assistance in these efforts. Has HHS considered having these FQHCs partner with local academic medical centers for this purpose? Answer. The All of Us Research Program believes that the nation’s federally Qualified Health Centers are unparalleled resources for engaging diverse, hard-to- reach communities across the U.S. As priority healthcare provider organization partners, we established an early pilot with six outstanding federally Qualified Health Centers (FQHCs) across the U.S. to help us define the best way for incorporating FQHCs to help fulfill the promise of All of Us. Conducted through a contract, the outcome of this critical pilot will be a set of learnings about the potential 51 options and best potential approaches for scaling up FQHC involvement in our program. We anticipate the final report with learnings in early 2018. We will use this report to guide our considerations and roadmap for scaling up FQHC partnerships, which may include partnering with academic medical centers. In addition to the FQHCs participating in the on-going pilot, it is noteworthy that there are several other FQHCs working with Regional Medical Centers that are participating in the program. The Illinois Precision Medicine Consortium, specifically at the University of Illinois at Chicago (UIC), and the California Precision Medicine Consortium, specifically the University of California at Irvine (UCI), have independently partnered with FQHCs in their areas. —The FQHC Mile Square Health Center is currently working with UIC, and there is a future plan for UIC to work with the Alliance Chicago, an organization that unites FQHCs in the Chicago area. —The FQHCs working with UCI are: —UC Irvine Health Family Health Center, Santa Ana —UC Irvine Health Family Health Center, Anaheim Our program is deeply committed to integrating federally Qualified Health Cen- ters into All of Us and we look forward to finalizing our approach to developing robust, scalable partnerships with them.

QUESTIONS SUBMITTED BY SENATOR JERRY MORAN

ESSENTIAL FACILITIES AND ADMINISTRATIVE COSTS Question. Do you believe that a diversity of universities and institutions pursuing life-enhancing biomedical research is valuable for the United States to maintain a robust medical research enterprise? If so, how are universities and laboratories expected to afford to support a new research endeavor if the essential facilities and administrative costs are not covered? Will the caps cause research to be condensed into only a few universities and result in less geographic distribution of biomedical research? Answer. Yes, we do believe that a diversity of universities and institutions pursing life- enhancing biomedical research is valuable for the United States to maintain a robust medical research enterprise. The effect of the indirect cost policy on grantees will vary by institution, depending on the current indirect cost rate and a variety of other factors. The impact will be greater on institutions that have a higher percentage of NIH funding compared to total funding, or a lower ability to cover indirect costs from other sources (e.g., donations, endowment income, state government, tuition). The Department continues to work on specific details of the NIH indirect cost policy for fiscal year 2018 and will assess the impact on grantees as the policy is finalized.

QUESTIONS SUBMITTED BY SENATOR SHELLEY MOORE CAPITO

ALZHEIMER’S DISEASE Question. Regarding the National Plan to Address Alzheimer’s Disease first introduced in 2012 with the goal of preventing or effectively treating Alzheimer’s by 2025, what progress has NIH made 5 years into this project and is it your sense that the current administration is supporting continuity of this program? Answer. Recent and historic levels of investment in Alzheimer’s disease and related dementias have enabled the Nation to provide more robust support for researchers working toward a cure. Their progress has already been significant. Since the National Plan was established in 2012, NIH-supported investigators have: —Helped map the brain’s innermost connections and the molecular fabric of Alz- heimer’s. —Deepened our understanding of metabolic changes at the heart of the disease. —Detected disease progression through neuroimaging and discovery of novel biomarkers. —Used new technologies, through unprecedented multidisciplinary collaborations, to make large data sets available with greater accuracy and speed to the research community. —Leveraged new investment in epidemiological research to increase our understanding of the complexity of variation across space and over time in disease incidence and prevalence, with the goal of identifying new clues for prevention. —Looked at health disparities in new ways, with studies of genetics and risk factors that may be contributing to higher dementia rates among certain groups. 52

—Begun testing technological innovations in the home that aim to increase the ability of older adults to age in place. A number of these advances have been made possible through some of NIH’s flag- ship programs, which have been created or expanded under the National Alz- heimer’s Project Act (NAPA). They include: —Molecular Mechanisms of the Vascular Etiology of Alzheimer’s Disease: This consortium aims to improve our understanding of how the vascular system may be involved in the onset and progression of Alzheimer’s and related dementias. —Alzheimer’s Disease Neuroimaging Initiative (ADNI): This long-running study has contributed to many important discoveries. For example, work through ADNI has led to the discovery of how Alzheimer’s-related brain changes cor- respond to clinical findings. —Alzheimer’s Disease Preclinical Efficacy Database: This cutting-edge, web-based portal for housing, sharing, and mining of preclinical efficacy data will facilitate data- sharing among researchers in drug development. —Model Organism Development and Evaluation for Late-onset AD: This research center is developing improved mouse models of late-onset disease. —The Collaborative Aging (in Place) Research Using Technology: This multi-NIH institute and joint agency initiative will create a sustainable research infrastructure through which investigators can identify, qualify and collect data on user-friendly and effective technology that will allow older adults to age in place. —The Alzheimer ’s disease Drug Development Program: Since 2012, NIH has funded nine preclinical drug development projects through this program, including a new immunotherapeutic vaccine; a novel gene therapy that protects nerve cells and improves their function; and a small molecule inhibitor of brain inflammation. These are expected to enter clinical testing within the next 2 years. We look forward to making continued progress on our goal of eliminating the threat of Alzheimer’s disease and related dementias from the lives of all Americans. The National Plan to Address Alzheimer’s Disease: 2017 Update is expected to be released shortly, and contains detailed information on the recent progress of NIH as well as other partner agencies.

QUESTIONS SUBMITTED BY SENATOR JOHN KENNEDY

INDIRECT COSTS Question. Director Collins, thank you again for hosting my colleagues and me at the NIH a few weeks ago, and thank you for taking the time to meet with us today. I wanted to briefly ask about the cap on indirect costs that was included in this budget. As you stated in your testimony, the NIH currently spends approximately 28 percent of its extramural budget on indirect costs. This budget would cap indirect costs at 10 percent. Do you think that this cap will negatively affect Institutional Development Award (IDeA) states like Louisiana which do not receive as much funding for biomedical research? Answer. The effect on grantees will vary by institution, depending on the current indirect cost rate and a variety of other factors. The impact will be greater on institutions that have a higher percentage of NIH funding compared to total funding, or a lower ability to cover indirect costs from other sources (e.g., donations, endowment income, state government, tuition). The Department continues to work on specific details of the NIH indirect cost policy for fiscal year 2018 and will assess the impact on grantees once the policy is finalized.

QUESTIONS SUBMITTED BY SENATOR PATTY MURRAY

AHRQ Question. The budget proposes to fold the Agency for Healthcare Research and Quality into NIH. As you know, AHRQ’s research is focused on making healthcare safer and more effective, while NIH is largely committed to basic research. Dr. Collins, given their somewhat different missions, do you believe AHRQ would be a good fit for NIH, and if so, please explain why. Answer. Yes. The 2018 President’s Budget transitions AHRQ to an Institute at the NIH—the National Institute for Research on Safety and Quality (NIRSQ). If the proposed transition were to occur, NIH would take steps to ensure that the important research that AHRQ supports is continued at this agency. By capitalizing on the expertise of the AHRQ in ensuring that evidence is used to make healthcare 53 safer, higher quality, and affordable, the new NIRSQ would be poised to ensure that NIH’s investments in biomedical science are better translated into knowledge and practical tools that can be adopted by physicians and other healthcare professionals to benefit patients. NIH and AHRQ have complementary missions. NIH’s mission is to seek fundamental knowledge about human health and disease and to apply that knowledge to enhance health, lengthen life, and reduce illness and disability. AHRQ’s mission is to produce evidence to make healthcare safer, higher quality, more accessible, equi- table, and affordable, and to work within HHS and with other partners to make sure that the evidence is understood and used. There are similarities in the types of research that is funded. For example, while it is a relatively small proportion of the NIH budget, both agencies support health services research, comparative effectiveness research (CER), and patient safety research. NIH regularly examines its portfolio to ensure that NIH and AHRQ’s efforts are complementary, rather than duplicative. The NIH and AHRQ portfolios in these common areas may relate to the same health problem, but the questions pursued and the approaches taken differ. For example, an NIH CER study will involve a clinical trial designed to address a fundamental question about the effectiveness of two interventions. AHRQ, on the other hand, will support a research review to look at all the available evidence about the benefits and harms of each intervention for different groups of people. A case study helps illustrate the different approaches. Both NIH and AHRQ have done CER on the prevention of sudden death due to heart disease. The Sudden Cardiac Death in Heart Failure Trial 2 exemplifies the approach NIH takes. The trial, which involved thousands of patients with congestive heart failure, compared the effectiveness of a device called an implantable cardioverter-defibrillator (ICD) and an antiarrhythmia drug in preventing sudden death from cardiac arrest. The study demonstrated that the defibrillator reduced mortality by 23 percent, whereas the drug had no favorable effect on survival. AHRQ’s contribution was to carry out a systematic review of the scientific lit- erature resulting from many research studies—including the findings from the NIH trial—on the efficacy, effectiveness, and safety of ICDs compared to a different type of therapy for arrhythmia. AHRQ’s research produced an important evidence report 3 that confirmed the value of defibrillators in saving lives in appropriately selected patients. The agencies’ missions and approaches produced complementary research results. Because of their complementary roles and missions, NIH and AHRQ have the opportunity for synergistic collaborations. For example, the two agencies partner on the U.S. Preventive Services Task Force (USPSTF), an independent panel of non- Federal experts that conducts scientific evidence reviews of a broad range of clinical preventive healthcare services and develops recommendations. AHRQ convenes the Task Force and provides scientific, administrative, and dissemination support. NIH coordinates with AHRQ/USPSTF to ensure that the Task Force’s evidence reports and recommendations are informed by the most recent NIH-supported research and that the recommendations are clearly explained to the public. The NIH’s Office of Disease Prevention (ODP) also serves as the NIH liaison to USPSTF and works with NIH ICs to facilitate NIH scientific review and input. ODP will continue to work with AHRQ and the USPSTF to identify opportunities to address evidence gaps, monitor progress, and enhance coordination.

BIG DATA Question. One of the greatest challenges facing science today is how to manage and effectively use the massive amounts of data. Without tools for managing and manipulating data, its value is significantly reduced. Likewise, we don’t want scientists spending time recreating data that exists from other research studies. We directed NIH in the 2017 omnibus to develop a strategic plan to address these issues. Dr. Collins, what’s the status of work on the plan and who is heading up this effort? Dr. Hodes, how are the plan authors coordinating their work with your team, given your responsibility for managing the Alzheimer’s disease data sets? Dr. Lowy, what role is NCI playing in developing the data infrastructure plan?

2 Bardy et al. 2005. Amiodarone or an Implantable Cardioverter—Defibrillator for Congestive Heart Failure. NEJM 352:225–237. http://www.nejm.org/doi/full/10.1056/NEJMoa043399. 3 AHRQ. 2007. Cardiac Resynchronization Therapy and Implantable Cardiac Defibrillators in Left Ventricular Systolic Dysfunction. Https://www.ahrq.gov/downloads/pub/evidence/pdf/defib/ defib.pdf. 54

Answer. NIH recognizes the significant opportunities and challenges presented by big data in biomedical research and is taking an NIH-wide approach to develop a strategy for making biomedical big data sustainable, accessible, and usable. Con- sistent with the recommendations of the Advisory Committee to the Director of NIH, the National Library of Medicine (NLM) is playing the lead role in developing NIH’s strategic plan for biomedical big data. It is consulting broadly with other NIH Insti- tutes and Centers that are active in generating and using big data, including the National Institute on Aging, National Cancer Institute, and Center for Information Technology. It is also coordinating its efforts with the NIH Scientific Data Council and Data Science Policy Council, which guide NIH-wide efforts to address the evolving challenges and opportunities associated with big data and data science in biomedical research and the policy issues associated with scientific data management and sharing. NIH has made considerable progress in developing its strategic plan for big data, which draws upon and synthesizes the experience gained from multiple activities. As part of its continued investment in the Big Data to Knowledge (BD2K) initiative, managed by the NIH Common Fund, NIH is launching the Data Commons Pilot Phase. The Data Commons Pilot Phase aims to develop and evaluate cloud-based approaches where investigators can store, share, access and use data and tools generated from NIH-supported biomedical research. A Funding Opportunity Announce- ment was issued in July 2017 for a Data Commons Pilot Phase Consortium tasked with developing plans and prototypes of Data Commons cloud solutions and to assess the pilot for cost, utility, efficiency, and usability, with awards expected to be issued before the end of the fiscal year. NIH’s Center for Information Technology is closely involved in these efforts and is evaluating the feasibility of providing cloud solutions and consistent security approaches to support NIH-wide data needs. In addition, NLM’s National Center for Biotechnology Information is exploring cloud- based approaches for providing secure access to high-value data sets, such as the data from more than 1.5 million subjects contained in the database of Genotypes and Phenotypes (dbGaP). It is considering ways such models could be extended to other data types. NLM’s own strategic plan, which will include an explicit focus on data science and open science, is expected to be completed in early 2018 and will also inform the NIH plan for biomedical big data. In developing its strategic plan, NLM has convened four expert external panels to advise on future directions and priorities, including one panel focused specifically on NLM’s role in data and open science. The National Institute on Aging (NIA) is contributing to the NIH strategic plan based on its experience with managing Alzheimer’s disease (AD) data. NIA supports multiple programs involving management of big data sets, including the Alzheimer’s Disease Neuroimaging Initiative, the Genetics of Alzheimer’s Disease study, and several large complex clinical trials on Alzheimer’s disease. Efforts are underway to further integrate data sets across NIA-funded centers and consortiums. NIA is represented on the NIH Scientific Data Policy Council and will use its experience managing and archiving large data sets and conducting data harmonization activities to help NLM identify consistent approaches to managing big data, including data managed by NIH grantees and data coordinating centers. The National Cancer Institute (NCI) is contributing to the strategic plan by sharing its expertise and the experience gained from its work on the Genomic Data Com- mons (GDC) which was launched in 2016. The GDC currently includes genomic data on nearly 15,000 cases and nearly 40 disease types, and it is available for free to qualified researchers. In addition, NCI is supporting the NCI Cancer Genomic Cloud Pilots that aim to incorporate genomic, proteomic, metabolomic, clinical, and imaging data in an interoperable environment to change the way that cancer researchers can share their data, and accelerate cancer research. NCI continues to learn from the development and management of this unique resource and will share experi- ences with NLM in the development of the NIH-wide strategic plan. These efforts aim to develop and evaluate infrastructure and tools for managing and manipulating biomedical big data. They will provide insight into approaches for valuing and prioritizing data for long-term preservation and will form the basis of NIH’s strategic plan for big data.

MECHANISM TABLES Question. Please provide updated Mechanism tables reflecting the fiscal year 2016 actual, fiscal year 2017 enacted level and fiscal year 2018 President’s Budget for each of the 27 current institutes at the National Institutes of Health. Answer. The updated mechanism tables requested, covering all of the NIH Insti- tutes and Centers, were provided to the Committee on July 19, 2017. Because of 55 timing of final 2017 appropriations action, the fiscal year 2018 President’s Budget was based on the fiscal year 2017 Continuing Resolution. [The mechanism tables follow:] 56

QUESTIONS SUBMITTED BY SENATOR BRIAN SCHATZ

STOP PAIN INITIATIVE Question. HHS recently committed to pursue a three-part approach to opioid misuse and addiction, including finding non-addictive alternatives for chronic pain through the NIH. Last Congress, I introduced the STOP Pain Act with Senator Hatch, which passed into law as part of the CARA package in July 2016. It directs the NIH to research chronic pain and non- opioid alternatives to treat chronic pain. I am calling for a STOP Pain Initiative to be led by the NIH. The goal would be to put real dollars behind the goals of the STOP Pain Act and to elevate this initiative to the level of the Precision Medicine Initiative or the BRAIN Initiative. The opioid crisis is taking too many lives to not invest in a new, and well-funded, STOP Pain Initiative. I know there are multiple efforts going on across the government, including the Federal Pain Strategy, the Interagency Pain Research Coordinating Committee, and the President’s Commission on Combating Drug Addiction and the Opioid Crisis. Could you share an update about the status of pain research at the NIH given these initiatives? Answer. Many institutes, centers and offices across the NIH fund pain research. In 2016, NIH invested $483 million dollars on pain research. As the lead institute for pain, the National Institute of Neurological Disorders and Stroke (NINDS) has a designated pain policy office to coordinate pain research efforts across NIH through the NIH Pain Consortium and across Federal agencies through the Inter- agency Pain Research Coordinating Committee (IPRCC). The NIH Pain Consortium is a trans-NIH group representing 25 NIH institutes, centers and offices that support pain research. The mission of the NIH Pain Consortium is to enhance pain research through collaborative research initiatives, pain-related workshops and symposia. Pain research funding opportunities initiated by the NIH Pain Consor- tium Institutes and Centers have led to multidisciplinary pain studies that seek to understand pain mechanisms, the experience of pain and associated treatment challenges. The IPRCC has led a number of important pain research initiatives. The National Pain Strategy (NPS) released in March 2016, is being implemented by the HHS Agencies and other Departments under the leadership of the HHS Office of the As- sistant Secretary of Health and NIH. It recommends approaches to improve understanding, prevention and evidence-based treatments of pain. NIH is supporting implementation of some of the objectives in the National Pain Strategy along with other Federal agencies and external stakeholders. Examples of NIH- supported research activities include development, testing and validation of a screening tool for chronic pain; and nationwide studies on treatment coverage for back pain. Achieving the objectives of this strategy will strengthen HHS efforts to reduce harms of opioids. The IPRCC and NINDS Office of Pain Policy developed a long-term strategic plan to enhance Federal pain research. The Federal Pain Research Strategy (FPRS) includes a number of important research priorities spanning from basic to clinical research across the continuum of pain (acute to chronic) including disparities in pain care. A set of priorities specifically focuses on development of novel drugs and non- pharmacological treatments for pain. The FPRS recommendations are being considered as research priorities by NIH and other Federal agencies. In recognition of the urgency to address the important public health issue of the opioid epidemic and the related chronic pain crisis, the NIH recently launched a public-private initiative beginning with a series of workshops that were held in June and July 2017. These workshops were designed to identify scientific strategies with the greatest potential for solutions to the opioid problem. The first workshop focused on development of medications for opioid abuse and addiction and overdose prevention and reversal. The second workshop focused on development of safe, effective, and non-addictive pain treatments. The third and final workshop focused on understanding the neurobiological mechanisms of pain with the goal of developing novel pain treatments. Pain is a perception that is hard wired in neural circuits in the brain, spinal cord and peripheral nerves. Chronic pain is a prototypical disorder of the pain circuit. The NIH BRAIN Initiative is a major effort to develop tools to 1) map neural circuits, 2) monitor their activity to characterize circuit disorders, and 3) modulate circuit activity for health benefit. The advanced neurotechnologies from the BRAIN initiative will enable much more powerful approaches to diagnose, classify and treat 57 pain. This initiative along with the precision medicine ‘All of Us’ initiative will be leveraged to support the pain research agenda. While many strategies currently are being utilized to reverse the epidemic of opioid overdoses, there remains a pressing need to develop safer and more effective treatments for pain. Pain research at the NIH spans basic, translational and clinical studies on pharmacological and non- pharmacological approaches for pain management. Several NIH-supported investigations are underway to identify compounds for pharmaceutical development that target molecules known to be integral to pain signaling pathways. For example, persons with a specific gene mutation in nerve cells are unable to sense pain (an off-switch), others with a different mutation in the same gene suffer from chronic painful conditions (an on-switch). Other compounds involved in pain signaling are being studied to understand their therapeutic potential for pain treatment when used in combination with other drugs. One has been shown to ameliorate painful spasms of multiple sclerosis. Inflammation plays a role in developing and maintaining chronic pain. NIH supports studies on the potential of anti-inflammatory compounds to stop acute pain from becoming chronic and to alleviate chronic pain. For example, NIH supported basic research that led to a better understanding of the role of the inflammatory agents, calcitonin gene-related peptide in migraine pain and nerve growth factor in osteoarthritis pain. Compounds to block activity of these compounds currently are in phase 3 clinical trials to treat respectively, migraine and osteoarthritis pain. NIH recognizes the importance of balancing the need for mitigating the harmful effects of opioids while ensuring that people with pain receive appropriate care. NIH pain research and strategic planning efforts will support the goal of improving the lives of people with pain while reducing the reliance on opioids.

TELEHEALTH Question. Telehealth improves outcomes and saves costs in our healthcare system. Along with Senators Wicker, Cochran, Cardin, Thune, and Warner, I introduced the CONNECT for Health Act to lift outdated restrictions on Medicare’s reimbursement of telehealth. We have seen numerous studies that show that telehealth and remote patient monitoring save money and improve outcomes. We have spoken previously about telehealth research at the NIH. Can you give me an update about what research the NIH is funding in terms of telehealth and remote patient monitoring? Answer. NIH supports development of telehealth technologies and interventions to support the provision of healthcare at a distance. Innovation in communication technology, computer science, and medical technologies are helping to advance this field in numerous ways, such as the development of biosensors. Specifically, the Na- tional Institute of Biomedical Imaging and Bioengineering (NIBIB) is supporting research to address complex health problems such as asthma through the Pediatric Research using Integrated Sensor Monitoring Systems (PRISMS) to develop sensor- based, integrated health monitoring systems for measuring environmental, physiological, and behavioral factors in children. Collaborative teams of researchers are developing noninvasive health monitoring systems for pediatric asthma research and for other chronic diseases in the future. One arm of this collaboration is developing both wearable and non-wearable sensors to monitor environmental exposure, physiological signals (such as children’s activity), and behavior in children’s natural environments. To date, progress is being made in creating a variety of sensors for use by individuals or in households that could measure air pollution levels, physical activity, breathing patterns, inhaler use, or heart rate. The National Heart, Lung and Blood Institute (NHLBI) also supports research to bring more science-based, cost-effective telehealth approaches to communities that have limited access to healthcare facilities and providers, including rural communities. Examples of research in this area to improve patient care include a clinical trial of telehealth for patients with cystic fibrosis. In this study, remote monitoring using phone and Internet will be used to check-in twice per week with patients who perform a simple test to measure their own lung function (spirometry). Results of the test and a self-report on their health status are shared with physicians via a telemonitor. This in-home approach could replace a typical office visit and will help determine if intervening more quickly to treat exacerbations can help slow progression of this disease. In another example, the HyperLink study found that home blood pressure tele- monitoring and pharmacist case management achieved better blood pressure control compared with usual care during 12 months of intervention. Finally, NHLBI is supporting a network to address health disparities and to improve the system of care available to treat patients with sickle cell disease. The SC-Sickle Cell Statewide 58

Network is evaluating a variety of strategies, including telehealth approaches, to extend care to patients in rural areas. Another example of telehealth research is working to improve the informed consent process, a challenge in clinical research. One potential solution is the use of ‘‘teleconsent,’’ a video system that allows research staff to meet and discuss participation in studies with potential participants. This National Library of Medicine- funded study may address the unique needs of research studies while making studies more accessible and efficient. These and other telehealth approaches could have an impact on the ability to prevent illness or better manage chronic diseases.

ETHICS IN RESEARCH Question. I’ve been concerned about several recent stories of potential breaches of human subject protections in research studies. In a recent study about testosterone’s effects on anemia, the researchers failed to tell patients identified to have mild anemia that they had it. Even mild anemia can signal further health problems and should be treated. Could you speak to how you work in your own research to protect human subjects, and if you see any areas that need further Federal attention? Answer. NIH views our responsibility for stewardship of human subjects research as being of utmost importance. As such, working with the Office for Human Re- search Protections (OHRP), HHS, we have a number of policies and procedures in place to ensure the protection of participants in NIH-funded research and these are checked in several stages of the lifecycle of the research project. Institutions that request NIH funding for human subjects research must assure, to OHRP, that they will follow the HHS regulations to protect human subjects (45 CFR 46). Before submitting applications for grants or cooperative agreements to NIH, the proposed research must undergo internal review by institutions and approval by their organizational officials. Applications then undergo dual review by NIH, first by peer reviewers who are charged with assessing whether the design of proposed research includes appropriate protections from risks, and that the knowledge to be gained justifies any unavoidable risks. Second, Institute and Center Advi- sory Councils must approve applications for grants and cooperative agreements. All concerns identified by peer review or by NIH staff in grant applications that are approved for funding must be resolved prior to the expenditure of Federal funds for studies involving human subjects. NIH Notices of Award require that all protections will be implemented, as specified by NIH Grants Policy, HHS regulations (45 CFR 46), and FDA regulations as applicable. In order to receive an NIH award for research involving human subjects, institutions must assure that they will comply with all regulatory and policy requirements for human subjects research protections. Because protecting participants from risks associated with research is so important, NIH, institutional review boards (IRBs), and research institutions must review all proposed research. IRBs must review and approve all proposed studies and informed consent processes at least annually, as these Boards are responsible for protecting the rights and welfare of human subjects. In addition, clinical trial research must include plans for data and safety monitoring, the extent of which varies according to the nature, risk, and complexity of the research. All awardees must submit annual reports to funding NIH Institutes and Centers, in which they describe scientific and technical progress and any changes to approved research involving human subjects. These progress reports must be approved before funding for the project period can be allocated. Also to ensure that investigators are aware of their obligations to research participants, all investigators and all NIH Scientific Review Officials and Program staff must complete training in Human Research Participant Protections, and individuals involved in clinical trial research must complete Training in Good Clinical Practice. The combination of the requirements for human subjects research forms a safety net of protections that is designed to prevent avoidable risks and enhance the potential benefits of NIH-funded research.

QUESTIONS SUBMITTED BY SENATOR CHRISTOPHER MURPHY

EXTRAMURAL PARTNERSHIPS Question. Director Collins, I was concerned to learn that the proposed budget calls for a significant cut to the National Institute on Alcohol Abuse and Alcoholism (NIAAA) from over $483 million in fiscal year 2017 to $361 million next year. Given 59 the budget for the NIAAA would maintain a full FTE headcount despite the proposed cuts, I fear that extramural partnerships would be hurt the most if the overall funding were decreased. For instance, funding for the university-based Alcohol Re- search Centers, some of whom are doing innovative genomic research to try to discover the genes that predispose people to alcohol addiction, could be hurt. As you may know, this Committee expressed its support for last year for such efforts and asked the NIAAA for a detailed plan on larger-scale genetic screening initiatives. Do you believe such genomics based research on addictions is useful, and do you believe the NIAAA can proceed with more robust genetic screening initiatives with its academic partners in fiscal year 2018 and beyond under the current budget proposal? Answer. The mission of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) is to generate and disseminate fundamental knowledge about the effects of alcohol on health and well-being, and apply that knowledge to improve diagnosis, prevention, and treatment of alcohol-related problems, including alcohol use disorder (AUD), across the lifespan. Extramural partnerships with research institutions, including alcohol research centers, are essential to advancing this mission and cultivating a talented and diverse workforce to sustain the biomedical research enterprise. In its strategic plan, 2017–2021, NIAAA identified key research priorities spanning its broad portfolio to address the persistent public health challenges resulting from alcohol misuse in our nation, including research to elucidate the genetic factors that predispose individuals to, or protect them, from AUD and co-occurring mental health disorders. NIAAA-supported research has made substantial progress in understanding the contributions of genes and gene-environment interactions in AUD risk and resil- iency; however, many challenges remain in identifying the full extent of the role of genes in AUD. Recent genome wide association studies (GWAS), studies in which the entire genomes of study participants are examined to identify genetic variations leading to a particular disorder, have successfully identified gene variants that have small associations with risk for developing AUD. Much larger GWAS sample sizes are required to enable the detection of more substantive genetic associations with AUD risk. To achieve the sample sizes needed, NIAAA recently issued a policy encouraging applicants to use large scale GWAS approaches and meta-analyses of the data in their study designs. Complementary to these approaches, NIAAA will support the use of next generation sequencing technologies to identify gene variants that are rare in a population and have moderate to large associations with AUD risk. The knowledge generated will provide new insights into the mechanisms that underlie AUD pathophysiology and inform individualized prevention, treatment, and recovery.

INTER-AGENCY RESEARCH ON DOWN SYNDROME Question. People with Down syndrome are now living longer than ever thanks to medical and scientific advances. However, as this population ages, people with Down syndrome have a significantly higher risk of developing Alzheimer’s disease. The Committee applauds NIH’s leadership in driving scientific inquiries to better understand this connection through the Biomarkers of Alzheimer’s Disease in Adults with Down Syndrome Initiative, a collaborative effort between NIA and NICHD. Given that people with Down syndrome are also at greater risk for other conditions like leukemia, autoimmune disorders, and autism, do you see other opportunities for inter-agency research on Down syndrome? Answer. One benefit of communication and collaborations across NIH Institutes and Centers, and with the Down syndrome community, is increased coordination of research efforts. Led by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the public-private Down Syndrome Con- sortium, which includes 10 NIH Institutes and Centers, 13 national and international organizations whose missions focus on Down syndrome, and individuals with Down syndrome and family members, provided valuable input to the 2014 revi- sion of the NIH research plan on Down syndrome. DS Directions: The NIH Down Syndrome Research Plan has had an impact on the field of Down syndrome research; in submitting grant applications, many researchers have cited one of its objectives, particularly including the call for research on many of the comorbidities commonly experienced by people with Down syndrome (congenital heart disease, leukemia, and intestinal issues, and other developmental disorders). While life expectancy for people with Down syndrome who are living in the United States has increased dramatically over the last 50 years, these coexisting conditions still require more research and, in turn, a wider variety of expertise as represented across NIH. 60

Members of the Trans-NIH Working Group meet regularly about the wide-range of investigator- initiated research projects and other NIH-supported efforts to improve the health of people with Down syndrome, including those with co-existing conditions. The Alzheimer’s Biomarker Consortium—Down Syndrome (ABC–DS), funded collaboratively by the National Institute on Aging (NIA) and NICHD, provides an exciting opportunity to improve our understanding of Alzheimer’s disease among people with Down syndrome, 50 percent or more of whom develop brain changes associated with Alzheimer’s by age 40. This initiative seeks to identify biomarkers and track the progression of Alzheimer’s in people with Down syndrome, using brain imaging, as well as fluid and tissue biomarkers, to help us understand progression of the disease. These studies, by two teams of researchers, will include PET brain scans that detect levels of tau, to be tested for the first time in people with Down syndrome. The teams will make their data and samples freely available to qualified researchers worldwide, with the goal of improved testing of interventions. In addition, NIH’s Alzheimer’s research agenda continues to be informed by the recommendations of the April 2013 workshop ‘‘Advancing Treatments for Alz- heimer’s Disease in Individuals with Down Syndrome,’’ which was co-sponsored by NICHD and NIA, as well as the National Institute of Neurological Disorders and Stroke (NINDS), the Down Syndrome Research and Treatment Foundation, and Re- search Down Syndrome. Some NICHD-supported research on autism spectrum disorders will benefit individuals with Down syndrome who also have autism. A recent scientific workshop co- sponsored by NICHD and the National Institute on Mental Health helped guide research efforts in this area. One recent study showed that brain changes at age 6 or 12 months may help predict the development of autism spectrum disorders (ASD) by age 2 years among infants with a high family risk, an important finding since early diagnosis and appropriate intervention can ease symptoms and improve social, emotional and cognitive skills. Other NICHD-funded researchers have shown that metal toxicant uptake (lead) and deficiency in essential elements (manganese, zinc) during fetal development may increase ASD risk and severity. In addition, NIH assists the research community by providing research resources that might otherwise prove cost prohibitive for them to support individually. To advance research on Down syndrome, NICHD supports a contract for the leading re- pository of mouse models for Down syndrome. The Cytogenic & Down Syndrome Models Resource 4 at Jackson Laboratory maintains and distributes mouse models for Down syndrome, as well as the study of chromosomal aneuploidy, and has recently funded a new research project to develop new mouse models for Down syndrome. Together with NIMH and NINDS, NICHD encourages studies that develop, validate, and/or calibrate informative outcome measures for use in clinical trials for individuals with intellectual and developmental disabilities (IDD), including Down syndrome. And DS-Connect®, a Web-based DS patient registry that was established in 2013 and now includes about 3500 participants, provides researchers with a new tool to recruit for their research studies. The registry benefits families, too; ultimately, the registry will link to biorepositories of tissue samples and other resources, making it easier for participants to take part in clinical studies for new medications and other treatments for Down syndrome and its coexisting conditions.

DOWN SYNDROME Question. Although Down syndrome has long been viewed as a condition that affects children, the life expectancy for people today is almost 60 years. NICHD has traditionally been the home for Down syndrome research at NIH, but as people with this condition are living well into adulthood, how are other Institutes working to integrate research on Down syndrome into their portfolios? Answer. Through the NIH Working Group on Down Syndrome and the public-private Down Syndrome Consortium, the NIH is working across its component Insti- tutes and Centers (IC) to coordinate research efforts while maintaining the expertise of each IC. A good example was the coordinated effort to produce DS Directions: The NIH Down Syndrome Research Plan, which NIH published in late 2014. The public- private Down Syndrome Consortium, which includes the Trans-NIH Working Group (10 ICs), 13 national and international organizations whose missions focus on Down syndrome, and individuals with Down syndrome and family members, provided valuable input and a link to the Down syndrome community during development of the plan. The plan has had an impact on the field of Down syndrome research; in submitting their grant applications, many researchers have cited one of its objectives.

4 Http://www.jax.org/cyto/index.html. 61

Another good example is the recent effort to address Alzheimer’s disease. Esti- mates suggest that 50 percent or more of people with Down syndrome will develop dementia due to Alzheimer’s disease as they age, and the National Institute on Aging (NIA) supports several studies of Alzheimer’s in this population. With the Na- tional Institute of Child Health and Human Development (NICHD), the NIA supports the Alzheimer’s Biomarkers Consortium of Down Syndrome (ABC–DS), in which researchers from eight sites across the nation are identifying and using biomarkers to track disease progression in people with Down syndrome. Other NIA- supported studies include a Phase I trial to investigate an immunotherapy vaccine in adults with Down syndrome and a project investigating the natural history of amyloid deposition in adults over age 30 with Down syndrome. NIA is also a member of the trans-NIH Working Group on Down Syndrome. Finally, NIH’s Alzheimer’s research agenda continues to be informed by the recommendations of the April 2013 workshop ‘‘Advancing Treatments for Alzheimer’s Disease in Individuals with Down Syndrome,’’ which was co-sponsored by NICHD and NIA, as well as the National Institute of Neurological Disorders and Stroke, the Down Syndrome Research and Treatment Foundation, and Research Down Syndrome. At the other end of the lifespan, NICHD intramural scientists have conducted research to understand the neurobiology of Down syndrome and optimize fetal outcome through therapy during pregnancy, showing that spatial learning in mouse models could be enhanced. Currently, intramural researchers at the National Human Genome Research Institute are working to test the hypothesis that prenatal treatment of fetuses known to have Down syndrome will result in improved brain growth and neurocognition. The work, currently being performed in mouse models, has shown promising proof of principle by decreasing the time it takes for neonatal mice to achieve developmental milestones.

QUESTIONS SUBMITTED BY SENATOR JOE MANCHIN, III

NIMHD

RURAL HEALTH Question. In 2016, the America’s Health Rankings Report ranked West Virginia 43th in overall health. This low ranking is driven by high obesity rates, high rates of smoking, and high rates of drug related deaths. We’re also 48th highest in cancer deaths and 49th highest in the number of West Virginians with diabetes. West Virginia has, in many ways, been left behind as medical advances have saved lives in other places. In fact, I have heard from West Virginians who want to participate in clinical trials, but are forced to leave the state to do so. Dr. Collins, what is NIH doing to bridge this gap in health outcomes? How do you ensure that the medical research that you do benefits people in poor, rural communities? How can we better expand access to research studies and then to successful treatments to rural Americans, particularly in states like mine where the disease burden is so high. Answer. Rural communities face unique health disparities. To address the barriers facing rural communities, including residents of West Virginia, NIH supports research aimed at reducing health disparities experienced by rural populations, and improving health outcomes. In fiscal year 2016, NIH supported more than 500 grants focused on rural health for approximately $295 million, with about $24 million to fund projects in West Virginia. Among the key partners in West Virginia that NIH works with to address rural health disparities are West Virginia State Depart- ment of Health and Human Resources, West Virginia University, and Marshall Uni- versity. NIH encourages the scientists of West Virginia to apply for grants related to the health disparities experienced by your constituents in West Virginia, including diabetes, obesity, smoking, cancer, and substance use. NIH is committed to ensuring that research addresses the unique strengths and challenges of rural communities. In West Virginia for example, NIH supports the West Virginia Clinical and Translational Science Institute: Improving Health through Partnerships and Transformative Research (WVCTSI), which leads statewide collaborations and innovation in clinical and translational research. An important facet of the WVCSTI is the Clinical Research Resources and Facilities component that will support the Center in: (1) creating a Clinical Trials Center of Excel- lence to provide access to cutting-edge clinical trials for West Virginians, (2) facilitating outcomes research, predictive modeling, and geospatial analysis, and (3) stimulating environmental health research. The West Virginia IDEA Network of Biomedical Research Excellence (WV– INBRE) is funded by NIH to support a network of partners to develop the bio- 62 medical research infrastructure and capacity to provide biomedical research experi- ences for undergraduate and graduate students, as well as facilitate research progress, mentorship, training, and career development for investigators. WV– INBRE focuses on chronic diseases such as cancer, diabetes, cardiovascular disease, and obesity. NIH also supports several programs focused on cancer, cardiovascular disease, and other chronic diseases affecting rural communities. For example, Screen to Save 5 is a colorectal cancer outreach and screening initiative aimed at increasing cancer screening rates for individuals in rural communities, particularly among racial and ethnic minority populations. The Heart Truth Community Action Program 6 initiative engages and empowers women to learn about risk factors for heart disease and steps they can take to live a heart-healthy life. The Strong Hearts, Healthy Communities 7 program works to reduce rural disparities in cardiovascular disease through community-based interventions (e.g., nutrition and physical activity classes) in ten underserved, rural towns. NIH’s Exploratory Center of Excellence on Health Disparities in Rural Populations 8 works to train faculty interested in rural health, promote community health agency partnerships, and examine health promotion programs to improve diabetes, hypertension, and prostate cancer outcomes in rural communities. NIH’s Healthcare for Rural Populations Research Initiative 9 aims to enhance the resources and infrastructure underlying healthcare access and quality for rural populations, including methods for improving oral health in rural school- based cavity prevention programs. Recognizing the unique needs of Appalachian communities, NIH partnered with the Appalachian Regional Commission (ARC),10 to support a series of 1 year service planning grants aimed at combating the increase in mortality from injection opioid use among rural communities. A NIH-supported study on coronary artery disease (CAD) in central Appalachia,11 found that more than 98 percent of participants had one or more risk factors for the disease. The findings also suggest that the use of computerized tomography (CT) scans to detect hardening of the coronary arteries might be helpful in identifying people at highest risk of CAD, which is important in ensuring individuals get preventative care. Rural health is an important area of research for NIH in addressing the burden of health disparities. Continued collaborations and partnerships with scientists and organizations from rural communities, such as West Virginia, will help expand NIH’s reach in rural communities and support our work to combat rural health disparities.

INSTITUTIONAL DEVELOPMENT AWARDS Question. The Institutional Development Award (NIH IDeA) program has been critical for West Virginia and West Virginia University. It brings NIH funding to states that have historically not applied for as many NIH grants and helps to build the medical research programs in the state. West Virginia currently only receives about $2 million in NIH grant funding, but through the IDeA program, we have strengthened our investments and expanded access to medical research to the rural and underserved areas in my state. In fact, WVU estimates that the economic benefit of these grants in West Virginia is $180 million. That is why I have strongly supported funding for this program at NIH and why I am disturbed to see that the President’s budget would cut funding for the National Institute of General Medical Sciences—which houses this program—by more than $400 million. In addition, the fiscal year 2018 the budget request does not appear to specify a funding level for the NIH Institutional Development Award program. It was funded at a level of $333.4 million in the fiscal year 2017 Omnibus Appropriations bill. I believe that we should be expanding this program so that states like West Vir- ginia can have the opportunity to build their medical research programs.

5 Https://www.cancer.gov/about-nci/organization/crchd/blog/2016/screentosave-launch. 6 Https://www.nhlbi.nih.gov/health/educational/hearttruth/partners/grantees.htm. 7 Https://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=9245732&icde=34114853& ddparam=&ddvalue=&ddsub=&cr= 1&csb=default&cs=ASC&pball=. 8 Https://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=9023348&icde=35084347& ddparam=&ddvalue=&ddsub=&cr= 1&csb=default&cs=ASC&pball=. 9 Https://www.nimhd.nih.gov/programs/extramural/resource-related.html#healthcare-rural. 10 Https://www.drugabuse.gov/news-events/news-releases/2016/02/nida-arc-announce-funding- opportunity-research-projects-to- address-opioid-injection-use-its. 11 Http://www.sciencedirect.com/science/article/pii/S0091743516300585. 63

Dr. Collins, what impact will the cuts to NIH have on this important program? Can you tell me why this program was not specifically listed in the budget and what the recommended fiscal year 2018 funding level is? And can you please speak to the importance of funding research at a wide variety of institutions, particularly those in poorer, rural states? Answer. The National Institutes of Health (NIH) believes initiatives like the Insti- tutional Development Award (IDeA) program administered by the National Institute of General Medical Sciences (NIGMS) are important in ensuring that jurisdictions and institutions across the United States are afforded the opportunity to become active and significant contributors to this country’s biomedical research efforts. The IDeA Program will continue to fulfill its congressional mandate of broadening the geographic distribution of NIH funding for biomedical research and enhancing the competitiveness of investigators at institutions located in states like West Vir- ginia. NIH anticipates that West Virginia investigators will continue to submit proposals and will be in open competition with investigators from other IDeA states for support for new IDeA awards. Funding research at a wide variety of institutions is extremely important to ensure that a rich diversity of scientific and geographical perspectives are represented and that all available human capital is deployed in the critical work of addressing vital biomedical research questions and pressing health problems. Oftentimes, local investigators are the best equipped and experienced to conduct research on local health concerns. In West Virginia for instance, the IDeA–CTR award has been focused on the health concerns of the Appalachian population. Further, NIH strongly believes that scientific discoveries can arise anywhere that there are well-trained and determined investigators working in adequately resourced environments. En- suring that all jurisdictions and institutions across the United States are afforded the opportunity to become active and significant contributors to this country’s biomedical research efforts will increase the likelihood of breakthroughs in science and medicine.

FUNDING FOR RESEARCH INSTITUTIONS Question. The Administration’s fiscal year 2018 budget request recommends cutting reimbursements that fund university-based NIH research, suggesting that the government could save billions without hurting research. I understand that the Association of American Medical Colleges, the Association of American Universities, the Council on Government Relations, the Association of Public and Land-grant Universities, the Association of Independent Research Insti- tutes, and the American Council on Education have expressed their united deep concerns about this proposal. They report that universities would face billions in additional expenses for staff- ing, utilities, facilities, with many discontinuing research because it would be out- right unaffordable. Dr. Collins, as the long-standing Director of NIH, what is your expert view about the short and long-term impacts of scaling back indirect reimbursements to universities? Would this make it harder for institutions like WVU and Marshall in my state to be able to afford to do critical medical research? Answer. The effect on grantees will vary by institution, depending on the current indirect cost rate and a variety of other factors. The impact will be greater on institutions that have a higher percentage of NIH funding compared to total funding, or a lower ability to cover indirect costs from other sources (e.g., donations, endowment income, state government, tuition). The Department continues to work on specific details of the NIH indirect cost policy for fiscal year 2018 and will assess the impact on grantees once the policy is finalized.

QUESTIONS SUBMITTED BY SENATOR PATRICK LEAHY

GENERAL FUNDING Question. The National Institutes of Health (NIH) is one of the Nation’s most critical resources for the promotion and preservation of public health. Through groundbreaking biomedical research and clinical trials, the NIH offers the promise of hope to sick patients and their families. The NIH is also instrumental in pro- moting workforce development at institutions across the country in order to continue the important work of scientists for generations to come. Without strong, continuous resources for biomedical research, our nation’s researchers will lack the capacity to wage critical projects in their fields. Scientific knowledge changes con- 64 stantly, and biomedical research must parallel these advancements. We cannot turn these valuable research efforts on and off; our commitment must be sustained. Unfortunately, the administration’s proposed budget for fiscal year 2018 imposes a 21 percent cut to the NIH—a reduction of $7.2 billion compared to the fiscal year 2017 enacted level—undermining the critical work of each and every one of its institutes and centers, as well as the thousands of institutions across the country that rely on NIH dollars. The administration claims that the NIH is currently plagued by ‘‘unnecessary expenses,’’ but this is simply untrue The billions of dollars in cuts proposed by the administration target critical biomedical research labs, projects, equipment, personnel, and clinical trials, all of which bring us closer to combatting, controlling, and eradicating diseases. Please specifically describe the impacts of the administration’s proposed cuts to the NIH, especially on direct research and clinical trials for patients suffering from disease. Answer. The Budget presents an opportunity for HHS to reexamine how to optimize Federal investments in a way that best serves the American people. In addition to requested changes in the reimbursement of indirect costs for NIH grants, Federal research requirements for grantees will be streamlined to reduce grantee burden through targeted approaches as proposed by NIH. HHS is working with NIH to identify strategies to streamline processes and increase efficiencies. These targeted policies aim to reduce the time and expenses that grantees must currently spend to comply with Federal grant requirements.

INDIRECT COSTS Question. Under current law, institutions that receive Federal NIH grants enter an agreement with the agency to use a proportion of that funding for indirect costs, such as the cost of labs and equipment, researchers, facility maintenance, and utilities. These funds are critical to ‘‘keeping the lights on,’’ and ensure that the biomedical research intended by the grants can actually be carried out. In my home state of Vermont, our largest research institution, the University of Vermont (UVM), would lose more than half of what they are currently allotted for indirect costs, meaning biomedical research would ultimately cease to function at UVM, costing jobs and future medical breakthroughs. How does the administration’s proposal to cap indirect costs at 10 percent allow smaller institutions to contribute to lifesaving biomedical research? Answer. The effect on grantees will vary by institution, depending on the current indirect cost rate and a variety of other factors. The impact will be greater on institutions that have a higher percentage of NIH funding compared to total funding, or a lower ability to cover indirect costs from other sources (e.g., donations, endowment income, state government, tuition). The Department continues to work on specific details of the NIH indirect cost policy for fiscal year 2018 and will assess the impact on grantees once the policy is finalized. Question. How do you believe that institutions will be able to compensate for the millions of dollars lost as a result of this provision through fundraising alone? Answer. NIH is working with the Department to streamline process and increase efficiencies in order to reduce grantee burden. These targeted policies aim to reduce the time and expenses that grantees must currently spend to comply with Federal grant requirements, thus lowering grantees’ indirect costs and mitigating the impact of lower reimbursements.

INSTITUTIONAL DEVELOPMENT AWARD (IDEA) Question. The IDeA program, operated by the National Institute of General Med- ical Sciences (NIGMS) at the National Institutes of Health (NIH) has long been a fundamental source of support for institutions that participate in biomedical research. With a focus on health-related research, specifically in rural and medically underserved communities, IDeA is critical in the goal of supporting researchers’ work to uncover lifesaving methods to combatting disease. In Vermont, IDeA awards have contributed to advances in genetic research, new medical technologies, and vaccine and drug developments. With the help of IDeA awards, the University of Vermont, our state’s largest research institution, developed the Vermont Genetics Network, the Vermont Center for Immunology and Infectious Diseases, the Vermont Center for Neuroscience, and the Vermont Center on Behavior and Health. IDeA grants have also expanded the employment of STEM professionals in several other universities across the state. These institutes have contributed to some of the world’s most groundbreaking medical understanding on how to cure lung and heart disease and on understanding the effect of brain disorders on learning and development. 65

The administration’s proposed cuts to the NIH, including more than $300 million to NIGMS will undoubtedly place pressure on the IDeA by reducing the amount of grant dollars awarded for institutional biomedical research. This means less opportunities for our nation’s institutions to develop lifesaving treatments to debilitating disease. Given the impact of cuts to NIGMS on the IDeA, how does the administration suggest institutions continue to operate biomedical research centers and labs moving forward? Answer. NIH is committed to supporting the Institutional Development Award (IDeA) program to further the goal of broadening the geographic distribution of NIH funding for biomedical research and enhancing the competitiveness of investigators at institutions located in states like Vermont. For example, in fiscal year 2016, the IDeA Program supported the following awards in Vermont totaling close to $9 million: 1 IDeA Network of Biomedical Research Excellence (INBRE), 3 Centers of Bio- medical Research Excellence (COBREs), and 5 Co-funded awards. In fiscal year 2017, an IDeA Program Infrastructure for Clinical and Translational Research (IDeA–CTR) award is being made to a collaborative network that involves Maine, Vermont, and New Hampshire called The Northern New England Clinical and Translational Research Network. NIH anticipates that Vermont investigators will continue to submit proposals to the different IDeA initiatives and will be in open competition with investigators from other IDeA states for support for new IDeA awards.

QUESTIONS SUBMITTED TO DOUGLAS LOWY, M.D.

QUESTIONS SUBMITTED BY SENATOR PATTY MURRAY

NCI

THE IMPACT OF FUNDING CUTS ON SELECT DISEASES—CANCER Question. Dr. Lowy, I see the budget proposes to reduce cancer research by 22 percent, or more than $1.3 billion. The research community has been making tremendous strides in the treatment of many cancers in recent years. What would a reduction on this scale—far more than a billion dollars—mean for these efforts and future progress? Answer. The proposed budget reduction for fiscal year 2018 would require the Na- tional Cancer Institute (NCI) to make additional strategic choices to prioritize how funding is allocated for NCI research and training programs. During fiscal year 2018 NCI would minimize new program commitments and give greatest priority to the most promising opportunities from our existing portfolio of research.

QUESTIONS SUBMITTED TO GARY GIBBONS, M.D.

QUESTIONS SUBMITTED BY SENATOR ROY BLUNT

HEART VALVE DISEASE Question. A recent survey from the Alliance for Aging Research found that three out of four adults know little to nothing about valve disease. Heart valve disease also affects the very young—babies can be born with heart valve problems that usually develop sooner or later into heart valve disease. Nearly 600 newborns and infants under the age of one die each year from congenital heart valve disease. Dr. Gibbons, what has the NHLBI done to address heart valve disease, and where do you believe that research gaps remain? Answer. Heart valve disease is a complex group of disorders that represents an important public health problem. It affects approximately five million people in the Unites States each year. Although it is much more prevalent among older adults, heart valve disease can also be present at birth, affecting children from an early age. National Heart, Lung, and Blood (NHLBI) funded research helped pioneer the development of open heart surgeries for valve repair and replacement, and has paved the way for many of the non-surgical procedures available today, such as transcatheter aortic valve replacement (TAVR). While significant progress has been made, more research is needed to improve our understanding of these disorders and how to treat them. 66

To determine the underlying factors that lead to heart valve disorders, the NHLBI supports an extensive research portfolio, including our Bench to Bassinet program, which specifically focuses on how the heart develops and how congenital heart defects are formed. Researchers supported through the program have found several hundred genes that, when mutated, may lead to congenital heart disease, including valve defects. Identification of these genes and further study of their functions is helping us unravel the causes of these disorders. NHLBI also supports the development and use of innovative new imaging technologies to gain better insights into the causes, detection, and prognosis of heart valve disease. Additionally, NHLBI continues to support research to understand why valves de- generate as people age, and to develop more targeted interventions. This includes research on the risks and benefits from surgical procedures and non-invasive treatments such as TAVR, so that patients and doctors can make informed decisions about a patient’s treatment options. NHLBI’s Cardiothoracic Surgical Trials Network (CSTN) provides the infrastructure to develop, coordinate, and conduct multiple collaborative proof-of-concept studies and interventional protocols to improve cardiovascular disease outcomes and is yielding useful information for treating valve disease in distinct patient populations. Just this year, the American College of Cardiology/American Heart Association used CSTN findings to update their guidelines for management of valvular heart disease to recommend that patients with chronic severe ischemic mitral valve leakage (regurgitation) have their mitral valve replaced, rather than repaired during coronary artery bypass grafting. For patients with moderate ischemic mitral regurgitation, CTSN has found similar outcomes whether the patient had surgery to replace the leaky valve or repair it. These types of studies are providing patients with more personalized treatment options.

QUESTIONS SUBMITTED TO ANTHONY FAUCI, M.D.

QUESTIONS SUBMITTED BY SENATOR JOHN KENNEDY

ZIKA Question. Dr. Fauci, it was great meeting with you a couple weeks ago at the NIH. I understand that vaccine development for Zika is underway and that the Vac- cine Research Center developed a DNA vaccine candidate that is moving onto the next stage of testing. I read an article in which you stated that while this stage of testing is fully funded, it is unclear there will be funding for the next phase. Are you worried that a $838 million cut to the institute will affect the timeline for vaccine development? Answer. The National Institute of Allergy and Infectious Diseases (NIAID) currently supports research on the Zika virus, including vaccine development and testing, utilizing the $152 million in supplemental funding provided by the Zika Re- sponse and Preparedness Appropriations Act of 2016 (Public Law No. 114–223). NIAID anticipates these funds will be sufficient to support Zika- related activities currently planned through fiscal year 2017. NIAID is supporting the development of several leading Zika vaccine candidates, including the NIAID Vaccine Research Center’s DNA-based vaccine candidate. NIAID recently launched a multi-site Phase II/IIb clinical trial of the DNA-based vaccine candidate in March 2017 following encouraging results in Phase I testing. This Phase II/IIb trial will further evaluate whether the experimental vaccine is safe and able to stimulate an adequate immune response, and importantly whether it can prevent disease in areas with ongoing mosquito-borne Zika virus transmission. The study is expected to conclude in 2019, although the exact timing will depend on the intensity of Zika virus transmission and the efficacy of the vaccine candidate. A low level of Zika transmission may lengthen the amount of time required to obtain sufficient efficacy data from the clinical trial. NIAID remains committed to further development and testing of Zika vaccine candidates.

QUESTIONS SUBMITTED BY SENATOR PATTY MURRAY

THE IMPACT OF FUNDING CUTS ON SELECT DISEASES—ZOONOTIC DISEASES Question. Dr. Fauci, at a time when we’re experiencing an increasing threat from zoonotic diseases, the budget proposes to cut research on infectious diseases by almost 24 percent. What areas of research are likely to be most affected by a reduction of this scale? 67

How will flu research be affected by a 21 percent cut to research efforts there? Answer. The National Institute of Allergy and Infectious Diseases (NIAID) has a dual mandate to pursue a robust research portfolio in the areas of microbiology, infectious diseases, immunology, and immune-mediated disorders, as well as to quickly launch a research response to newly emerging and re-emerging infectious diseases, including zoonotic diseases. This dual mandate has been particularly evident in recent years as NIAID has accelerated research to address the unprecedented Ebola and Zika virus outbreaks. NIAID will continue to prioritize efforts to address the perpetual challenge of emerging and re-emerging infectious diseases, such as other recent zoonotic disease outbreaks of chikungunya virus and yellow fever virus; and potential new outbreaks from animal, arthropod, or environmental sources. NIAID research supports preparedness for pandemic influenza, including the potential for the spread of emerging strains of avian influenza, such as an avian H7N9 influenza virus strain that first emerged to cause sporadic infections in humans in China in 2013. NIAID is conducting and supporting preclinical and clinical studies on various investigational pandemic influenza vaccines. Further human clinical trials supported by NIAID are planned for 2017. Vaccine development to protect against other influenza subtypes with pandemic potential also is underway. In addition, NIAID’s comprehensive influenza research program aims to develop a ‘‘universal’’ influenza vaccine, or a vaccine that provides robust, long-lasting protection against multiple strains of influenza. Such a vaccine could eliminate the need to update and administer the seasonal influenza vaccine each year and could provide protection against newly emerging influenza strains with pandemic potential. NIAID’s support for basic, preclinical, and clinical research on influenza that informs the design of new and improved influenza countermeasures will remain a priority.

THE ROLE OF THE FOGARTY INTERNATIONAL CENTER Question. I was troubled to see that the budget fails to explain why the Adminis- tration is proposing to eliminate the Fogarty International Center, which over the years has shown itself to be a modest but wise investment. Dr. Fauci, what role did Fogarty graduates play in containing the Ebola outbreak 3 years ago? How does Fogarty support our efforts to contain pandemics at their origin, before they can spread to the United States? Answer. The Fogarty International Center (FIC) plays an important role in global health by supporting the training and early research endeavors of international research professionals. To date, FIC grants have enabled foreign institutions and their U.S. academic partners to create a cadre of more than 6000 trainee alumni throughout the world. Trained Fogarty program graduates drive local efforts to detect and address pandemics at their point of origin, contain outbreaks and minimize their impact, and they are equipped to conduct high-quality basic, clinical, and applied research. Fogarty program graduates continue to have access to the technical advice and support of Fogarty and NIH. For example, during the 2014–2016 Ebola outbreak in West Africa, Mali quickly identified and contained the cases thereby preventing the spread of Ebola around the country. This capacity was in place in part because of Fogarty’s longstanding training programs. In response to the 2014 Ebola virus outbreak FIC designed and initiated the ‘‘Emerging Epidemic Virus Research Training for West African Countries with Widespread Transmission of Ebola’’ program. This program provides grants to U.S. and African institutions to foster research training focused on emerging viral epidemics.

UNIVERSAL FLU Question. Dr. Fauci, like you I am very excited about the prospect of one day having an influenza vaccine that is able to cover all strains of flu. The thought of no longer needing to predict the strain of flu that will circulate each year will save us countless dollars and lives. However, having talked to experts like you I know that this next generation flu vaccine is years away from mass production and use, and until then we are going to have to continue to work with the technologies we have to protect the American public during the annual flu season, which by the way the CDC reported kills as many as 50,000 Americans a year. Think about that, 50,000 Americans a year! Dr. Fauci, are we investing enough as a country on influenza research, testing and evaluating our nations influenza vaccine response capabilities to ensure an ade- 68 quate health defense for influenza in the short term before we are able to perfect the next generation flu vaccine? Answer. The National Institute of Allergy and Infectious Diseases (NIAID) has a longstanding commitment to basic, preclinical, and clinical research on influenza. This comprehensive program informs the design of new and improved influenza vaccines, diagnostic tools, and antiviral drugs to assist in our preparedness for both seasonal and pandemic influenza strains. In fiscal year 2016, NIH funding for influenza research was $263 million. NIH funding for influenza research is estimated to be $272 million in fiscal year 2017. The President’s budget requests $215 million for fiscal year 2018. NIAID supports efforts to gain a basic understanding of how influenza strains emerge, evolve, and infect animals and humans. NIAID’s Centers of Excellence for Influenza Research and Surveillance (CEIRS) Program is supporting domestic and international influenza researchers studying the factors that control influenza disease severity and the emergence and transmission of influenza viruses among animals. The CEIRS Program continually monitors cases of animal and human influenza worldwide to rapidly detect and characterize viruses that may have pandemic potential, such as the avian influenza strain H7N9. NIAID also is developing and testing the next generation of influenza therapeutics, including broad-spectrum antiviral drugs for multiple virus families, monoclonal antibodies, inhibitors of an influenza surface protein called neuraminidase, and influenza RNA polymerase inhibitors. NIAID supported initial Phase I clinical studies of peramivir, a novel neuraminidase inhibitor subsequently approved by the Food and Drug Administration to treat influenza infection in adults in certain circumstances. Three NIAID clinical trials are underway in high-risk populations to explore the safety and effectiveness of several influenza therapeutic approaches, including human plasma containing high levels of anti-influenza antibodies, concentrated immunoglobulin with high levels of anti-influenza antibodies, and a combination of three licensed antiviral drugs. Concerns over vaccine efficacy and the threat of avian influenza have highlighted the opportunity for considerable improvement in influenza vaccines. In response to the emergence of H7N9 avian influenza in China in the spring of 2013, the U.S. Department of Health and Human Services produced, tested with NIAID support, and stockpiled a vaccine for the virus. In 2017, global influenza surveillance identified changes in the circulating H7N9 virus, and researchers discovered that the stockpiled 2013 H7N9 vaccine is unlikely to provide adequate protection against the current H7N9 strains. An updated H7N9 vaccine is being produced and will be evaluated for safety and immunogenicity in clinical trials by the NIAID Vaccine and Treatment Evaluation Units (VTEUs) as soon as it becomes available. The change in the H7N9 virus observed in 2017 and the resulting effort to develop a new vaccine reminds us of the utility of a vaccine that could provide protection against multiple strains of seasonal and pandemic influenza virus. A ‘‘universal’’ influenza vaccine could reduce the need for new or updated vaccines due to changes in circulating influenza strains or emergence of novel viruses with pandemic potential. NIAID is supporting the development of several promising universal influenza vaccine candidates, including a broad-spectrum BiondVax vaccine anticipated to enter a Phase II clinical trial in a NIAID VTEU in 2017. NIAID also recently convened leading influenza experts to identify gaps in influenza research and draft a research agenda and strategic plan for the development of a universal influenza vaccine. NIAID remains committed to basic and clinical influenza research to inform the development of new rapid diagnostics, therapeutics, and vaccines. NIAID will continue to place a high priority on the development of a universal influenza vaccine to help address the challenge of pandemic and seasonal influenza viruses.

QUESTIONS SUBMITTED TO RICHARD HODES, M.D.

QUESTIONS SUBMITTED BY SENATOR JOE MANCHIN, III

MEDICAL RESEARCH CAN SAVE MONEY—ALZHEIMER’S Question. I am someone who is very concerned about the Federal debt, but I have always supported strong funding for NIH because it is an investment that saves lives, preserves America’s role as a global innovator, and has the potential to save a lot more money in the future if we’re able to reduce the costs of treating expensive diseases. 69

Alzheimer’s disease, for example, cost West Virginia’s Medicaid program $368 million in 2016 and this cost is expected to increase as the number of people with the disease increases. The Alzheimer’s Association estimates that the cost of caring for people with Alzheimer’s and dementia will rise from $236 billion to $1.1 trillion in 2050. In short, we can’t afford to not invest in medical research. That is why I share my colleagues concern about the President’s budget cuts of more than $7 billion to NIH overall and more than $700 million to the National In- stitute on Aging in particular relative to the funding that we included in the fiscal year 2017 Omnibus. Dr. Hodes, as the Director of the National Institute on Aging, can you please speak to the research that your agency is doing on Alzheimer’s disease? Do you believe that investments in this research now is a fiscally responsible choice given the astronomical costs that our country is likely to face as our nation ages? Answer. Recent and historic levels of investment in Alzheimer’s disease and related dementias have enabled the NIH to provide more robust support for researchers working toward a cure. Their progress has already been significant. NIH supported investigators have: —Helped map the brain’s innermost connections and the molecular fabric of Alz- heimer’s. —Deepened our understanding of metabolic changes at the heart of the disease. —Detected disease progression through neuroimaging and discovery of novel biomarkers. —Used new technologies, through unprecedented multidisciplinary collaborations, to make large data sets available with greater accuracy and speed to the research community. —Leveraged new investment in epidemiological research to increase our understanding of the complexity of variation across space and over time in disease incidence and prevalence, with the goal of identifying new clues for prevention. —Looked at health disparities in new ways, with studies of genetics and risk factors that may be contributing to higher dementia rates among certain groups. —Explored new digital technologies to help support caregivers and patients, in a next generation of care strategies. There can be no doubt that the financial costs associated with Alzheimer’s disease are significant and can be devastating to affected families, as well as to society as a whole. Recent numbers published by the Alzheimer’s Association indicate: —Total payments in 2017 for all individuals with Alzheimer’s or other dementias are estimated at $259 billion. —Medicare and Medicaid are expected to cover $175 billion, or 67 percent, of the total healthcare and long-term care payments for people with Alzheimer’s or other dementias. —Out-of-pocket spending is expected to be $56 billion. Total annual payments for healthcare, long-term care and hospice care for people with Alzheimer’s or other dementias are projected to increase from $259 billion in 2017 to more than $1.1 trillion in 2050. This dramatic rise includes more than four- fold increases both in government spending under Medicare and Medicaid and in out-of-pocket spending. Furthermore, NIH-supported investigators recently found that healthcare expenditures among persons with dementia are substantially larger than those for other diseases, and many of the expenses are uncovered (uninsured). In their study, they reviewed data from the Health and Retirement Study on approximately 1,700 Amer- icans in the 5 years prior to death, and found that the average total cost of healthcare per decedent with dementia ($287,000) was significantly greater than that of those who died of heart disease ($175,000), cancer ($173,000), or other causes ($197,000). Although Medicare expenditures were similar across groups, average out-of-pocket spending for patients with dementia was 81 percent higher than that for patients without dementia; a similar pattern held for informal care. Given the data on the economic burden of Alzheimer’s disease, investment in research to better understand, treat, and cure this disease is vital. Previous research has suggested that small delays in disease onset would have a significant effect on disease burden, including the economic burden of disease, and NIA is currently supporting a project that will extend these results by assessing life- time risks of developing Alzheimer’s disease based on newly available biomarker screening tests, obtaining U.S. projections of numbers of persons with preclinical disease, and evaluating the impact of potential interventions on these projections. NIA is continuing to support research on the social and economic implications of Alzheimer’s disease, particularly as the U.S. population continues to age. For example, the National Health and Aging Trends Study (NHATS) and its companion study, the National Study of Caregiving (NSOC), are frequently used by scientists 70 to investigate the role of dementia in caregiving, including the economic stresses faced by caregivers. In addition, the NIA-supported Health and Retirement Study includes a new harmonized cognitive assessment protocol (HCAP) that will allow the more efficient re-estimation of dementia prevalence in the United States and allow us to investigate racial, ethnic, and gender disparities in dementia. These important studies will continue through fiscal year 2018.

QUESTIONS SUBMITTED TO NORA VOLKOW, M.D.

QUESTIONS SUBMITTED BY SENATOR ROY BLUNT

OPIOID ABUSE RESEARCH Question. Dr. Volkow, there has been a significant increase in prescription drug abuse over the last several years. Can you discuss the public/private partnership announced last month with the pharmaceutical industry to address this crisis and what you hope comes from this partnership? Answer. The dramatic increase in prescription drug abuse and related overdose deaths in recent years calls for innovative scientific solutions. As part of a government-wide effort to address this crisis and the Department’s Opioid Strategy, the National Institutes of Health (NIH) is launching a public- private collaborative research initiative to develop new, safe, and effective strategies to prevent and treat pain, opioid addiction, and overdose reversal and prevention. The goal is to cut in half the time it takes to develop new therapeutics. The initial plan for this initiative was recently described by Dr. Collins and National Institute on Drug Abuse Director Nora D. Volkow, M.D., in the New England Journal of Medicine.12 Three major areas for advancement have been targeted: (1) safe, more effective, and non- addictive strategies for chronic pain management to prevent abuse of and addiction to prescription opioids; (2) new and innovative opioid addiction treatments to reduce drug use and support recovery; and (3) overdose reversal and prevention interventions to reduce mortality and promote access to treatment. The public-private partnership is modeled on recent successful partnerships, including the Accel- erating Medicine Partnership, that demonstrate the power of collaborating across sectors to target various conditions, including Alzheimer’s disease, diabetes, rheumatoid arthritis/lupus, Parkinson’s disease, and cancer. To identify the scientific strategies with the greatest potential for solutions to the opioid problem, NIH recently brought together innovative experts from government, industry, and academia for a series of three cutting-edge science meetings. Meeting summaries will be available at: Https://www.nih.gov/opioid-crisis. Key Themes from Meeting #1: Medications Development for Opioid Use Disorders and Overdose Prevention & Reversal, June 5, 2017 —Families need and want the scientific and healthcare communities to have the same level of focus and urgency for developing a cure for addiction as they would for any disease that is taking over 50,000 lives each year. —Lack of treatment infrastructure for medications is a significant challenge, including reimbursement for medications for opioid use disorders. —Incentives are needed to encourage pharmaceutical and biotechnology company investment. —There is a need for better surveillance on overdoses and the use of naloxone to reverse them. —Technology can help to treat disorders and prevent overdose. Key Themes from Meeting #2: Development of Safe, Effective, Non-Addictive Pain Treatments: June 16, 2017 —There has been significant progress in target identification and structure based drug development; there are many therapeutics in the pipeline. —There is a need to reset expectations of what is achievable with pain treatment. —Heterogeneity among patients with chronic pain poses significant challenges in clinical trials; objective biomarkers are needed to improve the speed and efficiency of clinical trials. —More basic research is needed on a diverse range of pain conditions, including better animal models. —Advances in neuroscience technologies are poised to accelerate development of treatments for pain.

12 Volkow, N. D. and F. S. Collins (2017). ‘‘The Role of Science in Addressing the Opioid Cri- sis.’’ New England Journal of Medicine. 71

—There is significant potential value in coordinating across both pharmaceutical and academic research: (a) significant overlap in the targets being pursued by different companies, and (b) common technical challenges that everyone is working on independently. Key Themes from Meeting #3: Understanding the Biological Mechanisms of Pain, July 7, 2017 —Linkages between industry and academic researchers can promote the effective use of limited resources. —Pain research would benefit from leveraging available neuroscience technologies and encouraging more neuroscientists to enter the pain field. —Pain processing is complex throughout the brain and periphery. There is a need for multidisciplinary efforts to understand pain at the molecular, cellular, circuit, and system levels. —Standardized, objective biomarkers are needed that will predict the response to treatment in animal models and in humans. —Extensive patient phenotyping is needed to develop objective biomarkers which will enable precision medicine approaches to more effectively treat each patient’s pain, as well as the factors that impact the patient’s experience of pain. —There is a need for objective screens based on the neurobiology of pain to accelerate the drug development process. —There are research gaps regarding the prolonged effects of chronic pain, long term impacts of treatment (e.g. hyperalgesia due to chronic opioid use), and the transition from acute to chronic pain. An NIH action plan is currently being formulated. Promising potential action steps include: —Develop new formulations, combinations, and means to deliver existing medications to increase treatment effectiveness and support long-term recovery. —Medications for opioid addiction (e.g. extended release buprenorphine and naltrexone) —Overdose prevention and reversal (e.g. increased potency naloxone for fentanyl and carfentanil overdoses) —New technologies (e.g. implants, pumps, neural stimulation) to enhance treatments for pain and opioid addiction, and to prevent/reverse overdose. —Accelerate development of new non-addictive pain therapies through: —Enhanced data and information sharing collaborative between industry partners and with academic scientists —Develop and test a standardized platform for drug-target validation —Identify and validate biomarkers for pain and treatment response —Nociometer/Pain-meter Development and Testing —Rapidly bring to market novel non addictive drugs and devices to treat pain —Pilot clinical research networks to: —Measure strategies to improve treatment effectiveness for pain, opioid addiction, and overdose prevention/reversal in real-world settings. —Test new therapies for pain management, especially in high-impact, well defined pain populations —Understand the transition from acute to chronic pain Question. What are the barriers to opioid research and particularly conducting research on Schedule 1 drugs? Answer. The primary challenges to more research on opioids and treatments for opioid addiction are the regulatory barriers associated with conducting research on Scheduled drugs. Research on Scheduled drugs is subject to the regulatory oversight in the Controlled Substances Act (CSA). Most prescription opioids—such as oxycodone, hydrocodone, and fentanyl—are Schedule II controlled substances. Heroin and many new potent synthetic opioids (acryl fentanyl, etc.) are Schedule I drugs. The process for conducting research using Schedule I controlled substances includes: —For all research (involving animal or human subjects), the researcher must obtain a DEA registration for each Schedule I controlled substance. Some states have separate registration requirements that often need to be completed se- quentially.13,14 Obtaining a DEA registration includes: —Completing and submitting a DEA application for each Schedule I drug: —The applicable fee is currently $244 for a 1 year registration.

13 Https://www.txdps.state.tx.us/Internetforms/Forms/NAR–77–78.pdf. 14 Http://www.ct.gov/DCP/cwp/view.asp?a=1622&Q=500858&PM=1. 72

—The application includes the research protocol and the amount of drug needed for the study. —A DEA investigator conducts a site visit to ensure that diversion controls are in place. —Schedule I substances must be stored in a safe or steel cabinet of substantial construction. —If the safe or cabinet is less than 750 lbs., it must be mounted or secured to something of substantial construction (e.g., bolted to a wall or the floor, or the base imbedded in concrete). —The safe/cabinet should have an inner and outer door with the locks for each door keyed differently. —The DEA sends the research protocol to FDA for review. Once received, FDA has 30 days to review and respond to DEA about protocols involving human subjects and 21 days to respond for protocols involving non-human research. However, if more information is needed from the researcher, the DEA investigator will contact the researcher which can extend the time. —Once the DEA requirements have been satisfied, the researcher receives a DEA registration number; Registration must be renewed every year. —A local IRB approval must accompany the application for registration. —When the above steps have been completed, if the drug is not commercially available, it must be obtained through the NIDA Drug Supply Program (DSP). —For non-NIH-funded basic research not involving human subjects—research that has not undergone a Federal grant review or Investigational New Drug (IND) application review—the research protocol is reviewed for scientific merit by a minimum of two non-government scientists, identified by the DSP, with expertise in the research topic. Investigators must submit a detailed research protocol including: —The specific aims and goals of proposed study; —The experimental design, including number of experiments and experimental subjects and the dosages or concentration of drugs; —Justification of quantities of drug(s) requested; —A document demonstrating that the research is approved by the Animal Care & Use Committee and that adequate care in conducting animal research will be exercised (if applicable); and —Documentation of local IRB approval. These regulatory and administrative processes around Schedule I drugs pose challenges for researchers and disincentivize research on these substances. Researchers report to NIDA that the paperwork and delays (often a year or more before a proposed study can be started) are a disincentive to studying Schedule I substances. Schedule II substances also have high abuse liability but have an accepted medical value. They can be as or even more dangerous than certain Schedule I substances, yet the process for conducting research on Schedule II substances is significantly less burdensome. While the diversion control requirements (e.g., storage, access controls) are equivalent for Schedule I and II substances, a single DEA registration can be obtained authorizing research on any Schedule II substances, and no protocol review is required. Question. Has your Institute researched whether there are factors that predispose or, conversely, protect against opioid abuse and addiction? Answer. Prevention is a critical component of efforts to combat drug use and addiction. Research has identified many risk and protective factors that influence the likelihood that a person will abuse substances and develop an addiction, including both genetic and environmental influences. NIDA-funded research has identified several gene variants that influence how an individual’s body processes and responds to opioid drugs. These include variations in the mu- opioid receptor-1 gene (OPRM1) and the enzyme cytochrome P450 2D6 (CYP2D6). Other genetic factors have been linked to differences in pain perception and in response to opioid pain relievers, which is directly relevant to the problem of opioid addiction since by some estimates up to a third of patients chronically-prescribed opioids for pain may be dependent or addicted.15 An approach to pain treatment that seeks to integrate genetic findings is ‘‘pharmacokinomics,’’ in which information about pharmacogenetics (genetic differences in the response to drugs) and pharmacokinetics (how the body processes a

15 Juurlink, D.N., Dhalla, I.A. Dependence and addiction during chronic opioid therapy. J. Med. Toxicol., 8 (4), pp. 393–399 (2012). 73 drug) is combined to optimize opioid dosing to minimize addiction risk.16 These methods are still in the developmental phase but offer the potential to personalize pain medicine with an eye toward addiction prevention. Apart from individual genetic and biological risk factors, other factors affect risk of substance abuse, such as: present or prior history of addiction (e.g., alcohol or nic- otine); developmental stage (youth are more vulnerable to addiction); mental illness; and a myriad of environmental factors. Specific environmental factors include: social stressors; patterns of drug use; unemployment and lack of economic opportunities; substance use or conflict in the family; lack of adequate parental supervision; peers who use drugs; and availability of drugs in the community. Individuals in rural areas are more likely to abuse opioids, likely due to a range of factors, such as increased opioid availability, economic depression, and wider social networks facilitating diversion.17 Another significant risk factor is early initiation of any substance use. Individuals who receive an opioid prescription during their teens are more likely to abuse opioids as adults.18 Research has contributed to the development of numerous prevention programs that have been shown to reduce opioid abuse and addiction. The 2016 Surgeon Gen- eral’s Report on Alcohol, Drugs, and Health provides a comprehensive overview of evidence-based prevention interventions.19

QUESTIONS SUBMITTED BY SENATOR SHELLEY MOORE CAPITO

OPIOID ADDICTION Question. The National Institute on Drug Abuse has conducted invaluable research that has contributed to the development opioid addiction treatments including Probuphine (which is implanted in the arm and provides a steady, continuous levels of buprenorphine) and new formulations of naloxone designed to combat fentanyl overdoses. However, the administration’s proposed budget recommends reducing the funding for NIDA by $210 million and other anti- addiction resources at NIH including the National Institute of Mental Health by $400 million. Can you address how these reductions would impact the successful implementation of NIH’s goals of capitalizing on scientific advances to combat opioid addiction and reducing the impact of this epidemic within our communities? Answer. The opioid overdose epidemic is a serious, ongoing, and rapidly evolving public health crisis. Over 33,000 Americans died from opioid overdose in 2015 alone. Millions of Americans suffer from opioid abuse and addiction, and millions more suffer from chronic pain. The urgency and scale of this crisis calls for innovative scientific solutions and developing them is a top priority for the Department of Health and Human Services, including NIH and NIDA. We will continue to prioritize research to develop solutions for this crisis and strive to accelerate progress. As part of a government-wide effort to address this crisis and under the HHS Opioid Strategy, NIH is launching a public-private collaborative research initiative on pain and opioid addiction. The initial plan for this initiative was recently described by Dr. Collins and Dr. Volkow, M.D., in the New England Journal of Medi- cine and includes three major areas for advancement: (1) safe, more effective, and non-addictive strategies for chronic pain management to prevent misuse of and addiction to prescription opioids; (2) new and innovative opioid addiction treatments to reduce drug use and support recovery; and (3) overdose reversal and prevention interventions to reduce mortality and promote access to treatment. To identify the scientific strategies with the greatest potential for solutions to the opioid problem, NIH recently brought together innovative experts from government (including FDA and CMS), industry, and academia for a series of three cutting-edge science meetings. Through these meetings, NIH has begun to formulate new approaches and recruit additional expertise with the aim of developing new safe and effective therapeutics for chronic pain, opioid addiction, and overdose in half the

16 Linares, O. A., Daly, D., Stefanovski, D. & Boston, R. C. The CYP2D6 gene determines oxycodone’s phenotype-specific addictive potential: implications for addiction prevention and treatment. Med. Hypotheses 82, 390—394 (2014). 17 Keyes KM, Cerda´ M, Brady JE, Havens JR, Galea S. Understanding the Rural—Urban Dif- ferences in Nonmedical Prescription Opioid Use and Abuse in the United States. American Jour- nal of Public Health. 2014;104(2):e52-e59. doi:10.2105/AJPH.2013.301709. 18 McCabe S, West B, Veliz P, et al. Trends in medical and nonmedical use of prescription opioids among US adolescents: 1976–2015. Pediatrics. 2016;139(4):e20162387. 19 Substance Abuse and Mental Health Services Administration (US); Office of the Surgeon General (US). Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health [Internet]. Washington (DC): US Department of Health and Human Services; 2016 Nov. Available from: Https://www.ncbi.nlm.nih.gov/books/NBK424857/. 74 time it currently takes. With the conclusion of the three scientific meetings, plans are underway to synthesize key themes discussed and suggestions provided into a draft strategy. The strategy will include major goals of the initiative, action steps, key partners, deliverables, timeline, and resources (in-kind and financial costs) to fully carry out the proposed action steps. Input on the final draft will be solicited from participants including Federal partners as well as other relevant stakeholders. Upon final approval of the plan, it will be posted on the NIH website at: Https:// www.nih.gov/opioid-crisis. Promising potential action steps include: —Develop new formulations, combinations, and means to deliver existing medications to increase treatment effectiveness and support long-term recovery. —Medications for opioid addiction (e.g. extended release buprenorphine and naltrexone) —Overdose prevention and reversal (e.g. increased potency naloxone for fentanyl and carfentanil overdoses) —New technologies (e.g. implants, pumps, neural stimulation) to enhance treatments for pain and opioid addiction, and to prevent/reverse overdose. —Accelerate development of new non-addictive pain therapies through: —Enhanced data and information sharing collaborative between industry partners and with academic scientists —Develop and test a standardized platform for drug-target validation —Identify and validate biomarkers for pain and treatment response —Nociometer/Pain-meter Development and Testing —Rapidly bring to market novel non addictive drugs and devices to treat pain —Pilot clinical research networks to: —Evaluate strategies to improve treatment effectiveness for pain, opioid addiction, and overdose prevention/reversal in real-world settings —Test new therapies for pain management, especially in high-impact, well defined pain populations —Understand the transition from acute to chronic pain

OPIOID ADDICTION TREATMENT Question. The 21st Century Cures Act last December provided $1 billion in funding for opioid addiction treatment. Can you address how priority funding for a state like West Virginia is supporting successful state-based programs like those being implemented in Huntington? Additionally, what do you see as priorities this Committee should be considering to continue this important work? Answer. While the State Targeted Response to the Opioid Crisis Grants are administered through SAMHSA, NIH has a strong commitment to supporting research that builds the evidence base for successful strategies to expand access to medications for the treatment of opioid addiction. To this end, NIDA posted a Funding Op- portunity Announcement in April of 2017 to solicit applications for studies evaluating the impact of states’ efforts to address the opioid crisis using the funds author- ized under the 21st Century Cures Act.20 These projects will test the effects of novel approaches for providing medications for opioid addiction and the overdose reversal drug naloxone on health outcomes including illicit drug use, overdose, and addiction. Funded projects will be announced later in 2017, but possible areas of research include: —Opioid addiction medications provided in emergency departments, pharmacies, inpatient units, and other healthcare settings. —Telehealth approaches for providing opioid addiction medications in the general healthcare sector. —Models of care in the general health sector that provide a choice of opioid addiction medications to patients. —Continuity of care models for those receiving medications for opioid addiction. Models of care and delivery designed to expand the provision of opioid addiction medications in primary care including, but not limited to the following: —The Massachusetts Nurse Care Manager Model. —The Hub and Spoke Model. —The Echo Model. —Other evidence-based models.

20 National Institute on Drug Abuse. Expanding Medication Assisted Treatment for Opioid Use Disorders in the Context of the SAMHSA Opioid STR Grants (R21/R33). RFA–DA–18–005. Available at: Https://grants.nih.gov/grants/guide/rfa-files/RFA-DA-18-005.html. 75

—Models of naloxone delivery that offer the opportunity for linkage to medication- assisted treatment (MAT) after receipt of naloxone for overdose. —Provision of interim methadone or buprenorphine while patients are waiting for admission to comprehensive treatment programs. One ongoing area of concern for the committee’s consideration is the importance of treatment continuity in addressing opioid addiction. Discontinuing medications before the patient is ready poses significant risk for relapse and subsequent overdose. The 21st Century Cures funding is critical for helping states address the ongoing opioid epidemic, but many patients will need ongoing treatment. It is important to develop strategies to ensure that patients do not lose access to these medications and critical counseling and behavioral therapies.

MEDICATION-ASSISTED TREATMENT (MAT) Question. Ensuring access to treatment for opioid addiction is essential to revers- ing the number of overdose deaths and the overall opioid epidemic. Medication-As- sisted Treatment (MAT) plays an important role in this treatment. Current treatments such as methadone and buprenorphine—while effective in many cases—often require continued use for long periods of time, sometimes years, and daily maintenance. Is NIDA researching new methods of MATs which would address these issues? Answer. The urgency and scale of the opioid crisis necessitates innovative scientific solutions. As part of a government-wide effort to address this crisis and under the HHS Opioid Strategy, NIH is supplementing existing research efforts with a public-private collaborative research initiative on pain and opioid addiction. In April 2017, NIH Director Francis S. Collins, met with research and development leaders from the world’s leading biopharmaceutical companies to discuss new ways for government and industry to work together to address the opioid crisis. The initial plan for this initiative was recently laid out by Dr. Collins and National Insti- tute on Drug Abuse Director Nora D. Volkow, in the New England Journal of Medi- cine.21 To identify the scientific strategies with the greatest potential for solutions to the opioid problem, NIH brought together innovative experts from government, industry, and academia for a series of three cutting-edge science meetings. On June 5, NIH convened the meeting Medications Development for Opioid Use Disorders and for Overdose Prevention and Reversal, and follow- up activities are in the planning stages. One of the main recommendations with potential for short term progress is prioritizing development of improved formulations of existing medications such as: —Long-acting formulations of addiction treatments buprenorphine, methadone, or naltrexone to ensure stable dosing and promote treatment adherence: —Depot shots that release a controlled amount of the medication into an individuals’ body over time, and —Biodegradable polymer implants that release a controlled amount of medication over time but do not need to be surgically removed after treatment, —Longer duration depot formulations of the opioid overdose reversal medication such as naloxone which can reduce the danger associated with naloxone wearing off before the danger of overdose has fully abated, due to the long half-life of many opioids. We are currently developing a draft strategy that will include major goals of the initiative, action steps, key partners, deliverables, timeline, and resources (in-kind and financial costs) to fully carry out the proposed action steps. Input on the final draft will be solicited from participants including Federal partners as well as other relevant stakeholders. Upon final approval of the plan, it will be posted on the NIH website at: Https://www.nih.gov/opioid-crisis.

NON-ADDICTING PAIN MEDICINES Question. Can you share an update on the research to develop non-addicting pain medicines for people who have to cope with chronic debilitating pain? Is there any effort to combat addiction resulting from acute pain episodes? Answer. The urgency and scale of the opioid crisis necessitates innovative scientific solutions. As part of a government-wide effort to address this crisis and under the HHS Opioid Strategy, NIH is supplementing existing research efforts with a public-private collaborative research initiative on pain and opioid addiction. In April 2017, NIH Director Francis S. Collins, M.D., Ph.D., met with research and development leaders from the world’s leading biopharmaceutical companies to dis-

21 Volkow, N. D. and F. S. Collins (2017). ‘‘The Role of Science in Addressing the Opioid Cri- sis.’’ New England Journal of Medicine. 76 cuss new ways for government and industry to work together to address the opioid crisis. The initial plan for this initiative was recently laid out by Dr. Collins and National Institute on Drug Abuse Director Nora D. Volkow, M.D., in the New Eng- land Journal of Medicine 22 and includes three major areas for advancement: (1) safe, more effective, and non- addictive strategies for chronic pain management to prevent abuse of and addiction to prescription opioids; (2) new and innovative opioid addiction treatments to reduce drug use and support recovery; and (3) overdose reversal interventions. To identify the scientific strategies with the greatest potential for solutions to the opioid problem, NIH brought together innovative experts from government (including FDA and CMS), industry, and academia for a series of three cutting-edge science meetings, two of which addressed pain research. On June 16, NIH convened the meeting Development of Safe, Effective, Non-Addictive Pain Treatments, and on July 7, NIH convened the meeting Understanding the Neurobiological Mechanisms of Pain. The combined expertise of the participants was focused on identifying the research directions and strategies that are most likely to result in rapid progress in development of therapeutics for pain without liability for abuse or overdose. We are currently developing a draft strategy that will include major goals of the initiative, action steps, key partners, deliverables, timeline, and resources (in-kind and financial costs) to fully carry out the proposed action steps. Input on final draft will be solicited from participants including Federal partners as well as other relevant stakeholders. Upon final approval of the plan, it will be posted on the NIH website at: Https://www.nih.gov/opioid-crisis. These efforts are in addition to NIH’s ongoing robust support of research in this area. NIH’s Interagency Pain Research Coordinating Committee’s Federal Pain Re- search Strategy was rolled out in June 2017, and supports development of safer alternatives to prescription medicines for pain care.23 Specific areas of focus include: —Development of non-opioid analgesics that target the molecular pathways of pain signaling —Development of novel opioid analgesics with reduced potential for addiction and overdose —Comparative effectiveness and precision medicine research to identify which treatments will be most effective for a specific patient. —Nonpharmacological treatments for pain, including the use of stimulation devices, biofeedback, genetic manipulation, nanotechnology, and behavioral and psychosocial treatments —Basic research on the mechanisms of pain

QUESTIONS SUBMITTED BY SENATOR JOHN KENNEDY

OPIOIDS Question. Dr. Volkow, thank you for taking the time to meet with our Committee to discuss the NIH’s budget request for fiscal year 2018. I read that the National Institute of Drug Abuse’s (NIDA) request included a $210 million cut from fiscal year 2017 allocations. As you know, my home state of Louisiana has been hit hard by the opioid epidemic, as have many of our states. In your opinion, will NIDA be able to curb opioid abuse with this amount of funding? Answer. The opioid overdose epidemic is a serious, ongoing, and rapidly evolving public health crisis. Over 33,000 Americans died from opioid overdose in 2015 alone. Millions of Americans suffer from opioid abuse and addiction, and millions more suffer from chronic pain. The urgency and scale of this crisis calls for innovative scientific solutions and developing them is a top priority for the Department of Health and Human Services, including NIH and NIDA. We will continue to prioritize research to develop solutions for this crisis and strive to accelerate progress. As part of a government-wide effort to address this crisis and under the HHS Opioid Strategy, NIH is launching a public-private collaborative research initiative on pain and opioid addiction. The initial plan for this initiative was recently described by Dr. Collins and Dr. Volkow, M.D., in the New England Journal of Medi- cine and includes three major areas for advancement: (1) safe, more effective, and non-addictive strategies for chronic pain management to prevent misuse of and addiction to prescription opioids; (2) new and innovative opioid addiction treatments

22 Volkow, N. D. and F. S. Collins (2017). ‘‘The Role of Science in Addressing the Opioid Cri- sis.’’ New England Journal of Medicine. 23 NIH’s Interagency Pain Research Coordinating Committee: Federal Pain Research Strategy. Available at: Https://iprcc.nih.gov/FPRS/FPRS.htm. 77 to reduce drug use and support recovery; and (3) overdose reversal interventions to reduce mortality and promote access to treatment. To identify the scientific strategies with the greatest potential for solutions to the opioid problem, NIH recently brought together innovative experts from government, industry, and academia for a series of three cutting-edge science meetings. With the conclusion of the three scientific meetings, plans are underway to synthesize key themes discussed and suggestions provided into a draft strategy. The strategy will include major goals of the initiative, action steps, key partners, deliverables, timeline, and resources (in-kind and financial costs) to fully carry out the proposed action steps. Input on final draft will be solicited from participants including Fed- eral partners as well as other relevant stakeholders. Upon final approval of the plan, it will be posted on the NIH website at: Https://www.nih.gov/opioid-crisis. Promising potential action steps include: —Develop new formulations, combinations, and means to deliver existing medications to increase treatment effectiveness and support long-term recovery. —Medications for opioid addiction (e.g. extended release buprenorphine and naltrexone) —Overdose prevention and reversal (e.g. increased potency naloxone for fentanyl and carfentanil overdoses) —New technologies (e.g. implants, pumps, neural stimulation) to enhance treatments for pain and substance use disorder, and to prevent/reverse overdose. —Accelerate development of new non-addictive pain therapies through —Enhanced data and information sharing collaborative between industry partners and with academic scientists —Develop and test a standardized platform for drug-target validation —Identify and validate biomarkers for pain and treatment response —Nociometer/Pain-meter Development and Testing —Rapidly bring to market novel non addictive drugs and devices to treat pain —Establish national clinical research networks to: —Measure strategies to improve treatment effectiveness for pain, opioid addiction, and overdose prevention/reversal in real-world settings —Test new therapies for pain management, especially in high-impact, well defined pain populations —Understand the transition from acute to chronic pain Addressing the opioid crisis is a top priority for the Department of Health and Human Services, including NIH and NIDA. We will continue to prioritize research to develop solutions for this crisis and strive to accelerate progress.

QUESTIONS SUBMITTED BY SENATOR PATTY MURRAY

THE IMPACT OF FUNDING CUTS ON SELECT DISEASES—DRUG ABUSE Question. Dr. Volkow, despite the horrible grip the opioid epidemic has in so many communities, the budget proposes to cut drug abuse research by almost 20 percent or more than $200 million compared to this year’s funding level. That would come on top of changes to Medicaid and the Essential Health Benefits that could restrict access to treatment. What are the possible impacts of a reduction of that magnitude on your research efforts? Answer. The opioid overdose epidemic is a serious, ongoing, and rapidly evolving public health crisis. Over 33,000 Americans died from opioid overdose in 2015 alone. Millions of Americans suffer from opioid abuse and addition, and millions more suffer from chronic pain. The urgency and scale of this crisis calls for innovative scientific solutions. As part of a government-wide effort to address this crisis and under the HHS Opioid Strategy, NIH is launching a public- private collaborative research initiative on pain and opioid addiction. The initial plan for this initiative was recently described by Dr. Collins and Dr. Volkow, M.D., in the New England Journal of Medicine and includes three major areas for advancement: (1) safe, more effective, and non-addictive strategies for chronic pain management to prevent misuse of and addiction to prescription opioids; (2) new and innovative opioid addiction treatments to reduce drug use and support recovery; and (3) overdose reversal interventions to reduce mortality and promote access to treatment. To identify the scientific strategies with the greatest potential for solutions to the opioid problem, NIH recently brought together innovative experts from government, industry, and academia for a series of three cutting-edge science meetings. Through these meetings, NIH has begun to formulate new approaches and recruit additional 78 expertise with the aim of developing new safe and effective therapeutics for chronic pain, opioid abuse and addiction, and overdose in half the time it currently takes. With the conclusion of the three scientific meetings, plans are underway to synthesize key themes discussed and suggestions provided into a draft strategy. The strategy will include major goals of the initiative, action steps, key partners, deliverables, timeline, and resources (in-kind and financial costs) to fully carry out the proposed action steps. Input on final draft will be solicited from participants including Federal partners as well as other relevant stakeholders. Upon final approval of the plan, it will be posted on the NIH website at: Https://www.nih.gov/opioid-crisis. Addressing the opioid crisis is a top priority for the Department of Health and Human Services, including NIH and NIDA. We will continue to prioritize research to develop solutions for this crisis and strive to accelerate progress.

NIDA TRANSLATIONAL RESEARCH Question. It is well documented that it takes years to translate the knowledge developed through NIH-support research into actual practice in service settings. This ‘‘translational work’’ received elevated attention at NIDA in the 2000’s through its ‘‘Blending Initiative.’’ This ‘‘Blending Initiative’’ included specific collaboration with State alcohol and drug agency directors, through the National Association of State Alcohol and Drug Abuse Directors (NASADAD), to conduct a regular dialogue between NIDA-supported researchers and the leaders of the safety net prevention, treatment and recovery system. I am concerned with what seems to be lessening activity dedicated to this issue. This conversation between researchers and State alcohol and drug agency directors is critical because (1) leaders of State alcohol and drug service systems benefit from hearing about the latest research from the Insti- tute and (2) researchers benefit hearing directly from State alcohol and drug agency directors regarding their research needs and challenges managing the publicly funded system—including challenges related to the opioid issue. This type of dialogue can accelerate the lag between scientific discovery and practice. Can you please outline the specific steps NIDA has taken to hold a regular dialogue that connects NIDA-supported researchers with State alcohol and drug agency directors to discuss tools to help improve services in public sector settings? Are there steps NIDA can take to re-energize the Blending Initiative to help improve State systems across the country? Please provide the proposed fiscal year 2018 budget and the previous 5 year final allocations for the following NIDA divisions: Epidemiology, Services and Prevention Research Branch; and Clinical Trials Network Answer. Accelerating the dissemination of research-based drug abuse treatment into clinical practice is a priority for the National Institute on Drug Abuse (NIDA) and represents the core mission of the Blending Initiative, a collaboration between NIDA and the Substance Abuse and Mental Health Services Administration (SAMHSA). Established in 2001, the Blending Initiative’s goal is to reduce the gap that exists between the publication of research results and impact on treatment delivery. Specifically, the Blending Initiative incorporates collaboration between clinicians, scientists, and experienced trainers to catalyze the creation of user-friendly treatment tools and products and facilitate the adoption of research-based interventions into front-line clinical settings. Through this initiative, NIDA transferred $1.5 million per year to SAMHSA to support SAMHSA’s Addiction Technology Transfer Cen- ters (ATTCs) to develop and disseminate treatment and training products based on results from studies conducted by the National Drug Abuse Clinical Trials Network (CTN) as well as other NIDA-supported research. State alcohol and drug abuse agencies have always been a critical partner in this effort to ensure that NIDA- based research findings are disseminated and applied in an efficient way to ensure widespread adoption. Since 2000, NIDA has supported the development of six major training products, convened 14 state- level blending meetings in partnership with State alcohol and drug abuse offices, and sponsored hundreds of training programs nationwide. In order to revitalize the Blending Initiative as described, NIDA could expand its dissemination efforts in partnership with SAMHSA and State alcohol and drug agency directors to improve services in public sector settings. This could include such things as conducting workshops and seminars at state-level conferences and meetings, convening webinar series targeting and engaging state agency directors or regular ‘‘roundtable’’ in person or virtual meetings to review best practices and strategies or solutions to address the opioid overdose epidemic and to improve access to medication for persons with opioid addiction in public sector settings. 79

FUNDING FOR NIDA DIVISION OF EPIDEMIOLOGY, SERVICES AND PREVENTION RESEARCH AND THE CLINICAL TRIALS NETWORK [Dollars in thousands]

Fiscal Year 2018– 2013 2014 2015 2016 217– President’s Actual Actual Actual Actual Estimate Budget

Division of Epidemiology, Services and Preven- tion Research...... 241,661 247,141 265,357 320,608 331,170 263,634 Clinical Trials Network ...... 44,508 45,291 41,718 41,281 44,264 35,237

QUESTIONS SUBMITTED BY SENATOR BRIAN SCHATZ

TUBERCULOSIS Question. Tuberculosis is the leading global infectious killer. It takes the lives of 1.8 million people annually around the world. My state of Hawaii is one of the most highly burdened states in the United States. How is the NIH responding to tuberculosis globally and domestically, especially in terms of developing faster diagnostics; shorter, more tolerable treatments; and effective vaccines to prvent the disease? Answer. The National Institute of Allergy and Infectious Diseases (NIAID) remains committed to supporting basic, translational, and clinical research that stim- ulates innovation in the diagnosis, treatment, and prevention of tuberculosis (TB). NIAID collaborates with other Federal agencies, national and international research organizations, philanthropic donors, and industry to address the domestic and global challenges posed by TB and its multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms. As part of these efforts, NIAID plays a key role in the National Action Plan for Combating Multidrug-Resistant Tuberculosis. NIAID supports fundamental research on Mycobacterium tuberculosis, the bac- terium that causes TB, to better understand how it causes disease and how it develops resistance to the drugs used to treat it. NIAID also provides preclinical research support services to mycobacterial researchers around the world to delineate the biological mechanisms of TB and to advance countermeasure development. These activities include the development and evaluation of a broad array of TB diagnostic tests, including those capable of detecting TB drug resistance. For example, NIAID supported key aspects of the development of the Xpert® MTB/RIF (Cepheid) test en- dorsed by the World Health Organization. A newer, more sensitive version of the test may help detect TB in patients who test negative using other diagnostic tests or aid in the challenging diagnosis of TB in children. Another new Xpert test version also is being evaluated for the capability to diagnose XDR TB. In addition, NIAID’s Tuberculosis Research Unit program has helped identify biomarkers that define the various stages of infection, such as latent, or dormant, versus active disease. NIAID also contributes to the global consortia that are mapping the genetic diversity of MDR and XDR strains of M. tuberculosis to further aid in diagnostic development. To prepare for clinical studies of TB countermeasures, NIAID has worked with organizations in India, Brazil, South Africa, Indonesia, the Philippines, and South Korea to develop a network of co-funded research sites to conduct international trials of promising new drugs, vaccines, and diagnostics. NIAID is funding research to prevent the spread of drug-resistant TB by supporting the development and optimization of new and existing therapeutics. To date, NIAID support has contributed to more than two-thirds of 20 investigational TB drugs and drug combinations. NIAID also is helping to identify new TB therapeutics by evaluating small molecule candidates provided by pharmaceutical companies as part of the TB Accelerator, a public-private partnership led by the Bill & Melinda Gates Foundation. In addition, NIAID is supporting a clinical trial in Peru and South Africa to determine the appropriate dosage of the antibiotic levofloxacin in combination with a standard TB antibiotic regimen to better treat MDR TB. This trial leverages support and infrastructure through the Centers for Disease Control and Prevention (CDC). NIAID also supports research designed to make TB treatment regimens easier to tolerate. For example, one NIAID-supported study is evaluating a novel digital monitoring system for individuals undergoing treatments for M. tuberculosis infection that require direct observation of the treatment by a medical professional. The goal of the system is to make treatment easier and less time 80 consuming for patients and healthcare providers. NIAID researchers also are investigating whether a 1-month treatment regimen for persons latently infected with M. tuberculosis is effective at preventing active TB in at-risk HIV-infected individuals. If effective, the shorter drug regimen also may increase treatment adherence compared to the standard regimen. A safe and highly effective TB vaccine will be a critical tool in first controlling, and ultimately eradicating the disease. To that end, NIAID supports basic, preclinical, and clinical development of innovative new vaccine candidates to protect against infection and/or TB disease in adults and children. NIAID support has contributed to about half of the vaccine candidates currently in clinical development. For example, NIAID is conducting a trial to assess the safety and immunogenicity of an adjuvanted TB vaccine candidate, ID93. NIAID also has released four funding announcements soliciting research to advance the science of TB vaccines, including studies on vaccines in individuals co-infected with TB and HIV who are at high risk for morbidity and mortality. NIAID remains committed to supporting the vital research necessary to develop new and improved diagnostics, therapeutics, and vaccines for TB. NIAID also will continue to advance the biomedical research goals and objectives of the National Ac- tion Plan for Combating MDR TB by engaging with multiple stakeholders, including academic, industry, and community collaborators, and by leveraging the clinical trial infrastructures established by CDC and the United States Agency for Inter- national Development.

NIDA

MEDICAL MARIJUANA RESEARCH Question. Marijuana research and policy issues continue to be very important. What are some of the barriers you are facing to funding and conducting this research? What do we know about marijuana’s potential to ease the opioid crisis? Answer. There are many open questions related to evolving marijuana laws that research can help to address, including how policy changes will affect: —Use of marijuana and related health outcomes, including mental illness —Health outcomes—positive and negative—related to State-level initiatives to permit the medical use of marijuana —Usage patterns of other drugs, alcohol, and tobacco —Public-safety outcomes related to drugged driving, crime, etc. —Potency and cannabinoid content of commonly consumed strains —New routes of administration (e.g., vaping, dabbing, edibles) —Societal norms and perceptions In addition, more research is needed to develop prevention interventions that target marijuana use among youth in the context of changing norms, to understand the health consequences related to the increasing potency of marijuana, to characterize the consequences of marijuana use on the developing brain, and to develop new treatment strategies for cannabis use disorders. NIDA-supported science aims to address these gaps and to help inform decision- making related to state and Federal marijuana policies. In addition, in line with NIDA’s mission of reducing the burden of drug use and SUDs, ongoing research will continue to explore the therapeutic potential of marijuana-derived compounds for pain and addiction. Research that utilizes the marijuana plant or its constituent compounds is gov- erned by specific regulatory and administrative processes that govern research on marijuana. Under the Single Convention on Narcotic Drugs (1961), the United States is subject to several obligations related to the regulation of marijuana cultivation for research.24 In addition, under the Controlled Substances Act (CSA), marijuana and its constituent compounds are classified as Schedule I controlled substances—defined as having high potential for abuse and no currently accepted medical use, and no accepted safety for use under medical supervision.25 As a result of these treaty obligations and marijuana’s status under the CSA, the Drug Enforce- ment Administration (DEA) with input from the Department of Health and Human Services regulates marijuana research and the cultivation of marijuana for research purposes through licensing requirements and by establishing annual aggregate production quotas. While research on marijuana and its constituent compounds is pos-

24 United Nations. Single Convention on Narcotic Drugs. March 1961. Https://www.unodc.org/ pdf/conventionl1961len.pdf. 25 Controlled Substances Act. Vol 21.; 1970. Https://www.gpo.gov/fdsys/pkg/STATUTE-984/pdf/ STATUTE-84-Pg1236.pdf. 81 sible, there remains a number of barriers, described below, for conducting this research.26 The registration process: Researchers have indicated that this process creates administrative burdens that can act as disincentives to conducting research. Single source of marijuana for research purposes: Currently, there is one registration for marijuana cultivation in the US—the University of Mississippi, which, through a contract with NIDA, supports the cultivation and distribution of research grade marijuana for the country. While the NIDA supply of marijuana has diversi- fied to include different strains with varying concentrations of cannabidiol (CBD) and other cannabinoids of interest to researchers, it is both costly and time consuming to grow, isolate, and/or refine new products that scientists would like to study. Given the scope of the ongoing opioid crisis, more research is needed to develop non-opioid based medications for pain. Ongoing research is actively investigating the potential of cannabinoids for this purpose. There is evidence that THC, the main psychotropic compound in marijuana, may be effective for treating pain.

QUESTIONS SUBMITTED BY SENATOR JOE MANCHIN, III

RESEARCH INTO ALTERNATIVE PAIN MANAGEMENT Question. Dr. Volkow, as you know, communities across the country, including many in my state of West Virginia, are seeing an alarming rise in substance abuse and addiction to prescription opioids. Nationally, prescription opioids and heroin killed more than 33,000 people in 2015. That’s 91 people every day. In West Vir- ginia, we lost more than 700 people in 2015. So many of these people who become addicted started taking these drugs because their doctor prescribed them for pain even though—according to the CDC—there is little evidence that opioids improve chronic pain, function, and quality of life. This is a public health crisis and we have to find a better way. That is why I am so worried about the President’s Budget Request to cut more than $200 million from the National Institute on Drug Abuse. Dr. Volkow, what research is being done to develop non-addictive alternative pain management options for patients—particularly those dealing with long-term, chronic pain who are currently being prescribed opioids despite the lack of evidence of their effectiveness? What impact would the proposed budget cuts have on NIDA’s ability to do continue to do this research? Answer. The opioid overdose epidemic is a serious, ongoing, and rapidly evolving public health crisis. As you note, over 33,000 Americans died from opioid overdose in 2015 alone. Millions of Americans suffer from opioid abuse and addiction, and millions more suffer from chronic pain. The urgency and scale of this crisis calls for innovative scientific solutions. As part of a government-wide effort to address this crisis and under the HHS Opioid Strategy, NIH is launching a public-private collaborative research initiative on pain and opioid addiction. The initial plan for this initiative was recently described by Dr. Collins and Dr. Volkow, M.D., in the New England Journal of Medicine and includes three major areas for advancement: (1) safe, more effective, and non-addictive strategies for chronic pain management to prevent misuse of and addiction to prescription opioids; (2) new and innovative opioid addiction treatments to reduce drug use and support recovery; and (3) overdose reversal and prevention interventions to reduce mortality and promote access to treatment. To identify the scientific strategies with the greatest potential for solutions to the opioid problem, NIH recently brought together innovative experts from government, industry, and academia for a series of three cutting-edge science meetings. Through these meetings, NIH has begun to formulate new approaches and recruit additional expertise with the aim of developing new safe and effective therapeutics for chronic pain, opioid addiction, and overdose in half the time it currently takes. Key themes from each meeting are below: Key Themes from Meeting #1: Medications Development for Opioid Use Disorders and Overdose Prevention & Reversal, June 5, 2017 —Families need and want the scientific and healthcare communities to have the same level of focus and urgency for developing a cure for addiction as they would for any disease that is taking over 50,000 lives each year.

26 Stith SS, Vigil JM. Federal barriers to Cannabis research. Science. 2016;352(6290):1182– 1182. doi:10.1126/science.aaf7450. 82

—Lack of treatment infrastructure for medications is a significant challenge, including reimbursement for medications for opioid use disorders. —Incentives are needed to encourage pharmaceutical and biotechnology company investment. —There is a need for better surveillance on overdoses and the use of naloxone to reverse them. —Technology can help to treat disorders and prevent overdose. Key Themes from Meeting #2: Development of Safe, Effective, Non-Addictive Pain Treatments: June 16, 2017 —There has been significant progress in target identification and structure based drug development; there are many therapeutics in the pipeline. —There is a need to reset expectations of what is achievable with pain treatment. —Heterogeneity among patients with chronic pain poses significant challenges in clinical trials; objective biomarkers are needed to improve the speed and efficiency of clinical trials. —More basic research is needed on a diverse range of pain conditions, including better animal models. —Advances in neuroscience technologies are poised to accelerate development of treatments for pain. —There is significant potential value in coordinating across both pharmaceutical and academic research: a) significant overlap in the targets being pursued by different companies, and b) common technical challenges that everyone is working on independently. Key Themes from Meeting #3: Understanding the Biological Mechanisms of Pain, July 7, 2017 —Linkages between industry and academic researchers can promote the effective use of limited resources. —Pain research would benefit from leveraging available neuroscience technologies and encouraging more neuroscientists to enter the pain field. —Pain processing is complex throughout the brain and periphery. There is a need for multidisciplinary efforts to understand pain at the molecular, cellular, circuit, and system levels. —Standardized, objective biomarkers are needed that will predict the response to treatment in animal models and in humans. —Extensive patient phenotyping is needed to develop objective biomarkers which will enable precision medicine approaches to more effectively treat each patient’s pain, as well as the factors that impact the patient’s experience of pain. —There is a need for objective screens based on the neurobiology of pain to accelerate the drug development process. —There are research gaps regarding the prolonged effects of chronic pain, long term impacts of treatment (e.g. hyperalgesia due to chronic opioid use), and the transition from acute to chronic pain. With the conclusion of the three scientific meetings, plans are underway to synthesize key themes discussed and suggestions provided into a draft strategy. The strategy will include major goals of the initiative, action steps, key partners, deliverables, timeline, and resources (in-kind and financial costs) to fully carry out the proposed action steps. Input on final draft will be solicited from participants including Federal partners as well as other relevant stakeholders. Upon final approval of the plan, it will be posted on the NIH website at: Https://www.nih.gov/opioid-crisis. Addressing the opioid crisis is a top priority for the Department of Health and Human Services, including NIH and NIDA. We will continue to prioritize research to develop solutions for this crisis and strive to accelerate progress.

VA AND NIH RESEARCH Question. In 2014, the VA and the National Institutes of Health launched a 5- year quality- improvement initiative to explore non-drug approaches to managing pain and related health conditions such as PTSD, drug abuse, and poor sleep. According to the VA, one-third of Veterans in VA care are prescribed an opioid, and one-third of those are on long-term opioid prescriptions despite the many side effects and the questionable efficacy of using these drugs to manage chronic pain. That is why this work is so critical. Dr. Volkow, can you provide any updates on this initiative and can you speak to the need to better understand the complex relationship between pain and other 83 health conditions, including mental health conditions, and the need to develop non- addictive, non-drug options for helping people manage pain? Answer. In 2014, the VA and the National Institutes of Health launched a 5-year quality- improvement initiative to explore non-drug approaches to managing pain and related health conditions such as PTSD, drug abuse, and poor sleep. According to the VA, one-third of Veterans in VA care are prescribed an opioid, and one-third of those are on long-term opioid prescriptions despite the potential for adverse effects and the questionable efficacy of using these drugs to manage chronic non-cancer pain. This is why developing new, safe, effective, non- addictive pain treatments is critical. Chronic pain is highly comorbid with mental health problems, such as post-traumatic stress disorder and depression; and chronic use of prescription opioids for noncancer chronic pain is higher among and increasing faster in patients with mental health and substance use disorders than in persons without those diagnoses.27 The VA and NIH initiative exploring nondrug approaches to managing pain and related health conditions includes thirteen research projects totaling approximately $21.7 million over 5 years. Some of the research being funded by this initiative include: —Testing the efficacy of combining transcranial direct current stimulation with cognitive behavioral therapy for the treatment of pain, opioid use, and related health issues; —Use of morning bright light treatment to reduce and help manage chronic low- back pain and improve PTSD symptoms, mood, and sleep; —The use of mobile devices to display real-time brain activity that veterans with PTSD and TBI can use to induce relaxation and reduce pain symptoms; —An integrated program to improve physical function/reduce disability and decrease rates of chronic opioid use of combat-injured veterans with multiple traumatic injuries; —Mindfulness-meditation-based pain relief; and —Complementary/nonpharmacologic health approaches for managing chronic pain. The next generation of research from this funding initiative is currently underway and is jointly funded by NIH, the Department of Defense, and the Veterans Admin- istration Health Services Research and Development. The overall goal of this initiative, titled the ‘‘NIH-DoD–VA Pain Management Collaboratory’’, is to develop the capacity to implement cost-effective large-scale pragmatic clinical research in military and veteran healthcare delivery organizations focusing on non-pharmacological approaches to pain management and other comorbid conditions. The NIH intends to commit $2 million in fiscal year 2017 to fund one coordinating center. Collectively, the agencies intend to commit $3.5-$4.25 million annually to fund approximately 5–7 2-year UG3 (Planning Phase) awards, and $5.65-$6.65 million/year to fund approximately five 4-year subsequent UH3 (Implementation Phase) Demonstration Projects, contingent upon budget considerations and receiving sci- entifically meritorious applications. To develop non-addictive pain treatments, NIDA is one of multiple institutes of the NIH supporting research into novel pain treatments with reduced potential for abuse and diversion, including abuse resistant opioid analgesics, non-opioid medication targets, and non-pharmacological treatments. Some of the most promising potential therapies include: —Non-Opioid Medications: Potential drug targets that could allow for pain relief without the addictive properties or overdose risk of opioids, by targeting different molecular pathways within the nervous system with promising prelimi- nary data include fatty acid binding proteins, the G-protein receptor 55, cannabinoids, and transient receptor potential cation channel A1; —Abuse-resistant opioid analgesics: New compounds that target opioid signaling pathways in different ways than traditional opioids may allow for analgesic effects without the rewarding and respiratory-depressing effects of existing opioid medications.16 —Nervous Stimulation Therapies: These include transcranial magnetic stimulation and transcranial direct current stimulation, as well as electrical deep brain stimulation, spinal cord stimulation, and peripheral nerves/tissues stimulation—have shown promise for the treatment of intractable chronic pain. These devises have been approved by the FDA for treatment of other conditions but more research is needed on their effectiveness for pain.

27 Edlund MJ, et al. Trends in use of opioids for chronic noncancer pain among individuals with mental health and substance use disorders: the TROUP study. Clin J Pain. 2010;26(1):1– 8. 84

—Neurofeedback: Neurofeedback is a novel treatment modality in which patients learn to regulate the activity of specific brain regions by getting feedback from real-time brain imaging. This technique shows promise for altering the perception of pain in healthy adults and chronic pain patients and may also be effective for the treatment of addiction. Finally, a public-private collaborative research initiative is being launched by NIH to develop new, safe, and effective strategies to prevent and treat pain, opioid addiction, and overdose in half the time it currently takes. The initial plan for this initiative was recently described by Dr. Collins and National Institute on Drug Abuse Di- rector Nora D. Volkow, M.D., in the New England Journal of Medicine 28 and includes three major areas for advancement: (1) safe, more effective, and non-addictive strategies for chronic pain management to prevent misuse of and addiction to prescription opioids; (2) new and innovative opioid addiction treatments to reduce drug use and support recovery; and (3) overdose reversal interventions to reduce mortality and promote access to treatment. We are currently developing a draft strategy that will include major goals of the initiative, action steps, key partners, deliverables, timeline, and resources to fully carry out the proposed action steps. Input on final draft will be solicited from participants including Federal partners as well as other relevant stakeholders. Upon final approval of the plan, it will be posted on the NIH website at: Https:// www.nih.gov/opioid-crisis.

QUESTIONS SUBMITTED TO JOSHUA GORDON, M.D., PH.D.

QUESTIONS SUBMITTED BY SENATOR PATTY MURRAY

THE IMPACT OF FUNDING CUTS ON SELECT DISEASES—MENTAL ILLNESS Question. Dr. Gordon, what would a cut of almost $600 million or 23 percent mean for efforts to find more effective treatments for the 44 million Americans who suffer from mental illness? Answer. Mental illnesses are significantly impairing and can be life-threatening. In 2015, an estimated 43.4 million U.S. adults reported having a mental illness in the past year.29 Based on recent estimates, mental illnesses accounted for 21.3 percent of all years lived with disability in the United States.30 These stark statistics serve as an important reminder of how essential it is to make continued progress in scientific research that will illuminate the causes, and corresponding treatments, of mental illnesses.

INTEGRATING HEALTHCARE FOR MENTAL ILLNESS Question. Dr. Gordon, during a hearing on mental health in February, one of our witnesses, David Johnson, the CEO of Navos Mental Health Solutions, noted that the total cost of care per patient could be reduced 35 percent in plans that integrated services between primary and behavioral healthcare, which is significant. De- spite our efforts, it does not appear that there has been an appreciable improvement in treatment or reduction in prevalence of most forms of mental illness. How do we address this problem? Should we rebalance the NIMH research portfolio to include more focus on research and training to reduce the public health burden of mental illness? In recent years, NIMH has prioritized neurobiological mechanisms of mental illness and development of pharmaceuticals rather than basic behavioral research that could improve our understanding of mental health and lead to treatments to address the immediate mental health conditions of the population. Answer. As the new Director of NIMH, I spent the last year working with Insti- tute leadership to refine NIMH priorities and continuing to ensure that our research portfolio is balanced. NIMH must invest in research that has the potential to improve clinical care over the short, medium, and long-term. While it is essential to deeply investigate the brain and its interactions with the environment to build our knowledge base and search for the truly transformative treatments of tomorrow, we must not neglect opportunities to fully investigate new treatment targets as they

28 Volkow, N. D. and F. S. Collins (2017). ‘‘The Role of Science in Addressing the Opioid Cri- sis.’’ New England Journal of Medicine. 29 Center for Behavioral Health Statistics and Quality. (2016). Key Substance Use and Mental Health Indicators in the United States: Results from the 2015 National Survey on Drug Use and Health. (HHS Publication No. SMA, NSDUH Series H–51). Retrieved from http:// www.samhsa.gov/data. 30 US Burden of Disease Collaborators. The state of US health, 1990–2010: burden of diseases, injuries, and risk factors. JAMA, 310(6): 591–608, 2013. 85 arise. Nor can we forget that research is often needed to help currently available, efficacious treatments reach all patients who need them. For over two decades, NIMH has invested in research to support systems of care that integrate mental and physical healthcare—Collaborative Care. In a Collabo- rative Care system, patient populations are screened and closely tracked in a registry that is used to monitor symptoms and inform evidence-based practices. A care manger, a psychiatric consultant, and other mental health professionals work collaboratively to support mental health treatment within primary care. Collaborative Care models have also been shown to improve treatment of mental disorders among people with co-occurring medical problems treated in primary care settings.31 This is critical because untreated mental disorders are common in patients seen in primary care settings; so much so that primary care is considered the de facto mental health service system in the United States. As well, findings from over 80 randomized controlled trials robustly support the effectiveness of the Collaborative Care model to improve depression, anxiety, post-traumatic stress disorder, suicide prevention, and other mental disorders in pediatric, adult, and geriatric populations.32 From the perspective of NIMH, the science behind Collaborative Care is clear: it is an effective model of care delivery. Our current focus is assisting other Federal agencies in understanding the evidence and allowing it to guide policy decisions. The Mental Health Research Network (MHRN) serves as NIMH’s prototype of a learning healthcare system, and includes large-scale pragmatic trials and services research.33 The 13 healthcare systems that comprise MHRN integrate services to improve the speed, efficiency, generalizability, and uptake of mental health research and treatment for 13 million beneficiaries across the country. MHRN’s population- based approach to mental healthcare combines expertise in mental health research as well as epidemiology, health services, economics, disparities, outcomes, and quality assessment. One such study is examining the use of electronic medical health records by primary care providers to identify appropriate care and control cardiovascular risk factors for patients with serious mental illness (SMI).34 NIMH also funds research on the detection and treatment of general medical conditions in individuals with SMI.35 Common modifiable health risks associated with premature mortality, such as elevated blood pressure, A1C glucose, and BMI, as well as smoking and obesity, often go undetected and untreated in individuals with SMI. NIMH is funding studies on effective strategies to reduce obesity, improve fitness, promote smoking cessation and improve cardiometabolic risks in people with SMI.36,37,38,39 In August 2016, NIMH funded three large- scale trials in youth with SMI to test population-based approaches to preventing and reducing cardiometabolic risks at the earliest possible opportunity.40 Routine screening is essential for early detection of mental illnesses and subsequent referral to treatment. In 2016, the United States Preventive Services Task Force updated its recommendations regarding depression to include screening for depression in the general adult population, and especially among persons with chronic illnesses. NIMH supports research on effective methods for identifying individuals with depression and other mental disorders, and on effective interventions for treating mental disorders in both general medical and specialty care settings. For example, NIMH funds studies on integrating depression screening and care into OB/GYN settings for pregnant women, and delivering online therapy for depression and anxiety to adult primary care patients.41,42,43

31 Https://www.ncbi.nlm.nih.gov/pubmed/16675360. 32 Https://www.ncbi.nlm.nih.gov/pubmed/23076925. 33 Http://hcsrn.org/mhrn/en/. 34 Https://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=9312868&icde=35162345. 35 Http://grants.nih.gov/grants/guide/rfa-files/RFA-MH-14-060.html. 36 Http://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=8764463&icde=22739367. 37 Http://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=8764228&icde=22739259. 38 Http://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=8764333&icde=22739523. 39 Http://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=8763974&icde=22739601. 40 Http://grants.nih.gov/grants/guide/rfa-files/RFA-MH-14-060.html. 41 Https://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=9253314&icde=35019783. 42 Https://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=9046911&icde=35019783. 43 Https://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=9086425&icde=35019827. 86

QUESTIONS SUBMITTED BY SENATOR CHRISTOPHER MURPHY

NIMH

RECOVERY AFTER AN INITIAL SCHIZOPHRENIA EPISODE (RAISE) PROJECT Question. Last year I worked with Senators Alexander, Murray and Cassidy to pass a major mental health reform bill as part of the 21st Century Cures bill. This bill made a clear statement from the Congress about mental health is both important and bipartisan. However, the stigma around mental illness continues and I believe that stigma extends to the research community. Unfortunately, the administration has proposed a cut of about $360 million to the National Institutes of Mental Health (NIMH) budget. The NIMH budget justification notes that we have made progress in reducing untreated psychosis through the Recovery After an Initial Schizophrenia Episode (RAISE) project. Specifically it states that coordinated specialty care (CSC)—a team- based, multi-component treatment program for individuals with first episode psychosis—produced superior clinical and functional improvements compared to typical care, especially among clients with shorter duration of untreated psychosis. Despite this success, the budget proposed a 20 percent cut to this effort. Dr. Collins and Dr. Gordon, what is the rationale behind the overall cut to NIMH and to this specific initiative? Shouldn’t we be building on the improvements that were made last year in the Mental Health Reform and send a signal to researchers that this is an important area by investing in programs that have been shown to be effective? Answer. The mental health reforms in the 21st Century Cures Act promote and support Federal and state mental health and substance misuse initiatives, programs, and services. Specifically, the Act requires states to use Federal block grant funds on evidence-based practices such as coordinated specialty care (CSC), which was examined in the NIMH-supported Recovery After an Initial Schizophrenia Epi- sode (RAISE) project. As noted in the NIMH budget justification, findings from RAISE indicate that CSC for first episode psychosis (FEP) produced superior clinical and functional improvements compared to typical care, especially among clients with shorter duration of untreated psychosis.44 To build on the successes of RAISE, in May 2016, The National Institute of Men- tal Health (NIMH) reissued funding opportunity announcements seeking projects aiming to reduce the duration of untreated psychosis.45,46 Specifically, NIMH aims to support research that tests strategies for reducing the duration of psychosis among persons with FEP by eliminating bottlenecks or closing gaps in the pathway to CSC services. NIMH currently funds eight such studies aiming to reduce the duration of untreated psychosis. Early identification of FEP, rapid referral to evidence- based services, and effective engagement in CSC are essential to shortening the duration of untreated psychosis, pre-empting the functional deterioration common in psychotic disorders, and reducing the economic burden of these devastating illnesses on society. Additionally, NIMH launched the Early Psychosis Intervention Network (EPINET), with the goal of creating a learning healthcare system among early psychosis treatment clinics.47 EPINET clinics will create a common database with information gathered during routine clinical encounters, with patients’ consent. EPINET will allow clinicians and researchers to learn more about the effectiveness of early psychosis treatment and accelerate studies of psychosis risk factors, biomarkers of illness, and pre-emptive interventions. The initial phase of EPINET, which included identification of valid, reliable, and feasible measures to support standardized clinical assessment and outcome evaluation in early psychosis clinics, was completed in January 2017.48 The second phase of EPINET is underway and aims to identify feasible strategies for harmonizing clinical data collection across community-based treatment programs for FEP. An NIMH-sponsored meeting on data harmonization across CSC programs is planned for September 2017. The meeting will bring together key stakeholders, including

44 Https://www.ncbi.nlm.nih.gov/pubmed/26481174. 45 http://grants.nih.gov/grants/guide/pa-files/PAR–16–264.html. 46 Http://grants.nih.gov/grants/guide/pa-files/PAR–16–265.html. 47 Https://www.nimh.nih.gov/funding/grant-writing-and-application-process/concept-clearances/ 2015/early- psychosis-intervention-network-epinet-a-learning-healthcare-system-for-early-serious-mental-illness.shtml. 48 Https://grants.nih.gov/grants/guide/notice-files/NOT-MH-17-009.html. 87

FEP researchers, representatives of state mental health authorities, clinical providers and program administrators, and members of mental health advocacy groups. Overall reductions in the NIMH budget would be distributed across all pro- grammatic areas and basic, translational, and clinical research—including programs focused on reducing the duration of untreated psychosis.

WARNING SIGNS Question. Dr. Gordon, we are now a couple weeks removed from a mass shooting that injured Rep. Steve Scalise and others. The courage and professionalism of law enforcement saved the lives of many Senators, Members, staff, and ordinary citi- zens. We continue to have mass shootings perpetrated by individuals with troubled pasts but we also know that individuals with mental illness are more likely to be the victim of violence than the perpetrator. What have we learned about how to recognize the warning signs from those who might be at risk to commit an act of violence? What research is being done to help those at risk? Lastly, where do we go from here to provide better mental health research and services to those in need? Answer. Tragic mass shooting events often focus the nation’s attention on gun violence, mental illness, and the sometimes-difficult balance of ensuring personal free- doms while protecting public safety. Following the recent shooting that injured Rep. Steve Scalise, the FBI reported that the perpetrator did not have a history of mental illness. Indeed, individuals with serious mental illness (SMI) are no more violent than the general population when symptoms are controlled. Notably, violence among people with SMI is more likely to be self-directed (e.g., suicide) than directed towards others, and people with SMI are 11 times more likely than the general population to be victims of violence. When substance abuse is combined with untreated SMI, there is an increased risk of violence, but risk of violent behavior among people with SMI is reduced with appropriate treatment.49,50 Recent, publicized acts of mass violence often involved young people whose illness was either not detected and/or not appropriately treated. Studies find a substantial delay between the onset of psychotic symptoms and the initiation of care; in the U.S., treatment is typically delayed between 1 and 3 years.51,52 As such, evidence- supported approaches to early detection to initiate treatment and facilitating sustained engagement in effective care are key strategies for preventing violent acts among young people with SMI and for reducing long-term disability and functional impairment, in general. A current NIMH initiative is focused on reducing the duration of untreated psychosis.53,54 NIMH also funded six studies to develop and test interventions to improve the care of persons at clinical high risk for psychotic disorders.55,56,57,58,59,60 Several of the researchers conducting these studies presented their findings at an NIMH and SAMHSA co- sponsored meeting in July 2017 on Im- plementing Early Intervention Services for Clinical High Risk for Psychosis in U.S. Community Settings: What Do We Know and What Do We Need to Know? In response to the shooting at Sandy Hook Elementary School in Newtown, CT, NIH called for research on the health determinants and consequences of violence and its prevention, particularly firearm violence.61,62,63 In fiscal year 2015, NIH funded nine grants, four with a focus on mental health outcomes. One such NIMH- funded study is examining emergency department discharge practices that include counseling on limiting access to guns during times of mental health crisis.64 Another

49 Https://www.ncbi.nlm.nih.gov/pubmed/9596041. 50 Https://www.ncbi.nlm.nih.gov/pubmed/16061769. 51 Https://www.ncbi.nlm.nih.gov/pubmed/16143729. 52 Https://www.ncbi.nlm.nih.gov/pubmed/25588418. 53 Https://grants.nih.gov/grants/guide/pa-files/PAR–16–264.html. 54 Https://grants.nih.gov/grants/guide/pa-files/PAR–16–265.html. 55 Http://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=8789627&icde=22682321. 56 Http://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=8789633&icde=22682325. 57 Http://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=8789537&icde=22682326. 58 Http://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=8786741&icde=22682332. 59 Http://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=8789569&icde=22682334. 60 Http://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=8786233&icde=22682335. 61 Https://grants.nih.gov/grants/guide/pa-files/PA–13–363.html. 62 Https://grants.nih.gov/grants/guide/pa-files/PA–13–368.html. 63 Https://grants.nih.gov/grants/guide/pa-files/PA–13–369.html. 64 Https://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=8806202&icde=27520350. 88

NIMH-funded study is exploring the relationship between inflammation in the brain and aggression.65 While these and many other NIH-funded studies are promising, continued support of research focused on the improvement of services is needed to ensure that those most in need receive evidence-based treatment. Risk factors for violence among those with mental illness are largely the same as for those without mental illness. These risk factors include substance abuse, family conflict, early social and emotional isolation, school failure, as well as early and persistent delinquent behavior among youth. In the future, NIH will continue to support research to develop practical tools for clinicians and patients to monitor violence risk, allowing them to take action to prevent violence, including suicide.

SUBCOMMITTEE RECESS Senator BLUNT. The record will stay open for 1 week for additional questions. And the subcommittee will stand in recess until June 27th at 10:30 a.m. [Whereupon, at 11:29 a.m., Thursday, June 22, the subcommittee was recessed, to reconvene at 10:30 a.m., Tuesday, June 27.]

65 Https://projectreporter.nih.gov/projectlinfoldescription.cfm?aid=8887832&icde=27520350.