[Senate Hearing 115-690]
[From the U.S. Government Publishing Office]


                                                    S. Hrg. 115-690

                         IMPLEMENTATION OF THE
                        21ST CENTURY CURES ACT:
                         PROGRESS AND THE PATH
                     FORWARD FOR MEDICAL INNOVATION

=======================================================================

                                HEARING

                                 OF THE

                    COMMITTEE ON HEALTH, EDUCATION,
                          LABOR, AND PENSIONS

                          UNITED STATES SENATE

                     ONE HUNDRED FIFTEENTH CONGRESS

                             FIRST SESSION

                                   ON

  EXAMINING IMPLEMENTATION OF THE 21ST CENTURY CURES ACT, FOCUSING ON 
          PROGRESS AND THE PATH FORWARD FOR MEDICAL INNOVATION

                               __________

                            DECEMBER 7, 2017

                               __________

 Printed for the use of the Committee on Health, Education, Labor, and 
                                Pensions

[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]

        Available via the World Wide Web: http://www.govinfo.gov

                              __________
                               

                    U.S. GOVERNMENT PUBLISHING OFFICE                    
27-828 PDF                  WASHINGTON : 2019                     
          
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          COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS

                  LAMAR ALEXANDER, Tennessee, Chairman
MICHAEL B. ENZI, Wyoming             PATTY MURRAY, Washington
RICHARD BURR, North Carolina         BERNARD SANDERS (I), Vermont
JOHNNY ISAKSON, Georgia              ROBERT P. CASEY, JR., Pennsylvania
RAND PAUL, Kentucky                  AL FRANKEN, Minnesota
SUSAN M. COLLINS, Maine              MICHAEL F. BENNET, Colorado
BILL CASSIDY, M.D., Louisiana        SHELDON WHITEHOUSE, Rhode Island
TODD YOUNG, Indiana                  TAMMY BALDWIN, Wisconsin
ORRIN G. HATCH, Utah                 CHRISTOPHER S. MURPHY, Connecticut
PAT ROBERTS, Kansas                  ELIZABETH WARREN, Massachusetts
LISA MURKOWSKI, Alaska               TIM KAINE, Virginia
TIM SCOTT, South Carolina            MAGGIE WOOD HASSAN, New Hampshire
               David P. Cleary, Republican Staff Director
         Lindsey Ward Seidman, Republican Deputy Staff Director
                 Evan Schatz, Democratic Staff Director
             John Righter, Democratic Deputy Staff Director

                                  (ii)

  
                            C O N T E N T S

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                               STATEMENTS

                       THURSDAY, DECEMBER 7, 2017

                                                                   Page

                           Committee Members

Alexander, Hon. Lamar, Chairman, Committee on Health, Education, 
  Labor, and Pensions, opening statement.........................     1
Murray, Hon. Patty, Ranking Member, Committee on Health, 
  Education, Labor, and Pensions, opening statement..............     4

                               Witnesses

Collins, Francis, M.D., Ph.D., Director, National Institutes of 
  Health, Bethesda, MD...........................................     6
    Prepared Statement...........................................     8
Gottlieb, Scott, M.D., Commissioner, Food and Drug 
  Administration, Silver Spring, MD..............................    14
    Prepared Statement...........................................    16
                              ----------                              

                         QUESTIONS AND ANSWERS

Responses by Francis Collins to questions of:
    Senator Murray...............................................    51
    Senator Cassidy..............................................    53
    Senator Collins..............................................    54
    Senator Roberts..............................................    56
    Senator Warren...............................................    58
    Senator Whitehouse...........................................    58
Responses by Scott Gottlieb to questions of:
    Senator Alexander............................................    59
    Senator Murray...............................................    61
    Senator Baldwin..............................................    63
    Senator Cassidy..............................................    64
    Senator Roberts..............................................    65
    Senator Warren...............................................    67
    Senator Whitehouse...........................................    68

 
                         IMPLEMENTATION OF THE
                        21ST CENTURY CURES ACT:
                         PROGRESS AND THE PATH
                     FORWARD FOR MEDICAL INNOVATION

                              ----------                              


                       Thursday, December 7, 2017

                               U.S. Senate,
       Committee on Health, Education, Labor, and Pensions,
                                                    Washington, DC.
    The Committee met, pursuant to notice, at 10:10 a.m., in 
room SD-430, Dirksen Senate Office Building, Hon. Lamar 
Alexander, Chairman of the Committee, presiding.
    Present: Senators Alexander [presiding], Collins, Cassidy, 
Young, Hatch, Roberts, Scott, Murray, Casey, Bennet, 
Whitehouse, Baldwin, Murphy, Warren, Kaine, and Hassan.

                 OPENING STATEMENT OF SENATOR ALEXANDER

    The Chairman. The Senate Committee on Health, Education, 
Labor, and Pensions will please come to order.
    This is another bipartisan hearing, which is what most of 
our hearings are, which means that Senator Murray and I have 
agreed on the subject and on the witnesses. In fact, I would 
say every Member of this Committee would probably agree on the 
subject and the witnesses today, because this is a hearing 
entitled ``Implementation of the 21st Century Cures Act: 
Progress and the Path Forward for Medical Innovation'' to hear 
from Dr. Francis Collins, the Director of the National 
Institutes of Health, and Dr. Scott Gottlieb, the Commissioner 
of Food and Drugs.
    We'll have--as I mentioned to Senator Murphy, we'll have a 
hearing next Wednesday on another important part of the Cures 
Act, which was the first reorganization of our mental health 
laws in a decade, which Senator Cassidy and Senator Murphy 
played a major role in. We look forward to that.
    Senator Murray and I will each have an opening statement. 
Then we'll introduce our panel of witnesses. After our 
witnesses, each Senator will have 5 minutes of questions. I 
expect we'll have a large number of Senators coming and going 
to this hearing.
    In 2007, Doug Oliver, who is in the front row, I believe, a 
computer programmer, began to have trouble seeing and after a 
near accident had his driver's license taken away and was 
declared legally blind. The culprit was a rare form of Macular 
Degeneration. Doug moved to Nashville, where his doctor at the 
Vanderbilt Eye Institute told him that while there were no 
cures, Doug could search online for a clinical trial.
    Doug found a regenerative medicine clinical trial in 
Florida, where doctors took cells out of the bone marrow in his 
hip, spun them in a centrifuge, and then injected those into 
his eye. Three days later, he began to see. His eyesight 
eventually improved enough to get his driver's license back and 
enough that he became an effective advocate for more support 
for regenerative medicine, done the proper way, which we 
included in the 21st Century Cures Act. Earlier this year, Doug 
gave me the cane he used while he was blind. He said, ``I don't 
need it anymore.'' I treasure it, and I keep it in my office, 
and I thank him for his advocacy, and we hope others have the 
same advantage.
    When Congress passed the 21st Century Cures Act, we hoped 
to unleash medical innovation and give Americans more access to 
life-changing treatments and cures so more Americans could 
experience medical miracles. It is especially appropriate to be 
having this hearing today because it marks the 1-year 
anniversary of the Senate passing Cures.
    When it became law last December, I said that President 
Obama had signed a second Christmas miracle. The first one, in 
2015, was the Every Student Succeeds Act, the law fixing No 
Child Left Behind, which came from this Committee. Last year, 
it was the 21st Century Cures Act, which Majority Leader 
McConnell called the most important legislation Congress passed 
last year.
    I have often said of the Every Student Succeeds Act that a 
law is not worth the paper it's printed on if it is not 
implemented properly. I intend to ensure Cures is also 
implemented properly. We began our oversight on Cures with a 
hearing in October on the electronic health records provisions, 
and, in addition to today's hearing, I mentioned that we will 
continue our oversight next Wednesday on the mental health 
provisions.
    Today, we are hearing from Dr. Collins and Dr. Gottlieb on 
the provisions related to biomedical research. We are fortunate 
to have two such talented leaders who know their agencies, are 
widely respected in Congress, and capable of getting results. 
It doesn't always happen. Sometimes you have capable leaders, 
and they don't have any money, or they don't have new 
authority. Sometimes you have new authority, new money, and the 
leaders don't have a clue what they're doing. In this case, 
we've got new authority, we've got new money, and we've got two 
of the most capable leaders we could have. So we're delighted 
with that.
    While the legislation included provisions to improve 
electronic healthcare records, resources to fight the opioid 
epidemic, and the first update to mental health programs in a 
decade, the major purpose of the legislation was to provide 
additional resources and authorities to speed drugs and devices 
through the research and development process into doctors' 
offices and patients' medicine cabinets while ensuring the FDA 
gold standard of safety and efficacy. It is not an 
overstatement to say that the 21st Century Cures Act has the 
potential to affect virtually every American family by taking 
advantage of breathtaking advances in biomedical research.
    Dr. Collins, at a Senate Appropriations Subcommittee 
hearing in 2016, you offered bold predictions--you called 
them--for future major medical advances if we continue funding 
the National Institutes of Health and ensure that the Food and 
Drug Administration has the tools it needs.
    One prediction is that scientists will find ways to 
identify Alzheimer's before symptoms appear as well as how to 
slow or even prevent the disease. Alzheimer's causes untold 
family grief and costs $259 billion a year. Another prediction 
of yours was, using a patient's own stem cells, doctors could 
rebuild his or her heart. This personalized heart would make 
transplant waiting lists and anti-rejection drugs obsolete and 
put doctors like former Senator Bill Frist out of business.
    [Laughter.]
    Dr. Collins, you have made other predictions that--because 
he was a heart transplant surgeon. Dr. Collins, you made other 
predictions equally breathtaking: the development of an 
artificial pancreas for diabetes patients, A Zika vaccine, a 
universal flu vaccine, an HIV/AIDS vaccine, all available 
within a decade, and new non-addictive pain medicines to help 
patients as we continue to battle the opioid crisis that kills 
91 Americans every day. You said this week in another hearing 
that might happen in as soon as 5 years.
    The 21st Century Cures Law put in place policies that will 
fund biomedical research at a time of limitless opportunity to 
help make Dr. Collins' predictions a reality. Today, we want to 
find out from Dr. Collins and Dr. Gottlieb, those leading this 
charge, how implementation of the law is going. For example, 
Cures included a surge of one-time funding of $4.8 billion for 
the NIH, including money for the Precision Medicine Initiative, 
Cancer Moonshot, and BRAIN Initiative.
    I know from talking with Vanderbilt University that the 
Precision Medicine Initiative--the plan to map the genomes of 1 
million volunteers to help researchers develop treatments and 
cures tailored to a patient's genetics, environment, and 
lifestyle--has already begun enrolling patients less than 1 
year after the program began. In addition to the Precision 
Medicine Initiative, I am curious about how funding has been 
spent and when and how you plan to keep Congress informed of 
your results.
    Cures required a process to look at burdensome regulations 
on researchers. I would like to hear if this is helping 
researchers spend more of their time and money on research and 
less on administrative tasks. Cures also put in place policies 
at the FDA to move safe and effective treatments and cures 
through the regulatory process more rapidly and at a lower 
cost.
    For example, Senators Burr, Bennet, and Hatch worked on a 
breakthrough provision for devices modeled after a breakthrough 
provision for drugs. The first breakthrough approval was just 
last week for an exciting cancer diagnostic. Senators Isakson 
and Casey worked on removing red tape from the review of 
combination products. I worked with Senator Murray to make sure 
FDA had the authority to hire and pay scientists to keep up 
with the rapid rate of innovation.
    21st Century Cures also added $30 million to support 
regenerative medicine and an accelerated pathway for these 
treatments at FDA so we can hear more stories like Doug 
Oliver's.
    FDA has begun implementing these provisions, and I look 
forward to hearing how FDA and NIH are working together to make 
sure the funding and authorities for regenerative medicine are 
helping to advance this important work, while ensuring that bad 
actors do not take advantage of the hope of this exciting field 
to harm or defraud patients. It is going to be difficult to 
cover everything today, but I look forward to hearing about the 
progress being made to unleash medical innovation and bring new 
drugs and devices to patients.
    Senator Murray.

                  OPENING STATEMENT OF SENATOR MURRAY

    Senator Murray. Thank you so much, Chairman Alexander.
    Welcome to our guests today. Thank you for joining us.
    Dr. Collins, it's good to have another opportunity this 
week to talk with you again about the work being done at NIH.
    Dr. Gottlieb, welcome to you as well. I'm looking forward 
to your updates from FDA.
    Next week marks 1 year since the signing of the bipartisan 
21st Century Cures Act, and as I said at the time of the 
passage--and I'll repeat it now--as much as this law helped to 
build on America's tradition of leadership in lifesaving public 
health initiatives and medical innovation, Cures was really 
first and foremost about providing hope, hope to the millions 
of people and families who are impacted by illness and disease; 
hope for our communities suffering at the hands of the opioid 
epidemic, for example. Like all of my colleagues, including our 
guests today, this crisis is something I hear about every day. 
I have visited with countless communities in my home State of 
Washington that have been devastated by addiction.
    While we know we can and must do more, I'm glad that Cures 
took an important first step and dedicated over $1 billion in 
new funding above and beyond the budget caps to help states and 
communities fight back against that crisis. We secured 
important changes to make sure this money went directly to the 
states that need it the most.
    For far too long, our health system has failed patients and 
families seeking treatment and support. That is why in Cures we 
prioritized expanding access to quality care for mental illness 
and substance use disorders, and we strengthened coordination 
between local agencies engaged in crisis intervention. I'm 
looking forward to discussing that work further at a hearing 
we're having next week.
    On today's topic, I'm proud of our work on Cures to address 
head-on some of the hardest to treat diseases by providing 
nearly $4.8 billion in funding for the NIH, including support 
for the Beau Biden Cancer Moonshot and the Precision Medicine 
and BRAIN Initiatives, all of which I would note are very 
important to my home state where we are spiriting much of that 
new research taking place as a result.
    Along with these investments, we included provisions in the 
law to equip NIH with the tools and authorities needed to meet 
the demands of biomedical research in the 21st Century. We made 
it a priority to improve the inclusion of women and children 
and other underrepresented populations in clinical research so 
that the promise of these initiatives like Precision Medicine 
are extended to all patients. As part of this work, I 
championed a provision that creates a task force to better 
support the evaluation of drugs for pregnant and lactating 
women, and we addressed many of the concerns that have been 
holding back progress in the research community by supporting 
young researchers and reducing the red tape.
    Cures also made sweeping reforms to FDA, and one of my top 
priorities was granting the agency greater hiring authority to 
recruit and retain qualified individuals who understand the 
latest science and technology, and I'm very interested to get 
an update from you, Dr. Gottlieb, on how you're filling those 
positions, especially in light of the hiring freeze that this 
year was mandated by the President.
    We also made sure Cures gave FDA the authority to ensure 
medical devices, like scopes that caused the outbreak of 
antibiotic-resistant infections in my home State of Washington, 
are safe for patients, and we gave more clarity to developers 
of drug device combination products and codified key provisions 
in the Prescription Drug User Fee Agreement, including to 
ensure patients are included in the drug development process.
    I'm glad we have the opportunity today to talk about the 
ongoing implementation of Cures, and I will be very focused on 
making sure we are committed to strong congressional oversight, 
rejecting this administration's efforts to roll back and 
undermine patient protections, and doing more to provide the 
strong investment needed at NIH and at FDA not just to support 
cures but also to advance 21st Century science and innovation.
    Now, in general, I'm glad that NIH and FDA have been active 
and timely in implementing the law, including many of the 
provisions that I just talked about. I'm encouraged by these 
efforts. I want us to keep moving in the right direction.
    Dr. Collins, in light of the extremely concerning direction 
the Trump administration has taken when it comes to healthcare, 
especially in regards to women's health, I want to hear more 
about what NIH is doing to bolster your researchers' work to 
further science over extreme ideology.
    Dr. Gottlieb, during your confirmation hearing, you said 
that 21st Century Cures is a good roadmap for what you hope to 
accomplish as Commissioner. I'd like to hear about how you at 
FDA are pushing back against this administration's deregulatory 
approach and making sure Cures is being efficiently and 
faithfully implemented. Specifically, I will be asking more 
about what FDA is doing to ensure the medical devices patients 
rely on are safe and effective.
    Again, both NIH and FDA have made important steps in 
implementing and meeting Cures deadlines this year. But we have 
a lot more deadlines coming up in 2018, and since we know 
funding remains an issue, I look forward to hearing from each 
of you on how we can make sure that we're truly putting 
patients and families first.
    Again, welcome to both of you. Thank you for being here.
    The Chairman. Thank you, Senator Murray.
    Each witness will have 5 minutes to give his testimony. The 
first witness we'll hear from is Dr. Francis Collins. He's been 
Director of the National Institutes of Health, overseeing the 
work of the largest supporter of biomedical research in the 
world since 2009. The second witness we'll hear from is Dr. 
Scott Gottlieb. He's Commissioner of Food and Drugs, ensuring 
our drugs and medical devices are safe and effective. He was 
formerly Deputy Commissioner of the same agency. He was 
confirmed on May 9 of this year.
    Welcome again to our witnesses. Dr. Collins, let's begin 
with you.

                  STATEMENT OF FRANCIS COLLINS

    Dr. Collins. Well, good morning, and thank you, Chairman 
Alexander, Ranking Member Murray, and other distinguished 
Committee Members. It is an honor to be here today with my 
colleague, Dr. Scott Gottlieb, the Commissioner of the FDA.
    As you well know, the 21st Century Cures Act aimed to 
catalyze a very important goal shared by all Americans; to 
speed the pace at which scientific discoveries are translated 
into lifesaving treatments and cures. We at NIH, actually, 
greatly appreciate your leadership in passing this bipartisan 
act by a vote of 95 to 4 in the Senate exactly 1 year ago 
today, December 7th.
    This enhances our authorities and resources in ways that 
will help us to achieve this goal. Many thoughtful provisions 
are included in the act, such as reducing administrative 
burdens so our scientists can devote more of their time to 
research, expanding our ability to award prizes for 
exceptionally creative ideas, and strengthening measures to 
protect patient privacy.
    In my written statement, I've submitted a comprehensive 
report on how NIH has worked quickly to implement the 
provisions of the act. We are motivated by a sense of urgency 
to help patients in need of breakthroughs.
    In my oral statement, I'd like to focus on the Cures 
Innovation Fund. Among the vital areas of NIH-supported 
research being accelerated by this fund are the BRAIN 
Initiative, the Cancer Moonshot, the Regenerative Medicine 
Innovation Project, and the Precision Medicine Initiative.
    Let's begin with the BRAIN Initiative. This pioneering 
effort is aimed at revolutionizing our understanding of the 
most complex structure in the known universe, the human brain. 
In fiscal year 2017, we leveraged our Cures Innovation Funding 
with our annual appropriation to launch no less than 110 
exciting new brain research projects. Some of these will 
develop detailed maps of neural circuits. Others will create a 
census of the cell types in the brain, and still others will 
create powerful new tools to monitor and modulate brain 
activity. This will advance efforts to develop new ways of 
detecting, treating, and even preventing many serious brain 
disorders, including Alzheimer's Disease, Parkinson's, 
schizophrenia, autism, drug addiction, epilepsy, traumatic 
brain injury.
    With the help of the Cures Innovation Fund, a second 
research area, the Cancer Moonshot, is aggressively pursuing a 
very ambitious goal to accelerate advances in cancer 
prevention, diagnosis, treatment, and care. To achieve that 
goal, we must take a variety of innovative steps, and that 
includes enhancing the research infrastructure by creating a 
clinical trials network with an unwavering commitment to data 
sharing and to move cancer treatment programs forward more 
rapidly.
    In another of these innovative moves, NIH recently joined 
with the FDA and with 12 biopharmaceutical companies to launch 
the Partnership for Accelerating Cancer Therapies, or PACT. 
This public-private partnership will initially develop 
biomarkers to speed the development of cancer immunotherapies, 
an exciting new approach to treatment that enlists the 
patient's own immune system.
    Recently, we have seen some amazing responses to cancer 
immunotherapy. But we need to bring that kind of success to far 
more people with more types of cancer and do it quickly. The 
Cures Innovation Fund, with the support of this Congress, is 
helping to make that happen.
    The Cures Act also provides support for regenerative 
medicine research. This emerging area of science involves the 
use of cells and other technologies, such as engineered 
biomaterials and gene editing, to repair or replace damaged 
cells, tissues, or organs.
    As a result of the Cures Act, NIH has launched the 
Regenerative Medicine Innovation Project. This project recently 
made eight clinical research awards covering a broad spectrum 
of science and technology and going well beyond the funding 
specifically provided by the Cures Act. Some are focused on 
common diseases, including diabetes and vision disorders, such 
as the one that afflicted Doug Oliver that you referred to 
earlier, while others are aimed at rarer conditions, such as 
sickle cell disease and idiopathic pulmonary fibrosis.
    In partnership with the FDA, we are hosting a major 
workshop, actually right now, beginning yesterday and going all 
the way through today, to explore the state of regenerative 
medicine research involving adult stem cells. Both Scott and I 
spoke at this workshop at the beginning of it yesterday 
morning. This conference will inform our future research 
directions by helping us to identify the areas of greatest 
scientific and therapeutic promise.
    Finally, I want to tell you how thrilled I am that you 
supported the Precision Medicine Initiative, PMI, by including 
an authorization and funding in the Cures Act. The centerpiece 
of PMI is the All of Us Research Program, which will enroll 1 
million or more Americans from every walk of life. These 
volunteers will contribute their health data in many ways over 
many years to create a research resource that will catalyze a 
new era of precision medicine.
    This is an ambitious goal, and we know that NIH cannot 
succeed on its own. All across the Nation, NIH is teaming up 
with the Veterans Administration, health provider 
organizations, community health centers, a Data Center at 
Vanderbilt, and other groups to figure out the best ways to 
recruit participants, especially those that are traditionally 
underrepresented in biomedical research. NIH has also partnered 
with five companies to create a Participant Technology Center, 
and our partners are testing how wearable devices, like the 
ones I'm wearing today, may provide easy ways for all of us 
volunteers to contribute data on physical activity, sleep, 
heart rates, and so on.
    Getting all these partners on board would have been nearly 
impossible had not the Cures Act included Other Transaction 
Authority, OTA, for PMI, making it possible for NIH to move 
forward with unprecedented speed and flexibility to carry out 
beta testing of all the many components, and we are now 
scheduled to launch fully in the spring of 2018. As someone who 
grew up in a theater family, I know the value of a dress 
rehearsal before the curtain goes up. That's what our beta test 
is right now. We've enrolled over 10,000 people.
    But when the full launch does happen, you and everyone else 
who supported the 21st Century Cures Act will deserve applause. 
By the way, if you want to find out more about that, that is 
the website that will keep you posted. That applause will be 
not just for all of us, but for each of the many, many ways in 
which Cures supports the work of the National Institutes of 
Health, or, as some have called us, the National Institutes of 
Hope, as Senator Murray recently referred to.
    Speaking of hope, let me then just conclude with a favorite 
exhortation from the British poet, Peter Levi: Hope in every 
sphere of life is a privilege that attaches to action. No 
action, no hope.
    Thank you for your action in enacting the Cures Act. I'll 
be happy to take your questions.

    [The prepared statement of Dr. Collins follows:]

              Prepared Statement of Dr. Francis S. Collins

    Chairman Alexander, Ranking Member Murray, and Distinguished 
Members of this Committee, thank you for hosting this important 
hearing.
    More so, thank you for creating the need for this hearing--for the 
21st Century Cures Act (Cures Act) which was enacted 1 year ago. The 
Cures Act touches on so many important issues. From providing support 
for four cutting edge research priorities, to enhancing privacy 
protections to inclusion of various communities in research trials, to 
reducing administrative burden to expanded prize authority, we at NIH 
appreciate your leadership and dedication in enacting new authorities 
to speed the pace of research and improve how science is conducted to 
transform the way we translate discovery into therapies.
    In my testimony, I will highlight how NIH is implementing some of 
the key provisions of the Cures Act and how it is benefiting the 
biomedical research community and, most importantly, patients.
   Big Data: The Promise of Data Sharing Balanced With the Need for 
                                Privacy
    As in most fields, computing power is changing the way research is 
done. The promise of big data cannot be overstated for finding patterns 
of disease and health and targeting therapeutics to sub-populations. 
The Congress, in the Cures Act, wisely recognized both the potential 
and the risks inherent in sharing data sets and NIH has moved quickly 
to get the appropriate protections in place.
    First, on September 7th, NIH issued a Guide Notice to our research 
community implementing the significant enhancements this Committee made 
to the Certificates of Confidentiality, making them both automatic and 
compulsory. To implement this change while minimizing the burden to our 
researchers, we streamlined the issuance of Certificates into the terms 
and conditions of every research award we make involving human 
subjects. \1\ Since October 1st, every NIH award has this added layer 
of protection for research participants.
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    \1\  https://humansubjects.nih.gov/coc/index.
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    Second, on September 17th, guidance on the FOIA exemption for 
genomic information was disseminated to all NIH FOIA officers.
    Only now that the new Cures Act privacy protections are in place, 
are we moving forward on the exciting new authority to require data 
sharing. This will be a sea change in biomedical research so we must be 
deliberate about how to measure the usefulness of data sets, where 
shared data should be stored, how patient protections are insured, how 
interoperability is achieved, and what tools researchers most need in 
the shared environment. On November 6th, NIH made 12 awards in a Data 
Commons Pilot to answer just these kind of questions. We selected three 
prominent NIH datasets researchers can use to test their processes. The 
biomedical research community will be watching this pilot program very 
closely.
                               Inclusion
    We've made tremendous progress in managing diseases through the 
development of new drugs and devices over the years that were tested in 
clinical trials. But trials haven't always included the full spectrum 
of humanity, and this limits the applicability of study results. It 
also limits our ability to target therapies and address disparities. 
Congress helped NIH address this issue through the Cures Act in three 
focus areas: inclusion of children and seniors; inclusion of pregnant 
and lactating women; and continuing our focus on women, and racial and 
ethnic minorities.
    On June 1-2, 2017, as required by the Cures Act, NIH held a 
workshop on inclusion across the lifespan. It might seem easy to 
include all age ranges but both children and older adults require 
special considerations. At the workshop, investigators with expertise 
in conducting clinical studies with pediatric and older populations, 
ethics experts, and other stakeholders had a robust discussion about 
barriers and facilitators to the inclusion of volunteers of all ages in 
research. The findings and recommendations will be presented at my 
Advisory Committee meeting on December 14-15, 2017, and we will 
determine what policy changes are needed to ensure individuals across 
the lifespan are appropriately included in clinical research.
    The Cures Act also asks NIH to continue making progress on the 
inclusion of women and ethnic and racial minority populations in 
research. This has been a partnership of the Congress and NIH for many 
years--the Congress authorized both the NIH Office of Research on 
Women's Health and what is now the National Institute on Minority 
Health and Health Disparities in 1993. With the help of the Congress 
and the Cures Act, we continue to improve. We are now collecting 
inclusion data on a study-by-study basis and in the coming year NIH 
will report, for the first time, inclusion data from studies on a 
disease and condition basis. At the December meeting, the expert 
Advisory Committee will have a public discussion of recommendations for 
further advancing the field and updating our inclusion guidelines. I 
look forward to the conversation and I will be happy to update you as 
decisions are made.
    Finally, the Cures Act created a Task Force on Research Specific to 
Pregnant Women and Lactating Women (PRGLAC) to advise the Secretary of 
Health and Human Services regarding gaps in knowledge and research on 
safe and effective therapies for pregnant women and lactating women. 
\2\ This area of research is vital, but it is absolutely critical that 
we carefully consider intentional exposures in this potentially 
vulnerable time of life. NIH established PRGLAC on March 13, 2017, 
bringing together Federal and non-Federal experts, including the Food 
and Drug Administration, representatives from relevant medical 
societies, non-profit organizations, and industry, to discuss these 
important issues.
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    \2\  https://www.nichd.nih.gov/about/advisory/PRGLAC/Pages/
index.aspx.
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    PRGLAC has already held two meetings--the first on August 21-22, 
2017, to determine the scope of current Federal activities on safe and 
effective therapies for pregnant and lactating women, and the second on 
November 6-7, 2017, to understand the ethical issues surrounding 
research to develop therapies for pregnant and lactating women. The 
third meeting on February 26-27, 2018, will be on communication 
strategies for health care providers and the public about the use of 
therapies for pregnant and lactating women, and the fourth meeting on 
May 14-15, 2018, will be on recommendations to address the gaps in 
knowledge, ethical issues, and communication strategies for therapies 
used by pregnant and lactating women.
    Based on the outcome of the Task Force meetings, a report with 
recommendations will be developed for the HHS Secretary. NIH is 
grateful to the Congress for recognizing the need for careful 
consideration in this area of research and looks forward to addressing 
any recommendations made by the Task Force.
                   Strengthening Biomedical Workforce
    NIH and its stakeholder community have for many years been 
concerned about the long-term stability of the biomedical research 
enterprise. As a consequence of NIH's loss of more than 20 percent of 
its purchasing power from 2003 to 2015, researchers were forced to vie 
for limited resources, leading to a hypercompetitive environment. With 
success rates below 20 percent, many highly meritorious applications 
continue to go unfunded. This has too often resulted in misaligned 
incentives and unintended consequences for talented researchers at all 
career stages who are trying to succeed and stay in science. The 
current environment is particularly challenging for many new-and mid-
career investigators.
    Over the last several years, NIH has taken numerous steps to 
balance, strengthen, and stabilize the biomedical research workforce, 
but these measures have only taken us so far. While the percentage of 
NIH awards that support early career investigators has gone from 
declining to flat, these gains have been offset by a decline in the 
percentage of NIH awards that support mid-career investigators.


    As a direct result of the Cures Act, in June 2017, NIH launched the 
Next Generation Researchers Initiative \3\ aimed at strengthening the 
biomedical workforce with a focus on early career investigators or 
investigators who are at an early stage in their career. NIH intends to 
take a multi-pronged approach, which we outlined in an article 
published on November 7, 2017, \4\ to increase the number of NIH-funded 
early stage and mid-career investigators and to stabilize the career 
trajectory of scientists.
---------------------------------------------------------------------------
    \3\  https://grants.nih.gov/ngri.htm.
    \4\  Michael Lauer, Lawrence Tabak, and Francis Collins, ``Opinion: 
The Next Generation Researchers Initiative at NIH,'' PNAS, 114 (2017): 
11801-11803.
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    NIH will develop evidence-based, data-driven strategies to assure 
that NIH investments are directed in ways that maximize scientific 
output. Institutes and Centers will also place greater emphasis on 
current NIH funding programs to identify, grow, and retain new-and mid-
career investigators across these critical career stages. The NIH 
Office of the Director will track progress across ICs and assess if 
these strategies are working. I am personally committed to this issue 
and thank the Committee for their support of early and mid-career 
investigators.
   System Innovation: Reducing Administrative Burden and Increasing 
                               Efficiency
    Policies generated with the best intentions sometimes have serious 
adverse consequences for research. The Cures Act included numerous 
provisions that cut the bureaucratic red tape that slows the progress 
of science. It also provided NIH with new authorities to improve 
efficiencies and speed up the discovery process.
    The Cures Act included provisions to improve ClinicalTrials.gov. 
ClinicalTrials.gov is a data base of privately and publicly funded 
clinical studies conducted around the world that plays a crucial role 
in ensuring the transparency and accountability to the public of 
researchers and their sponsors. In addition, this resource is used by 
researchers to stay up-to-date on developments in their field, find 
collaborators, and identify unmet needs, and it is also used by 
patients and families to search for potential studies to enroll in or 
learn about new treatments that are being tested. NIH strives to make 
this resource as user friendly as possible so it can benefit 
researchers, patients, and their families, and the Cures Act is helping 
in several ways.
    First, the Cures Act made technical fixes to the legislation 
establishing ClinicalTrials.gov that ensure NIH is able to capture more 
clinical trials in the system and improve our oversight and 
transparency. Second, it required NIH to consult with relevant Federal 
agencies and other stakeholders to receive recommendations to enhance 
ClinicalTrials.gov's usability, functionality, and search capability. 
In February 2017, the National Library of Medicine (NLM), along with 
18F, a digital services consultancy within the General Services 
Administration, began conducting user research on ClinicalTrials.gov 
with a range of stakeholders. As a result of this work, NIH rolled out 
a first in a series of changes to ClinicalTrials.gov on June 19, 2017. 
On September 25, 2017, NLM released more updates as the next phase in 
its ongoing effort to enhance the functionality of the data base. In 
response to the Cures Act, NLM will work continuously to make it easier 
for users to find and participate in clinical trials.
    In an effort to improve efficiency, the Cures Act provided a new 
EUREKA prize authority and allowed NIH to use Other Transactions 
Authority (OTA) in two areas that need extra flexibility and 
collaboration: the Common Fund and the All of Us Research program, part 
of the NIH Precision Medicine Initiative.
    The EUREKA prize authority is being implemented in three ways:

      On November 2d, the National Institute on Aging issued a 
request \5\ for public input on (1) the feasibility of three potential 
prize competitions focused on Alzheimer's disease (AD) and related 
dementias (ADRD): Validating predictors of AD progression; PET 
radiotracer to measure in vivo synaptic integrity; and low cost 
innovation of improving systems of care for AD/ADRD patients and 
caregivers; and (2) any other suggestions on AD/ADRD research goals to 
connect to a prize. Comments are due on December 31, 2017.
---------------------------------------------------------------------------
    \5\  https://grants.nih.gov/grants/guide/notice-files/NOT-AG-17-
018.html.

      NIH formed the EUREKA Prize Coordination Committee to 
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review future proposals for future EUREKA prize competitions.

      NIH funded the National Academy of Sciences (NAS) to 
study Innovation Prizes and Federal R&D with specific emphasis on 
strategies to determine which ``EUREKA'' prize topics are consistent 
with congressional intent. The NAS study will also consider the 
strengths and weaknesses of various measures of health outcomes and 
effects on government expenditures. The NAS intends to hold a workshop 
in 2018.

    OTA is integral to our exploration of how best to structure data 
sharing, known as the Data Commons Pilot Phase, \6\ which was announced 
on November 6th. The goal of the NIH Data Commons is to accelerate new 
biomedical discoveries by providing a cloud-based platform where 
investigators can store, share, access, and compute on digital objects 
(data, software, etc.) generated from biomedical research and perform 
novel scientific research including hypothesis generation, discovery, 
and validation. The use of OTA awards allows flexibility for the 
awardees to work together to design innovation solutions that meet the 
computational and scientific needs of the Pilot.
---------------------------------------------------------------------------
    \6\  https://commonfund.nih.gov/bd2k/commons/awardees

    The All of Us Research Program aims to enroll one million 
individuals in a decades-long research project. That ambitious goal 
requires flexibility, complex and dynamic interactions, and ways to 
engage non-traditional NIH awardees to advance the mission. For 
example, All of Us has used OTA to make awards to the Healthcare 
Provider Organizations to help build the research protocols, test 
enrollment procedures, and collect essential health data and biological 
---------------------------------------------------------------------------
specimens.

    The Cures Act also recognizes that two of the cornerstones of 
scientific advancement are rigor in designing and performing scientific 
research and the ability to reproduce biomedical research findings. In 
recent years, the scientific community has become aware of the need to 
improve rigor and reproducibility. In 2014, NIH worked with scientific 
publishers to develop a set of principles and goals that 79 publishers 
have now endorsed. As the Cures Act requires, my Advisory Committee has 
convened a Working Group on Rigor and Reproducibility and they are 
reviewing the experience of the last few years, leading to the 
development of recommendations for a formal policy. I look forward to 
updating you as this effort takes shape.
                          NIH Innovation Fund
    Last, but certainly not least, the Cures Act provided multi-year 
funding through the NIH Innovation Fund for four highly innovative 
scientific research initiatives: the Precision Medicine Initiative 
(PMI), the Brain Research through Advancing Innovative 
Neurotechnologies (BRAIN) Initiative, the Cancer Moonshot, and the 
Regenerative Medicine Innovation Project. As required by the Cures Act, 
on March 28th, I solicited recommendations from my Advisory Committee 
on how to allocate the funds. We had a robust conversation about each 
of the initiatives and the Advisory Committee members provided critical 
advice on how to move forward. As a result of that discussion, and 
conversations with my NIH colleagues, we drafted the NIH Innovation 
Fund Work Plan, \7\ which was submitted to Congress in September 2017, 
outlining how the agency will use the NIH Innovations Funds for each of 
these four initiatives. I would like to tell you a bit about each of 
these initiatives and how the NIH Innovation Funds are helping to move 
each initiative forward.
---------------------------------------------------------------------------
    \7\  https://www.nih.gov/sites/default/files/research-training/
initiatives/nih-cures-innovation-plan.pdf.
---------------------------------------------------------------------------
                   The Precision Medicine Initiative
    Precision medicine is a revolutionary approach for disease 
prevention and treatment that takes into account individual differences 
in lifestyle, environment, and biology. While some advances in 
precision medicine have been made, the practice is not in use for most 
diseases. The All of Us Research Program, a key element of PMI, is 
building a national resource--one of the world's largest, most diverse 
biomedical data sets in history--to accelerate health research and 
medical breakthroughs, enabling individualized prevention, treatment, 
and care. All of Us will engage one million or more U.S. volunteers 
from all life stages, health statuses, races/ethnicities, and 
geographic regions to reflect the country's diverse places and people 
to contribute their health data over many years to improve health 
outcomes, fuel the development of new treatments for disease, and 
catalyze a new era of evidence-based and more precise preventive care 
and medical treatment.

    Across the Nation, NIH has engaged 10 large health provider 
organizations, six community health centers, and the Veterans 
Administration to be our partners in this ambitious study. The program 
is launching in stages. The beta phase began in May 2017 during which 
each of our partners are testing their systems and processes to ensure 
a good experience for participants.

    In July 2017, the program made its first four community partner 
awards to motivate diverse communities to join and remain in the 
program, with a focus on those traditionally underrepresented in 
biomedical research. Each of these organizations has deep, trusted 
relationships within and ties to their communities, and we are so very 
pleased to have the opportunity to partner with them to enhance our 
outreach into communities that have traditionally been underrepresented 
in biomedical research. NIH has also engaged with organizations to 
create mobile apps to enroll, obtain consent from, collect data from, 
and communicate with All of Us participants. One of our partners is 
working with FitBit on a pilot that will start in mid-2018 to test out 
ways for participants to easily and efficiently contribute data on 
physical activity, sleep, heart rates, and other behavioral health 
information.

    We anticipate to roll out nationally in spring 2018. Following the 
national launch, we will make continuous improvements and updates to 
the program based on participant feedback and emerging scientific 
opportunities and technological advances. The Cures Act Innovation 
Funds will be critical to ensuring the success of All of Us and the 
promise of personalized medicine.
                          The BRAIN Initiative
    The BRAIN Initiative is aimed at revolutionizing our understanding 
of the human brain, the most complex structure in the known universe. 
Launched in 2013, this large-scale effort will push the boundaries of 
neuroscience research and equip scientists with insights necessary for 
treating a wide variety of brain disorders. By accelerating the 
development and application of innovative technologies, researchers 
will be able to produce a revolutionary new dynamic picture of the 
brain that, for the first time, shows how individual cells and complex 
neural circuits interact in both time and space. Long desired by 
researchers seeking new ways to treat, cure, and even prevent brain 
disorders, this picture will fill major gaps in our current knowledge 
and provide unprecedented opportunities for exploring exactly how the 
brain enables the human body to record, process, utilize, store, and 
retrieve vast quantities of information, all at the speed of thought.

    NIH leveraged the Cures Act's fiscal year 2017 Innovation Funds, in 
addition to our annual appropriation, to launch 110 exciting new 
research projects. \8\ These projects are focused on developing 
detailed brain circuit maps and powerful new tools to monitor and 
modulate brain activity in animal models to benefit patients with 
neurological and psychiatric disorders. Understanding the way the brain 
processes information and how it lays down memories and retrieves them 
will be instrumental for understanding brain health, and ultimately, 
preventing brain disorders such as Alzheimer's disease, Parkinson's, 
schizophrenia, autism, drug addiction, and traumatic brain injury. 
These awards add to work already underway to give us a high-resolution 
picture of the circuits and networks in the brain, how they work, and 
where they can go wrong.
---------------------------------------------------------------------------
    \8\  https://www.braininitiative.nih.gov/funding/fundedAwards.htm.
---------------------------------------------------------------------------
                          The Cancer Moonshot
    The Cancer Moonshot, \9\ funded in the Cures Act, has an ambitious 
goal: to dramatically speed advances in cancer prevention, diagnosis, 
treatment, and care. The National Cancer Institute (NCI) solicited 
direct input from the public and convened a Blue Ribbon Panel (BRP) of 
the Nation's top cancer researchers, oncologists, patient advocates, 
and private-sector leaders. In September 2016, the BRP presented its 
report outlining ten ambitious and achievable recommendations to the 
NCI's National Cancer Advisory Board. These recommendations shape the 
scientific blueprint of the Cancer Moonshot representing areas of 
research that are poised to accelerate our understanding of cancer and 
bring benefit to patients. Overall, the recommendations create a vision 
for future cancer research and treatment in which:
---------------------------------------------------------------------------
    \9\  https://www.cancer.gov/research/key-initiatives/moonshot-
cancer-initiative.

      Researchers can identify possible targets for the 
development of new cancer treatments and preventive interventions, 
including immunotherapy and immunoprevention, and learn more about how 
---------------------------------------------------------------------------
to avoid or overcome cancer drug resistance in patients;

      Diverse groups of patients contribute information about 
their cancer, obtain a genomic profile, learn what treatments might 
work best given their profile, and identify clinical trials that may be 
appropriate for them;

      Infrastructures are established so that health care 
providers and researchers can share, access, and analyze information 
that improves the understanding of how tumors evolve, better predicts 
treatment outcomes, and helps control patient symptoms and side 
effects.

    Some of these goals are scientific in nature, and some are 
systemic. If we are to speed advances, we cannot simply do more of the 
same. We must transform the way we conduct research, the way we share 
results, and the way we get discoveries into patient care. In fiscal 
year 2017, NIH made 142 Cancer Moonshot awards, including efforts to 
leverage advances in immunotherapy, understand drug resistance, and 
develop of new technologies to characterize tumors and test therapies. 
These national and international collaborations will drive discovery 
for cancer patients and their families. I would like to highlight one 
of those collaborations for you today.

    On October 12, 2017, NIH and 11 leading biopharmaceutical companies 
launched the Partnership for Accelerating Cancer Therapies (PACT), a 5-
year public-private research collaboration totaling $215 million as 
part of the Cancer Moonshot. \10\ PACT will initially focus on efforts 
to identify, develop, and validate robust biomarkers--standardized 
biological markers of disease and treatment response--to advance new 
immunotherapy treatments that harness the immune system to attack 
cancer. We have seen dramatic responses from immunotherapy, often 
eradicating cancer completely for some cancer patients. We need to 
bring that kind of success--and hope--to more people with more types of 
cancers, and we need to do it quickly. A systematic approach like PACT 
will help us to achieve success faster.
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    \10\  https://www.nih.gov/news-events/news-releases/nih-partners/
leading-biopharmaceutical-companies-accelerate-development-new-cancer-
immunotherapy-strategies-more-patients.
---------------------------------------------------------------------------
    With the support of the Congress, the Cancer Moonshot will 
transform the way cancer research is conducted and ensure that 
substantial progress is made for patients and their families.
              The Regenerative Medicine Innovation Project
    Regenerative medicine is an emerging area of science that holds 
great promise for treating and possibly even curing a variety of 
injuries and diseases. Regenerative medicine includes using stem cells 
and other technologies, such as engineered biomaterials and gene 
editing--to repair or replace damaged cells, tissues, or organs. Stem 
cell-based approaches are under development in labs around the world, 
and some have already moved into clinical trials. Such progress 
notwithstanding, much work remains to be done toward the development of 
safe and effective regenerative medicine interventions to realize the 
full potential of this field.

    As a result of the Cures Act, NIH launched the Regenerative 
Medicine Innovation Project to support clinical research on adult stem 
cells while promoting the highest standards for carrying out scientific 
research and protecting patient safety. The $2 million Cures provided 
for this initiative in fiscal year 2017 were amplified through matching 
funds and NIH Institute contributions to reach a total of just under $5 
million. In September, NIH made eight clinical research awards \11\ 
that cover a broad spectrum of science and new technologies, and have 
the potential to advance understanding and treatment of common 
diseases--including diabetes, anemia, corneal and other eye diseases, 
and chronic skin ulcers--as well as rare diseases, including idiopathic 
pulmonary fibrosis, inherited skin diseases, and sickle cell disease.
---------------------------------------------------------------------------
    \11\  https://www.nih.gov/rmi/fy-2017-funded-awards.
---------------------------------------------------------------------------
    Several awards will explore the use of adult stem cells to make 
specialized cells and tissues that could help reduce the need for whole 
organ transplants or otherwise restore normal function. Others aim to 
develop reliable methods of generating red blood cells and platelets in 
the lab to improve the safety and supply of blood available for 
transfusion.

    NIH looks forward to the opportunity the Cures Act provides to 
advance this field of science and is hosting a workshop on December 6-
7, 2017, \12\ to explore the state of regenerative medicine science 
involving adult stem cells, with a focus on approaches for the 
development of safe and effective products. This will help inform our 
funding decisions in future fiscal years.
---------------------------------------------------------------------------
    \12\  https://www.nih.gov/research-training/medical-research-
initiatives/cures.
---------------------------------------------------------------------------
                               Conclusion
    Thank you for your leadership and dedication that resulted in 
enacting the Cures Act 1 year ago. Over the past year, the Cures Act 
has provided NIH with critical resources and tools to advance our 
mission--to seek fundamental knowledge about the nature and behavior of 
living systems and the application of that knowledge to enhance health, 
lengthen life, and reduce illness and disability. We appreciate 
Congress's support for NIH through the Cures Act and will continue to 
implement the law to accelerate scientific discoveries and benefit 
patients.
                                 ______
                                 
    The Chairman. Thank you, Dr. Collins. I hope sometime 
during the Q and A, you'll have a chance to comment on your 
belief that the Other Transactions Authority, which you already 
have, would be helpful in other areas to help us get where we 
all want to go.

    Dr. Gottlieb.

                  STATEMENT OF SCOTT GOTTLIEB

    Dr. Gottlieb. Thanks a lot, Chairman Alexander, Ranking 
Member Murray, and Members of the Committee. Thank you for the 
invitation to testify at this hearing to discuss the 
implementation of the 21st Century Cures Act.
    Cures set FDA on a transformative path. It set out to 
optimize our investments in science by modernizing how FDA 
oversees breakthrough technologies. You asked us to advance 
innovations more efficiently while maintaining our gold 
standard for protecting patients. This focus on innovation 
couldn't come at a better time. Across multiple fields of 
science, we stand at an inflection point in medicine where new 
technology is creating foundational opportunities to treat and 
cure disease in ways that weren't possible just a short time 
ago.
    Take, for example, our recent experience with gene therapy. 
We have seen two recent approvals of CAR-T therapies for cancer 
where a patient's own immune cells are reengineered using the 
tools of gene therapy to target a patient's individual cancer. 
This form of gene therapy represents a whole new paradigm in 
treating cancer, and the early results are changing the way we 
treat serious tumors.
    This experience shows how a single fundamental breakthrough 
in science can open up a whole new way of combating disease. In 
gene therapy, that breakthrough has been the development of 
vehicles that can deliver genes more efficiently to their 
target inside the body. These are often referred to as vectors, 
and they've taken the form of viruses that are specifically 
engineered for this purpose.
    In particular, the advent of a specific kind of largely 
inert adeno-associated virus, or AAV vector, was an inflection 
point in this field. I liken the advent of the AAV vectors to 
the development of processes for making antibody drugs and 
making these medicines nearly identical to fully human cells 
that they were mimicking.
    Monoclonal antibodies represented a promising field of 
potentially breakthrough medicines in the 1990's, but for a 
long time, these therapeutic drugs fell short of their promise. 
That was because these drugs were made with antibodies from 
mice, and the antibody drugs themselves were soon rejected by 
patients' immune systems. Then came the science for humanizing 
these antibodies so they would more fully mimic the normal 
human counterparts, and pretty soon, we saw many breakthrough 
drugs as a result. A whole new field of medicine grew up very 
fast.
    I believe we're at a similar turning point when it comes to 
gene therapy. Over the next several years, we'll see this 
approach become a mainstay of treating and probably curing a 
lot of our most devastating and intractable illnesses. At FDA, 
we're focused right now on establishing the right policy 
framework to capitalize on this scientific opening.
    Researchers at MIT recently estimated that about 40 gene 
therapies might win FDA approval by the end of 2022 from a 
current pipeline of 932 development candidates. They estimate 
that 45 percent of total gene therapy drugs are expected to 
target cancer. I can't affirm their estimate, but I can confirm 
that we're at the early stages of a transformation in medical 
treatment as a consequence of this new technology, and the 
benefits are likely to accelerate quickly.
    The advance of this field is not risk free. Yet there are 
good examples of how FDA's embrace of the Cures Act and our 
effort to build on what Congress set out to do in balancing 
safety with scientific promise is expanding our ability to 
capitalize on this breakthrough innovation. In this case, Cures 
provided a pathway for certain regenerative medicine products 
to receive expedited review by FDA through the RMAT 
designation. We extended that opportunity.
    FDA has considered CAR-T products to be a form of gene 
therapy since the key therapeutic manipulation that's made to 
the cells is through a gene product delivered by a vector. In 
FDA's new draft guidance on expedited programs for regenerative 
medicine therapies for serious conditions, FDA clarified that 
regenerative medicine therapies would include gene therapies 
that lead to durable modifications of cells and tissues, 
including genetically modified cells. This would include CAR-T 
products when these gene therapy products lead to a durable 
modification of cells and tissues and, therefore, deliver a 
sustainable effect in the body.
    For example, if a gene therapy alters tissue to allow the 
body to express certain therapeutic proteins, or if a CAR-T 
cell has resiliency and maintains its presence and delivers a 
sustainable therapeutic effect, we would consider them to be 
regenerative medicine therapies. By FDA taking these science-
based decisions, it means that gene therapies, including CAR-T, 
may be eligible for the RMAT designation.
    Next year, we'll be building on these opportunities. We'll 
begin issuing a suite of disease specific guidance documents on 
the development of specific gene therapy products. We intend to 
lay out modern and more efficient parameters, including new 
clinical measures for the evaluation and approval and review of 
gene therapy for different high-priority diseases where the 
platform is being targeted. We plan to focus the first guidance 
document on the use of gene therapy in hemophilia.
    Other documents will address clinical areas where there's a 
lot of interest in using these techniques, such as certain more 
common single gene disorders. We'll provide innovators with 
advice and development pathways, including potential 
accelerated approval endpoints.
    Gene therapy is just one opportunity in transforming 
medicine. This year, FDA may be on track to approve the highest 
or second highest number of novel medicines across our combined 
biologics and drug centers in FDA's entire history. We'll also 
approve the highest number of generic medicines ever, and we're 
on pace to approve the highest number of novel medical devices 
in our modern history, all this year, all at one time.
    The result of these benefits is measured in product 
approvals and in some important and some highly novel medicines 
like the gene therapies. But, ultimately, it's measured in its 
human impact.
    I look forward to answering your questions, and on behalf 
of my colleagues at FDA, I want to thank you for your support 
of our mission.
    [The prepared statement of Dr. Gottlieb follows:]

                Prepared Statement of Dr. Scott Gottlieb

    Chairman Alexander, Ranking Member Murray, and Members of the 
Committee:
    Thank you for the opportunity to testify today on FDA's 
implementation of the 21st Century Cures Act (Cures Act), almost 1 year 
after the law's enactment.
    The Cures Act was a significant legislative achievement that 
coincided with a distinctive moment in medicine and technology. This 
legislation grew out of a bipartisan, bicameral recognition that we are 
at a moment in science when we have more opportunity to fundamentally 
alter the course of many human ailments and even cure diseases or 
reverse the effects of injury and illness.
    The Cures Act includes provisions that have the potential to impart 
far-reaching effects on scientific advancements in medical product 
development. The new law complements many efforts underway at FDA, all 
aimed at transforming the way we support product development and 
marketing authorization and solidifying FDA's gold standard for safety 
and effectiveness.
                        Implementation Overview
    The Cures Act provides the Agency with important tools that help us 
continue to meet our mission to protect and promote the public health. 
As such, it has been a top priority of mine to ensure timely 
implementation so patients can realize the benefits of this new law. By 
providing product developers a clear and predictable path for new 
advances, patients and consumers can realize the benefits of 
innovations while maintaining confidence that the resulting medical 
products are safe and effective.
    The aim of these policies is to improve patient access to 
innovative medical products while continuing to protect those who rely 
on these products. The provisions help FDA in its commitment to 
continue taking a fresh look at how we regulate products developed 
through truly novel medical advances to ensure that FDA is encouraging 
their development and creating efficient, risk-based pathways.
    Our implementation of the Cures Act has been integrated into our 
broader agency efforts. From day one, FDA has worked across medical 
product centers and offices to fully implement the law and build on its 
provisions. FDA's headway in pursuing the opportunities enabled by the 
Cures Act illustrates the Agency's enthusiasm and commitment to the 
spirit and letter of the law's provisions.
    Practically, we have facilitated this through the creation of an 
intra-agency steering committee to ensure a coordinated approach to 
implementation. This steering committee, working with subject matter 
experts in the relevant Centers and offices, helps guide the Agency's 
timely implementation of the Cures Act provisions. It is led by FDA 
Office of Commissioner staff ensuring a high-level focus on the 
implementation of the Cures Act.
    The steering committee's first task was to develop the Agency's 
required work plan to explain the approach we intended to take to 
implement certain provisions of the Cures Act, both now and in future 
years. The resulting work plan lays out our vision for the $500 million 
in authorized new funds over 9 years, if appropriated, that is included 
in the law. \1\ The steering committee also conducted an analysis of 
the law's provisions and compiled a list of all FDA-related 
requirements. The steering committee uses these documents to ensure 
transparency with the public on our progress by maintaining a website 
on the Cures Act, as well as a public tracker of deliverables required 
by the Cures Act. The current tracker lists our commitments and 
progress toward fulfilling them. \2\ This public information allows a 
wide range of stakeholders to keep up with our implementation efforts.
---------------------------------------------------------------------------
    \1\  The Cures Act Work Plan can be accessed here: https://
www.fda.gov/downloads/RegulatoryInformation/LawsEnforcedbyFDA/
SignificantAmendmentstotheFDCAct/21stCenturyCuresAct/UCM562852.pdf.
    \2\  The Cures Act Deliverables Tracker can be found on our Cures 
Act webpage and accessed here:https://www.fda.gov/
RegulatoryInformation/LawsEnforcedbyFDA/
SignificantAmendmentstotheFDCAct/21stCenturyCuresAct/ucm562475.htm21.
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    We also have worked with our colleagues at the Department and other 
Health and Human Services (HHS) agencies, such as the National 
Institutes of Health (NIH), to implement crosscutting provisions. For 
example, FDA's Office of Women's Health has collaborated with NIH and 
others on the Task Force on Research Specific to Pregnant Women and 
Lactating Women to help improve the availability of information 
available to providers and patients for making evidence-based treatment 
decisions.
    Throughout the implementation process, FDA has utilized our new 
authorities in the Cures Act to pursue new ways to improve the climate 
for innovation and advance products to those who need them. In doing 
so, we have challenged ourselves to look at how we can make the 
development process more efficient by modernizing our processes and 
removing obstacles that add to time and cost without meaningfully 
improving our knowledge about safety and effectiveness.
                         Implementation Updates
                     oncology center for excellence
    One of our first achievements under the Cures Act was to stand up 
FDA's new Oncology Center for Excellence (OCE). The OCE marks a shift 
in FDA's traditional operating structure. It creates cross-center teams 
to work together to examine products to treat cancer. Rather than 
focusing on the primary mechanism of action, or on the kind of product 
platform being used, teams are grouped based on their deep 
understanding of the disease.
    This approach to product review already has had an impact in the 
setting of oncology--in August, FDA approved the first cell-based gene 
therapy ever in the U.S. to treat certain children and young adults 
with B-cell acute lymphoblastic leukemia. A second product to treat 
adult patients with certain types of large B-cell lymphoma was approved 
in October. Both products had clinical reviews conducted by the OCE, 
while our Center for Biologics Evaluation and Research (CBER) conducted 
all other aspects of review and made the final product approval 
determinations.
    This is an organizational model that we seek to adopt in other 
settings. We are evaluating the creation of additional disease-specific 
offices as part of a more modern approach to the Office of New Drugs 
(OND) in the Center for Drug Evaluation and Research (CDER). Some of 
the areas under consideration are immunology and neuroscience. The 
goals are to provide stakeholders with a single point of contact and to 
foster synergies and surge capacity across different offices.
                  Minimal Risk Clinical Investigations
    Another cross-cutting initiative has been to produce guidance 
related to section 3024 of the Cures Act. This section provides FDA 
with the authority to permit an exception from informed consent for 
minimal risk clinical investigations when specific criteria are met. 
Our medical product centers for biologics, drugs, and devices partnered 
with our Office of Good Clinical Practice and Office of 
Counterterrorism and Emerging Threats to issue a final guidance related 
to this provision in July. The guidance will facilitate the conduct of 
certain minimal risk clinical investigations that are important to 
address significant public health needs without compromising the 
rights, safety, or welfare of human subjects.
                         Regenerative Medicine
    One of the most promising new fields of science and medicine is the 
area of cell therapies and their use in regenerative medicine. These 
new technologies, most of which are in early stages of development, 
hold significant promise for transformative and potentially curative 
treatments for some of humanity's most troubling and intractable 
maladies.
    The Cures Act recognized these opportunities and highlighted the 
need to establish enhanced pathways for these promising therapies. 
Immediately after the law passed, CBER moved quickly to establish the 
Regenerative Medicine Advanced Therapy (RMAT) designation program, as 
authorized in section 3033. This program aims to facilitate an 
efficient development program, expedited review of innovative 
regenerative medicine therapies, and provide more timely access to 
potentially life-saving products. Products granted designation are 
eligible for increased early interactions with FDA, including all the 
benefits available to breakthrough therapies. As of October 31, FDA had 
granted 11 RMAT designations.
    Building on these activities, a few weeks ago, FDA announced the 
Agency's Comprehensive Policy Framework for Regenerative Medicine. The 
framework clarifies the Agency's current risk-based, flexible 
regulatory approach and implements provisions of the Cures Act related 
to regenerative medicine through a series of two final and two draft 
guidance documents. When finalized, the draft guidances will further 
assist in the development of innovative regenerative medicine 
therapies. The first draft guidance document addresses expedited 
programs for regenerative medicine therapies products, including the 
new RMAT designation program, while the other addresses devices used in 
recovery, isolation, or delivery of RMAT products.
    In particular, the draft guidance on expedited programs describes 
regenerative medicine therapies eligible for RMAT designation as 
including cell therapies, therapeutic tissue engineering products, 
human cell and tissue products, and combination products using certain 
such therapies or products, as well as gene therapies that lead to a 
durable modification of cells or tissues (including genetically 
modified cells). For example, CAR-T products, which represent a durable 
modification to certain T-cells of their recipients, have been 
considered by FDA to be a form of gene therapy. Therefore, RMAT 
designation is available to CAR-T products that meet the other criteria 
for designation.
    CBER is also working to facilitate an effort to coordinate and 
prioritize the development of standards and consensus definitions of 
terms to support the development, evaluation, and review of 
regenerative medicine therapies and regenerative advanced therapies, 
including with respect to the manufacturing processes and controls of 
such products. In September 2017, FDA awarded a contract to support the 
coordination and development of these standards and consensus 
definitions through a public process, in consultation with the National 
Institute of Standards and Technology and other stakeholders.
                             Digital Health
    FDA also is working to implement the digital health provisions of 
the Cures Act. Earlier this summer, FDA released an action plan that 
included the Agency's precertification pilot program, which explores 
how to apply a tailored, risk based approach toward digital health 
technology by looking at the software developer or digital health 
technology developer rather than primarily at the product. The Cures 
Act expands on policies advanced by FDA's Center for Devices and 
Radiological Health (CDRH) and makes clear that certain digital health 
technologies--such as clinical administrative support software and 
mobile apps that are intended only for maintaining or encouraging a 
healthy lifestyle--generally fall outside the scope of FDA regulation. 
Such technologies tend to be low risk but can provide great benefits to 
patients and to the health care system by helping keep patients and 
consumers more informed and engaged in their health. In the coming 
months, FDA will publish guidance to further clarify what falls outside 
the scope of FDA regulation and to explain how the new provisions 
affect pre-existing FDA policies.
    In late October, the Agency issued the ``510(k) Software 
Modifications'' guidance--the first of several guidance documents 
clarifying our policy in this space. FDA will also provide guidance to 
clarify the Agency's proposed position on products that contain 
multiple software functions, where some functionalities fall outside 
the scope of FDA regulation, but others do not. In addition, FDA will 
provide new guidance on other technologies that, although not addressed 
in the Cures Act, present low enough risks that FDA does not intend to 
enforce certain pre-market regulatory requirements. Greater certainty 
regarding the types of digital health technology that are subject to 
regulation and more clarity on FDA's compliance policies will not only 
help foster innovation, but also will help the Agency to devote its 
resources to higher-risk priorities.
                      Breakthrough Devices Program
    While FDA is taking steps to improve efficiency in all our review 
programs, the Agency is especially committed to helping devices that 
fill an unmet need move through the process as efficiently as possible. 
The Cures Act gave FDA new authorities to help achieve this goal. The 
Agency has issued a draft guidance regarding a new Breakthrough Devices 
Program, which was created by the Cures Act. Building on our Expedited 
Access Pathway program, which had been in place since 2015, the 
Breakthrough Devices Program is intended to help patients have more 
timely access to certain devices that more effectively diagnose or 
treat life-threatening or irreversibly debilitating diseases or 
conditions, such as technologies with no alternative or that offer a 
significant advantage over existing FDA-cleared or approved 
alternatives.
    As described in the draft guidance, the program would enable a more 
agile pre-submission process for breakthrough devices. Breakthrough 
device innovations that are highly novel can also be more complex to 
assess. Thus, earlier and more frequent interaction between FDA and 
manufacturers should allow manufacturers and the Agency to make the 
best use of resources to bring novel medical technologies to the market 
more quickly.
                          510(k) Modifications
    Many devices undergo modifications based upon feedback from medical 
professionals, patients, and other users who help innovators make 
adaptations to improve a device's performance. A regulatory framework 
that responds quickly to iteration is key to improving device safety 
and performance.
    FDA finalized two guidance documents on device modifications in 
October. They are designed to help innovators determine when they need 
to submit a new premarket notification (510(k)) prior to making a 
change to a legally marketed device subject to 510(k) requirements. The 
final guidance documents will help innovators introduce iterative 
improvements that can improve a product's safety and performance by 
establishing more predictable, consistent, and transparent criteria 
regarding when FDA needs to review and clear changes.
    These new guidance documents do not change FDA's review standard. 
Instead, the new guidances enhance predictability and consistency for 
innovators deciding when to submit new 510(k)'s by better describing 
the regulatory framework, policies, and practices underlying such a 
decision.
    This improved clarity will help reduce the barriers to beneficial 
innovation and improve patient care by reducing unnecessary submissions 
to FDA for changes that could not significantly affect device safety or 
effectiveness, so patients can benefit from enhancements more quickly.
                           510(k) Exemptions
    Under provisions of the Cures Act, FDA exempted more than 70 Class 
I device types and more than 1,000 Class II device types from the 
requirement to submit to FDA a 510(k) submission. This Cures directive 
is part of our ongoing strategy to decrease regulatory burdens on the 
development of beneficial technologies and reduce the costs of 
innovation. Device types that are exempt from 510(k) are not generally 
exempt from other regulatory controls (such as current good 
manufacturing practice requirements, adequate and proper packaging and 
labeling, and registration and listing), which ensures consumers can 
continue to rely on the Agency's oversight of these products while 
giving FDA more capacity to focus its oversight on higher risk 
products.
                 Modernizing Review of Reusable Devices
    The Cures Act also provided FDA an important authority to require 
instructions for use and validation data regarding cleaning, 
disinfection, and sterilization for certain reusable devices, such as 
duodenoscopes. In June, as required by the Cures Act, FDA published a 
list of reusable devices for which the requirement applies, and we 
believe this will ensure that the premarket requirements for these 
device types are clear and predictable, facilitating more efficient 
review of these 510(k)'s and safer products for patients.
                     Least Burdensome Device Review
    The Cures Act also expands the least burdensome provisions for 
device review and requires important least burdensome training for 
review staff. In fact, even though the Cures Act mandated training only 
for employees involved in premarket device review, both CBER and CDRH 
require all medical device review staff to complete least burdensome 
training because it is integral to how we conduct business. When 
applied correctly, the least burdensome concept continues to help 
facilitate the availability of new device technologies without 
compromising scientific integrity in the decisionmaking process or 
FDA's ability to protect the public health. The least burdensome 
concept continues to be integrated into all device review and other 
device-related activities, not just select premarket activities.
    The Agency also has revised our guidance concerning the proper 
response to deficiencies in accordance with the least burdensome 
principles and updated our guidance to incorporate the requirement 
under the Cures Act that summaries of significant decisions include how 
the least burdensome principles were applied. FDA also intends to issue 
in the coming months updated guidance on our overarching principles of 
the least burdensome concept. This is another instance where FDA is 
using the authorities under the Cures Act to achieve our objective of 
making the review process more efficient and ensuring that we are 
collecting information only when necessary and at the right time during 
the review process, and without compromising safety and effectiveness.
                    Patient-Focused Drug Development
    In the drug approval space, the Cures Act is facilitating more 
patient-centered, efficient, and faster drug and biologics development 
through different mechanisms. We are putting this patient-centered 
approach at the center of our regulatory activities, which is why we 
intend to set up a dedicated patient engagement staff in our Office of 
Medical Products and Tobacco.
    The Cures Act emphasizes the need for patient engagement. It 
directs the Agency to provide information about how it is reviewing 
patient experience data in reviewing drugs and devices and issue 
guidance documents to facilitate the collection and review of patient-
focused data for drug development. In May 2017, FDA published a 5-year 
plan for issuing these guidance documents.
    FDA has already implemented an approach to record and track the 
submission and review of patient experience data. A new subsection 
called ``Patient Experience Data'' is now included in drug and biologic 
review documents. It will require reviewers to include a brief 
statement regarding patient experience data and related information if 
it is submitted and reviewed as part of an application.
    In just a few weeks, the Agency will conduct a public workshop, 
titled ``Patient-Focused Drug Development: Guidance 1--Collecting 
Comprehensive and Representative Input.'' The workshop is scheduled for 
December 18, 2017. FDA is holding this public workshop to obtain 
feedback from stakeholders, including patients, caregivers, patients' 
advocates, academic and medical researchers, expert practitioners, drug 
developers, and others, on considerations for: (1) standardized 
nomenclature and terminologies for patient-focused drug development; 
(2) methods to collect meaningful patient input throughout the drug 
development process, and (3) methodological considerations for the 
collection of patient data, and the reporting, management, and analysis 
of patient input. FDA has announced this workshop in the Federal 
Register and will publish a discussion document before it takes place.
                         Drug Development Tools
    Provisions designed to advance the development and use of drug 
development tools (DDTs) are some of the most meaningful provisions in 
the Cures Act. These provisions codify FDA's role in qualifying 
biomarkers and other DDTs, that is, determining that a DDT can be used 
for a particular context of use across different product development 
programs. Product development tools are critical to efficient, 
expedited product development.
    FDA is establishing a qualification process for DDTs (i.e., 
biomarkers, clinical outcome assessments (COAs), and animal models) for 
proposed contexts of use for drugs and biologics. There are similar 
efforts underway with respect to medical device development tools. FDA 
must develop a new regulatory process to qualify DDTs to facilitate 
timely and consistent review of DDT qualification submissions and 
publicly disseminate information about DDTs under review and following 
a qualification determination. Once a drug development tool is 
qualified under this new process, it can be used for its qualified 
context of use to support regulatory decisions regarding a drug or 
biologic, including decisions regarding an application for approval or 
licensure of a drug or biologic or to support the investigational use 
of a drug or biologic.
    To better integrate our work on drug development tools, on August 
15, 2017, CDER moved the Biomarker Qualification Program from the 
Office of Translational Sciences into the Immediate Office of the OND. 
This places the Biomarker Qualification Program in closer proximity to 
OND review divisions, fostering improved coordination, scientific 
understanding, and consistency between biomarkers developed for 
qualification and those under development as part of drug-specific 
programs. Similarly, the placement of biomarker and COA qualification 
programs in the OND Immediate Office enables greater efficiency of 
operations and greater opportunities for collaborative engagement with 
external stakeholder communities.
    These efforts are already having an impact: the first COA from the 
COA Drug Development Tool Qualification program has been accepted for 
review under these updated provisions--the Symptoms of Major Depressive 
Disorder Scale--and the Agency expects to act on that submission soon. 
The Scale is a 16-item, patient-reported outcome instrument intended to 
capture the patient voice by measuring the symptoms of major depressive 
disorder that matter most to patients.
    FDA has also been active with NIH and other stakeholders in the 
development of evidentiary criteria to support biomarker qualification 
efforts. Two recent multi-stakeholder collaborations have been held to 
help inform future guidance by the Agency, discussing the evidentiary 
criteria to support biomarker qualification efforts.
   Limited Population Pathway for Antibacterial and Antifungal Drugs
    The decline in antibacterial drug research and development as 
serious antibacterial drug resistant infections increase is a critical 
public health and patient care concern. FDA is working to implement the 
Limited Population Pathway for Antibacterial and Antifungal Drugs 
(Limited Population Pathway, or LPAD) provision of Cures to help 
address this. The Limited Population Pathway allows FDA, at an 
applicant's request, to approve an antibacterial or antifungal drug, 
alone or in combination with other drugs, as a limited population drug. 
This provision builds on ongoing efforts to spur drug development in 
this area by facilitating the development and approval of antibacterial 
and antifungal drugs intended to treat serious or life-threatening 
infections in a limited population of patients with unmet need. In 
certain circumstances, the Limited Population Pathway will be an 
important tool enabling FDA to conclude that the benefits of a drug 
outweigh its risks in the intended limited population.
    As required in the Cures Act, FDA is in the process of developing 
draft guidance describing the criteria, processes, and other general 
considerations for demonstrating the safety and effectiveness of 
limited population antibacterial and antifungal drugs. FDA also is 
familiarizing the scientific and policy community involved in 
antibacterial drug development with the Limited Population Pathway by 
mentioning it during public presentations, workshops, and Advisory 
Committee meetings where development of antibacterial drugs for serious 
or life-threatening infections is discussed. Additionally, FDA is 
working with drug sponsors who are interested in utilizing this new 
pathway by answering questions and providing application-specific 
information to sponsors when it is requested.
               Susceptibility Test Interpretive Criteria
    Susceptibility testing is performed in laboratories to determine 
which antibacterial drugs are likely to be active against the bacteria 
causing a patient's infection. This information helps healthcare 
providers to pick an appropriate drug to treat a patient's infection or 
to determine when additional infection control procedures should be put 
in place to reduce the chance of spread of resistant bacteria. Before 
Cures, FDA had a laborious, duplicative process to keep this 
information up-to-date in drug labeling. FDA is currently working to 
implement section 3044 of the Cures Act, which clarifies the Agency's 
authority to efficiently update susceptibility test interpretive 
criteria, including by leveraging work done by standards development 
organizations [SDOs], while FDA retains full authority over recognition 
decisions, and take advantage of tools like the web to modernize how we 
update susceptibility test interpretive criteria. This allows sponsors 
of antimicrobial susceptibility testing devices to utilize this 
information more quickly.
    On October 30, 2017, as a first step in implementing this new 
authority, FDA published a Federal Register notice asking for 
information to assist FDA in identifying SDOs that meet the statutory 
requirements in the Cures Act. FDA is working to meet its December 
statutory deadline to publish the Susceptibility Test Interpretive 
Criteria website. This website will include FDA's recognition, in whole 
or in part, of susceptibility test interpretive criteria established by 
SDOs. More information will be provided about the recognition process 
when the website is live.
                        Continuous Manufacturing
    Continuous manufacturing--a technologically advanced and automated 
manufacturing method--provides a faster, more reliable way to make 
pharmaceuticals. This can help reduce drug shortages and recalls 
related to problems with product or facility quality.
    The Agency is helping to bring continuous manufacturing into 
widespread use by supporting the pharmaceutical industry's transition 
to this manufacturing method. With this in mind, the Cures Act allows 
FDA to issue grants to study continuous manufacturing of drugs and 
biological products and similar innovative monitoring and control 
techniques.
    During fiscal year 2017, CDER granted an award to the University of 
Connecticut to develop and build a continuous manufacturing platform 
with modular components for complex dosage forms, as well as to create 
a library based on Graphical User Interfaces. These activities support 
quality-based risk assessment and provide a roadmap to modernize 
technology and solve continuous manufacturing challenges for complex 
dosage forms. They also can help the Agency with review processes and 
provide necessary information to guide policy development. This 
research is likely to advance the Agency's regulatory science and 
facilitate production of high-quality, cost-effective complex drug 
products for the benefit of the public.
                      Novel Clinical Trial Designs
    As technology improves, so does FDA's ability to explore novel 
trial designs that better fit the needs of researchers and patients. 
FDA is committed to supporting the use of novel trial designs, 
modeling, and simulations in drug development and review, to do things 
like support evidence of effectiveness, optimize dosing, and evaluate 
adverse event mechanisms.
    Building on work that was already underway at the Agency, the Cures 
Act specifically calls on FDA to assist sponsors in incorporating 
complex adaptive and other novel trial designs into proposed clinical 
protocols and applications for new drugs and biological products to 
facilitate more efficient product development. To do this, FDA is 
actively planning a public meeting for March 20, 2018. The Agency plans 
to issue guidance on, among other things, how to use such novel trial 
designs, how they can help to satisfy the substantial evidence 
standard, and what are recommended analysis methodologies.
                          Combination Products
    In line with section 3038 of the Cures Act, which addresses the 
full life-cycle for combination products, the Agency is taking a range 
of actions to advance the consistency, efficiency, predictability, and 
transparency of both the premarket review and postmarket regulation of 
combination products.
    FDA is committed to this work. Leadership of the medical product 
centers and other appropriate offices sit on the Combination Products 
Policy Council to guide efforts in the pre-and post-market space. For 
example, the Agency is currently completing a pilot of a more 
streamlined intercenter consult process that improves the efficiency of 
these consultations, an effort that has involved training for over one 
thousand review staff in the three medical product Centers. 
Additionally, we are enhancing our training of review staff, such as 
leveraging prior Agency determinations, to ensure a risk-based approach 
to regulation of combination products.
    FDA is also working to help streamline the process to get these 
important products to patients. In January, we released final guidance 
on current good manufacturing practices for combination products, which 
outlines flexible practices that can be utilized by manufacturers to 
reduce burdens.
    A key provision in the Cures Act calls for FDA's Office of 
Combination Products (OCP) and the three medical product Centers to 
work with and provide assistance to medical product sponsors upon 
request regarding the study design of their product. OCP continues to 
provide this assistance and has developed a new standard operating 
procedure for handling these requests to ensure faithful implementation 
of the Cures mandate.
                Real World Data and Real World Evidence
    Advances in technology also have the potential to improve the 
availability and utility of real world evidence (RWE) and real world 
data (RWD). The Cures Act specifically supports the Agency's evaluation 
of the potential use of RWE to support the approval of new indications 
of approved medical products or to satisfy post-approval study 
requirements for marketed products.
    Examples of RWD include data derived from electronic health records 
(EHRs), claims and billing data, data from product and disease 
registries, patient-generated data including in-home use settings, and 
data gathered from other sources such as mobile devices that can 
provide information about health status. RWD sources (e.g., registries, 
EHRs, and administrative and healthcare claims data bases) can be used 
as a data collection and analysis infrastructure to support many types 
of trial designs, including, but not limited to, randomized trials, 
such as large simple trials, pragmatic clinical trials, and 
observational studies (prospective and/or retrospective).
    The use of RWE and RWD have the potential to allow researchers to 
answer questions about treatment effects and outcomes more efficiently, 
saving time and money while yielding answers relevant to broader 
populations of patients than might be possible in a specialized 
research environment. This could help streamline clinical development. 
The use of these data also can help inform the safe and effective use 
of medical products.
    To do this, FDA will establish a program to evaluate the potential 
use of RWE to help support the approval of a new indication for an 
already approved drug or to help support or satisfy post--approval 
study requirements. Over the past year, CDRH, CBER, and CDER have 
harmonized their definitions for RWD, data relating to patient health 
status and the delivery of health care routinely collected from a 
variety of sources, the clinical evidence regarding the usage, and 
potential benefits or risks of a medical product derived from analysis 
of RWD. FDA has already finalized guidance on RWE for devices, and we 
will issue new guidance to define how we plan to incorporate these 
principles into product development for drugs and biologics.
    FDA's focus on RWE has already advanced patient care. On June 5, 
2017, FDA became the first regulatory body in the world to approve the 
most recent iteration of the Sapien valve, the Sapien 3, to treat high-
risk patients whose surgically placed aortic or mitral bioprosthetic 
valves were old and worn out. This approval was based in part on data 
from the Transcatheter Valve Therapy (TVT) Registry, a partnership of 
the American College of Cardiology and the Society of Thoracic 
Surgeons. The TVT registry collects clinical data on the performance of 
transcatheter valve replacement procedures performed in the U.S. once a 
product goes to market--including both on-label and off-label uses--
making it possible, under certain circumstances, to accumulate more 
data faster, without the need for costly and time-consuming formal 
clinical trials.
    FDA is currently focused on developing a framework for a program 
that will evaluate the use of real world evidence to support regulatory 
decisions for new indications or post-approval study requirements. The 
draft framework, required under the Cures Act, is due in December 2018, 
but the Agency is already gathering stakeholder input to move this 
field forward. For example, in September 2017, FDA collaborated on a 
workshop convened by Duke-Margolis Center for Health Policy to bring 
stakeholders, including industry, academia, and patient advocacy 
groups, together to discuss both the challenges and opportunities for 
applying RWE and RWD to drug development. Similarly, the National 
Academies of Sciences, Engineering, and Medicine have organized a 
series of meetings--with FDA participation--to explore these 
opportunities. The first, also held in September 2017, was entitled 
``Examining the Impact of Real-World Evidence on Medical Product 
Development: A Workshop Series.'' Two additional meetings are planned.
    FDA also is supporting numerous demonstration projects to advance 
the regulatory framework for how best to incorporate RWE into 
regulatory decisionmaking. For example, as part of a big data analytics 
initiative at the FDA called Information Exchange and Data 
Transformation (INFORMED), the OCE has a current collaboration with 
Flatiron Health to examine how RWD can be used to gain insights into 
the safety and effectiveness of new cancer therapies.
    In addition, in June 2017, FDA announced a partnership with 
CancerLinQ, the American Society of Clinical Oncology's big data 
initiative. FDA and CancerLinQ will be using real world, aggregate, de-
identified patient care data from oncology practices to understand a 
variety of issues related to the appropriate use of newly approved 
therapies. The initial focus will be on immunotherapy agents approved 
for melanoma. FDA is also leading an effort that includes NIH's 
National Center for Advancing Translational Sciences, National Cancer 
Institute, National Library of Medicine, and the HHS Office of the 
National Coordinator for Health Information Technology to develop a 
general framework by harmonizing several Common Data Models.
    FDA will continue to partner with a range of stakeholders to do all 
the Agency can to address the challenges and realize the opportunities 
posed by RWE and RWD, so that FDA can get effective treatments and 
therapies to those who need them more efficiently.
                        Medical Countermeasures
    At FDA, we remain fully committed to continuing to use our 
authorities to the fullest extent to help facilitate the development 
and availability of medical countermeasures--such as vaccines, 
therapies, and diagnostic tests--to counter chemical, biological, 
radiological, nuclear (CBRN) and emerging threats such as pandemic 
influenza and Zika virus.
    While many of the provisions in the Cures Act that are intended to 
facilitate the development and availability of medical products in 
general also will serve to help facilitate the development and 
availability of medical countermeasures, the Cures Act contains two 
FDA-specific provisions to help advance the development and 
availability of medical countermeasures.
    Section 3088 of the Cures Act amends FDA's Emergency Use 
Authorization (EUA) authority (section 564 of the FD&C Act) to permit 
EUAs that: (1) authorize emergency use of unapproved animal drugs or 
unapproved uses of approved animal drugs, (2) make applicable other 
emergency use authorities (e.g., to issue emergency dispensing orders, 
waive compliance with Current Good Manufacturing Practices, make 
available CDC Emergency Use Instructions, and extend expiration dates) 
to approved animal drugs, and (3) allow unapproved animal drugs to be 
held for emergency use. In January 2017, FDA issued guidance on 
Emergency Use Authorization of Medical Products and Related 
Authorities, in which we explained that the Emergency Use authorities 
and guidance recommendations are now applicable to animal drugs and 
encouraged anyone interested in utilizing these authorities to contact 
FDA to discuss how to proceed. FDA plans to address any issues raised 
as we develop more experience with these new authorities.
    Section 3086 of the Cures Act adds section 565A of the FD&C Act for 
FDA to establish a new priority review voucher (PRV) program to help 
incentivize the development of material threat medical countermeasures. 
Upon approval of a material threat medical countermeasure application, 
FDA will award a PRV provided certain criteria are met. The PRV may in 
turn be used by the sponsor who receives it, or sold to another sponsor 
who may then use it, to obtain priority review for a product 
application that would otherwise not receive priority review. In 
October 2017, we announced in the Federal Register the fee rate for 
using a material threat MCM PRV for fiscal year 2018 ($2,830,579; the 
rate was effective on October 1, 2017, through September 30, 2018). We 
also plan to issue guidance to address medical countermeasure-specific 
issues in the near future, with the intent to implement the program 
consistently with the other PRV programs, such as the Neglected 
Tropical Disease Voucher Program.
    The FDA stands ready to use these new authorities as appropriate to 
help facilitate the development and availability of medical 
countermeasures.
                               Conclusion
    These are just some of the ways the Cures Act has supported and 
enhanced FDA's work to make the process for bringing safe, effective, 
and innovative treatments to patients more efficient. FDA's 
improvements in transparency, consistency, predictability, and 
efficiency will benefit industry, healthcare providers, and, most 
importantly, patients. We expect our continued implementation of the 
Cures Act will further advance these goals. The Agency stands ready to 
work with Congress and stakeholders to help make the promise of the 
Cures Act a reality.
    Thank you for inviting FDA to testify today. I would be happy to 
answer any questions you may have.
                                 ______
                                 
    The Chairman. Thank you, Dr. Gottlieb.
    We'll now begin a round of 5-minute questions. In my 5 
minutes, I have several questions, so let me go through them 
pretty quickly.
    Both of you have talked about regenerative medicine. Your 
testimony has more about it. There are a number of Senators, 
including the majority leader, who are very interested in it, 
and it helps if we're trying to get more money and more 
legislation to have his continued interest.
    Would each of you, in the next few weeks, send to me and to 
Senator Murray a brief written report summarizing what you've 
done in the area of regenerative medicine, the kind of thing 
that I mentioned that helped Doug Oliver, both about how you 
create more hope for people like Doug, but also what you're 
doing about the bad actors in the field? I'd like for it to be 
the kind of memo I could give to other Senators who are 
interested in this to show that you've taken some action in the 
first year.
    Dr. Gottlieb. Absolutely.
    Dr. Collins. Yes.
    The Chairman. Thank you for that.
    [The following information can be found on page 13 and 18 
in the appendix:]
    The Chairman. Dr. Collins, could you say in about 30 or 45 
seconds what you mean when you say Other Transactions Authority 
has been helpful to you and you'd like to have more of it?
    Dr. Collins. Other Transactions Authority allows us to move 
very flexibly in an area of high need and where technology is 
advancing rapidly. It means that we can bring partners together 
without taking the whole year that it often takes to issue an 
opportunity for grants to be submitted and for us to do the 
reviews and make the awards, plus it gives us the flexibility 
to decide when a particular partner is not meeting milestones 
and we can just cut them off without any further to do. This is 
something that DARPA has used. We are delighted to have that 
for our common fund and for All of Us, the Precision Medicine. 
It makes things possible much faster.
    The Chairman. Where do you want it that you don't have it?
    Dr. Collins. We could really use this now in the opioid 
crisis. We have a big plan that we want to move forward 
quickly. This would be a great advantage to have as one of the 
tools.
    The Chairman. Senator Murray and Senator Blunt in their 
Appropriations Committee, I believe, have for the third 
consecutive year reported out a $2 billion increase in NIH 
funding. Can you summarize in less than a minute why you 
believe that as we appropriate money for opioids that some of 
that money ought to go for research into non-addictive pain 
medicines?
    Dr. Collins. The critical solution for the future is to 
have alternatives for opioids for people who suffer from 
chronic pain, and there are 25 million of them in the United 
States right now that have pain every day. We need to have 
better alternatives. There are ways to get there with some 
exciting new drug targets that have emerged. Working with 
industry, with a lot of contributions from NIH, we believe we 
can accelerate that process, particularly with OTA to help us, 
and to be able then to have available for those people who have 
that kind of pain answers and much more----
    The Chairman. You're talking about using additional 
appropriations and additional private money in a public-private 
partnership to accelerate that. Correct?
    Dr. Collins. Exactly, and we would expect companies to be 
willing to put some of their funds into this, too, just as 
we've done with other partnerships on Alzheimer's Disease, 
diabetes, rheumatoid arthritis, and Parkinson's.
    The Chairman. Finally, Dr. Gottlieb and Dr. Collins, but 
I'll start with Dr. Gottlieb, it takes sometimes 10 or 12 years 
to take a breathtaking new medical innovation from idea to the 
doctor's office. The whole goal of Cures is to shorten that 
period and shorten that cost and still do it in a way that's 
safe and effective. What are you doing--can you give me some 
specific examples of how FDA and NIH and CMS, which has to do 
with funding, are working together so that we don't make a lot 
of progress in research, for example, have it sit on the shelf 
while FDA works on something else, or make a lot of progress at 
the FDA and have it sit on the shelf while CMS is deciding 
whether to fund it?
    Dr. Gottlieb.
    Dr. Gottlieb. I think a lot of our ability--and thank you 
for the question, Senator. A lot of our ability to make the 
development process itself more efficient and lower cost is 
trying to develop better tools, better scientific tools to 
evaluate products that are being brought through the 
development process to ascertain their safety and effectiveness 
in more efficient ways, in ways that are faster, that can be 
done at a lower cost. That is a process of developing better 
science, better regulatory science for evaluating technology.
    There's a lot of work that we're doing in concert with the 
NIH in collaboration with Dr. Francis. A couple of initiatives 
I'd point out to you are the tissue on a chip initiative, which 
is an initiative for developing better tools for toxicology and 
looking at issues of safety and effectiveness, and a 
Partnership for Accelerating Cures, which is another 
collaboration where we are developing these tools.
    I'll just close by saying I think that if we can develop 
this better science, this is a case where we could have the 
best of both worlds, a process that's lower cost and more 
efficient, but also is going to give us a better measure of 
safety and effectiveness, the ability to determine those 
parameters.
    The Chairman. Well, I'm out of time. But as we continue our 
oversight--and I'm sure you're going to do this--we need to 
think of this as a seamless process, and we need to go from 
idea to the doctor's office to the patient, and we need to get 
it through the research into the FDA, through CMS, to make 
these things work, and I hope you'll pay a great deal of 
attention to that.
    Senator Murray.
    Senator Murray. Thank you very much.
    Dr. Gottlieb, let me start with you. As you know, we had 
some deadly outbreaks of antibiotic-resistant infections that 
were linked to contaminated duodenoscopes in my home state and 
actually across the country, and I championed a provision in 
the 21st Century Cures that provided FDA with some additional 
tools to make sure of the safety of reprocessed medical 
devices. I really appreciated the FDA meeting its guidelines to 
publish the list of devices for which the agency now requires 
valid evidence-based cleaning procedures.
    Can you update us on how many products now have these 
validated cleaning protocols because of this law?
    Dr. Gottlieb. Thank you, Senator, and I'll just preface my 
answer by saying we think that this is a very important 
authority and plan to make robust use of it, and as you 
mentioned, we put in place the provisions in August 2017. There 
have now been 14 products, I believe, to date that have gone 
through the 510(k) process outlined in this legislation. We 
have many more that we're having discussions with, and I can 
get you a fully up to date number because it's evolving. But 
it's about 14.
    Senator Murray. Okay, great. I really appreciate it, and I 
want to stay updated on this because I think we do need to 
respond quickly and appropriately when problems occur with 
these medical devices. So patients need to trust what's being 
used, so I really appreciate that.
    Dr. Collins, I was very proud to champion provisions in the 
Cures Act to improve the inclusion of historically 
underrepresented populations, as I mentioned--women, racial and 
ethnic minorities, children, seniors--into clinical research. 
One of the provisions was a task force to improve the 
evaluation of drugs for pregnant and lactating women. They are 
in a very difficult position often today, whether it's treating 
morning sickness or a chronic condition, because there's so 
little research today on how medication might impact them. We 
all know if they don't get an answer from the doctor, they go 
online, and that just, to me, is unacceptable in today's world.
    How do you plan to integrate the task force work into the 
broader efforts to advance innovation and impact clinical 
research?
    Dr. Collins. Thank you for the question. We welcomed that 
recommendation in the legislation, and we've moved swiftly to 
set up this group, the PRGLAC, chaired by Dr. Cathy Spong, who 
is a very respected neonatologist and OBGYN expert at NIH. That 
group has already met twice and is going to meet again twice 
more in the next coming months, and by May 2018, we'll have a 
series of recommendations, which we intend to take with great 
seriousness.
    As you understand very clearly, this is an issue where we 
want to be sure that we are carrying out the appropriate 
clinical trials to understand about efficacy and safety during 
pregnancy and lactation. But we also know those are very 
sensitive times in terms of not creating risks, and so getting 
the balance just right is what this Committee is wrestling 
with. It's a strong group. They've gotten very quickly engaged. 
I think you're going to see something very substantial come out 
of this.
    Senator Murray. Good. Well, I'm hearing from a lot of women 
who are very concerned about the direction our country is going 
today, whether it's family planning or allowing employers to 
deny access to birth control. So they are looking for good 
information.
    I know that one of the things we did in Cures was to strike 
a real balance between members of the Federal Government and 
external stakeholders on the task force. Today, the non-Federal 
members have not been hired by the task force and haven't been 
able to fully participate. I wanted to ask you how you are 
ensuring that the nongovernmental voices that Congress required 
to be included in this are heard from and they are incorporated 
fully into this.
    Dr. Collins. We very much want those voices to be critical. 
They're probably the most critical parts of this. They have 
been attending all of the meetings and are speaking. The 
problem is getting them officially appointed, which means going 
through the ethics clearances. I am assured that by the 
February meeting, they will all have gone through that process 
and will be fully installed and able to actually not just be 
present but also to vote.
    Senator Murray. Well, that's really important. Can you keep 
me updated on that? I'd like to make sure that's implemented.
    Dr. Collins. I'd be happy to.
    Senator Murray. Dr. Gottlieb, I just wanted to ask you--
I've just got a few seconds left. But we're living in a new 
digital age. It's been mentioned several times. Some of the 
products are low-risk. Some of them have a big impact on 
patients and their safety. People are wearing wearables. We're 
seeing a lot of different things, apps that use camera phones 
to diagnose diseases. These are really promising, but we have 
to make sure they work and their claims are backed up by hard 
evidence.
    I know the agency is working to speed that up right now. 
But, to me, it's less clear how FDA is going to ensure that the 
sheer quantity of products that are now on the market are being 
validated. I wanted to ask you what actions FDA is taking to 
make sure that patients and providers can put their trust in 
the digital health products.
    Dr. Gottlieb. I'll just quickly, Senator--and thanks for 
the question. We continue to receive adverse event reports even 
for software products and digital products that we might 
exclude from regulation based on the parameters outlined in the 
Cures statute. If there was a situation where we received an 
adverse event report that led to a recall of a product, even a 
product that we had excluded from regulation, that would be a 
reason for us to then bring that product back under regulation 
through the provisions in Cures, because if some adverse event 
or some issue with the software itself is leading to an adverse 
event, that tells us that it shouldn't have been excluded in 
the first place. So we continue to monitor even the products 
that we're scoping out of our active regulation.
    Senator Murray. Okay. We want to stay updated. That's going 
to take a lot of work in the future.
    Thank you.
    The Chairman. Thank you, Senator Murray.
    Senator Roberts and Senator Young have deferred to Senator 
Cassidy.
    Senator Cassidy, we have our hearing next Wednesday on 
oversight of mental health law that you and Senator Murphy 
worked on, so that will be here.
    Senator Cassidy. Wonderful. I thank my colleagues for 
allowing me to go. I'm supposed to be at the White House, so I 
thank you.
    This is not an Appropriations Committee, but it's a broad 
topic, and so if you don't mind--Dr. Collins, again, great 
respect for you and for your institutes. But as I have pointed 
out in the past, we don't seem to have an NIH which targets 
funding relative to disease burden. So when I look at NIDA, 
their budget only went up 2 percent last year, and it still 
remains far smaller than other institutes in which there is far 
less morbidity and mortality flowing from those disease 
conditions.
    If we are going to address the issues of opioids or mental 
health, both of which are playing into this, it seems like 
there has to be a greater shift in where our funding is going 
at NIH toward these disease conditions. Now, in the past, 
you've suggested that, well, we'll kind of organically grow--
hold this one stable and allow this one to grow--but when I 
look at it, all the institutes seem to be growing at about the 
same pace.
    I guess my question for you is it doesn't seem as if NIH is 
making these a priority if you look--over other conditions if 
you look at the relative funding increase of those institutes. 
You're a very thoughtful person. So please give me your 
thoughts on that.
    Dr. Collins. Senator, you point to a very important issue 
about how do we make decisions. I have to point out, however, 
that it's the Congress that assigns a budget. It's a line item 
every year in the appropriations process to each of those 
institutes. As the NIH director, I don't get to set those 
numbers, and so we follow what the Congress tells us ought to 
be the appropriation for a given year.
    Then we work with great flexibility to try to be sure that 
when there is a public health need, as there is now--for 
instance, with opioids, which I think you're referring to--
because, of course, we have a big opportunity there in terms of 
our understanding of how the brain works, the BRAIN Initiative 
is directly relevant here, and the Neurology Institute has an 
enormous investment in understanding pain, as does the National 
Center for Complementary and Integrative Health.
    One shouldn't look at our organizational structure and say 
that the money actually fits precisely into those buckets. We 
have lots of ways that we can mix and----
    Senator Cassidy. I accept that, if I may, just because I 
have limited time. So you're saying that if we want more money 
to go to the National Institute of Drug Addiction, we need to 
line item it in our budget.
    Dr. Collins. That's the only way it happens.
    Senator Cassidy. That said, the flexibility does seem as if 
it should be flexing toward things like NIDA. Pain is 
important, but, ultimately, pain translates into addiction. 
That's a final common pathway. So it does seem as if we should 
be flexing toward them. Is that where the flexing is taking 
place?
    Dr. Collins. I think that's what we're trying to do, is to 
shift with the priority opportunities we have more funds into 
that space, because we recognize this is a terrible public 
health emergency.
    Senator Cassidy. Let me ask on this, a different topic, 
again, trying to stay on time. There is a move afoot to suggest 
that marijuana usage can be used in lieu of opioids, that 
states that have legalized marijuana more liberally have lower 
incidents of opioid addiction.
    Dr. Collins. That's right.
    Senator Cassidy. But then I read about the brain being 
pretty plastic up until age 25, and so--and we all know the 
pothead, the kid that has Amotivational syndrome, if you will. 
So there's been at least one suggestion I've read that we 
should make a recommendation that legalization of marijuana 
should be restricted to those 25 and above. I say this not 
because I'm an expert but to get the thoughts of those such as 
the two of you who are experts.
    Dr. Collins. Well, there is published data, although it's 
still controversial, that heavy use of marijuana beginning in 
adolescence does have permanent consequences in terms of 
intellectual performance, that IQ points get lost in those 
individuals who have been exposed a lot to marijuana starting 
in adolescence. It is also true, as you said, that there seems 
to be a statistical relationship between the states that have 
legalized marijuana and a reduced incidence of opioid overdoses 
and deaths. But one has to be careful there. That's a 
correlation and not necessarily a causation. I would not want 
to leap to that.
    I would just go, though, to the point that we are 
increasingly studying the cannabinoid receptor pathway in the 
brain as a potential way that we might come up with 
alternatives that would be effective for managing pain and 
depression and anxiety--not marijuana itself, but using that 
pathway.
    Senator Cassidy. I accept that. But for the two of you, is 
it a reasonable public policy consideration that perhaps the 
age of legal marijuana for those states that are legalizing 
should be 25 and above?
    Dr. Collins. We're getting into difficult public policy 
territory. I will simply say the concerns about marijuana 
exposure to the developing brain would have to be strongly 
considered in anything that made access to adolescents more 
readily available, because we do have that concern.
    Senator Cassidy. The brain is developing at least through 
age 25.
    Dr. Collins. You could say 22. You could say 25. I don't 
know that I have a precise dividing line.
    Senator Cassidy. My wife says it's 60, but that's--you 
know.
    [Laughter.]
    Senator Cassidy. Dr. Gottlieb? I'm out of time. I'm sorry. 
I should yield back. I apologize. Thank you.
    The Chairman. Thank you, Senator Cassidy.
    Senator Casey.
    Senator Casey. Mr. Chairman, thank you very much. I do want 
to add my words of commendation to you and to the Ranking 
Member for the work you did to get this legislation passed. It 
is hard to believe that it's been a year, and I know we have a 
ways to go with regard to implementation. But in a place and in 
an institution where there aren't many days where you have not 
just bipartisanship but bipartisanship that undergirds a 
substantial matter of public policy of this importance, it's 
especially great to be able to celebrate this passage and to 
continue to work together.
    Dr. Gottlieb, I wanted to start with you on a question 
regarding 503B compounders. While we've primarily been focused 
in the hearing on getting new drugs to patients, I'm also 
concerned about maintaining the supply of drugs already in the 
market. We know that since Hurricane Maria hit Puerto Rico, 
I've heard from Pennsylvania hospitals regarding a shortage of 
IV fluid and amino acids for injection, a critical product for 
patients who must receive nutrients intravenously.
    While Puerto Rico is 1,500 miles away, providers in 
Pennsylvania now face product shortages due to challenges 
facing major medical product manufacturing facilities located 
on the island. The shortages are especially damaging, because 
in the case of the IV fluid and amino acids, the facilities on 
the island were the sole source of the product for the entire 
country. So when you mentioned continuous manufacturing and how 
that can help reduce drug shortages, I wanted to ask you: Could 
503B outsourcing facilities also help in the case of drug 
shortages?
    Dr. Gottlieb. The short answer is yes, Senator. We remain 
extremely concerned about the shortage situation in Puerto 
Rico, particularly as it relates to the IV fluids you 
referenced and the amino acids. We think that the steps we've 
taken in concert with the manufacturers and the authorities in 
Puerto Rico was thought to alleviate the shortage situation 
going into next year. But we still have to get through 
December, and we still face another hard month where there's 
going to be challenges getting access to an adequate supply. 
But we do expect this to continue to improve going forward.
    The issue with the 503B compounders--they theoretically can 
compound this product. They would have authority to do that. 
One of the issues is that the products that are in shortage 
aren't just the IV solutions themselves but the actual physical 
plastic bags to put the IV solutions in. So the 503B 
compounders also face a challenge getting access to the plastic 
bags that they need in order to compound the product, because 
those were also manufactured in Puerto Rico. So that has been a 
challenge, and whereas you would have expected the 503B 
facilities to be able to step in to supply more of this market, 
I think that they've been limited in their ability to do that.
    Senator Casey. I wanted to ask you as well--and I know we 
have limited time--but with regard to the Pediatric Priority 
Review Voucher Program, we know that an estimated one in 10 
people in the United States, two-thirds of whom are children, 
have a rare disease, according to the National Organization for 
Rare Disorders. Despite the need, private companies are less 
likely to pursue new therapies for rare diseases because it 
requires making an investment in products that will likely not 
re-coup the high costs associated with their research, 
development, marketing, and distribution.
    As you will remember, I worked with Senator Isakson, 
Chairman Alexander, and Ranking Member Murray to extend this 
review program at FDA, and this particular program provides 
important incentives to companies to invest in new therapies 
for rare pediatric diseases. When we last spoke, the FDA was 
still working on implementing changes that were made to the 
program, most importantly the definition of what constitutes, 
quote, ``rare pediatric disease,'' unquote.
    Can you give us a sense of the progress that you've made on 
the update of that definition, and are you meeting the 
statutory requirements to respond to requests for companies 
seeking designation for their products within 60 days? I know 
that's a lot.
    Dr. Gottlieb. I'm proud to say we are, Senator, and we have 
put forward some guidance. I think there's some additional 
guidance coming out on implementing the PRV Program. You know, 
we continue to look at this as a potential opportunity. We're 
awaiting the GAO report, as are others, to better evaluate 
these. I would just close by saying I think that there's a lot 
of other things that we can and are doing to try to create 
additional efficiencies to address some of the challenges that 
you outline with respect to pediatric drug development, 
including one we took yesterday. So I just want to put a plug 
in for a policy we put out yesterday trying to outline a more 
efficient clinical development pathway for drugs targeted to 
very rare pediatric diseases.
    Senator Casey. Thanks, Doctor.
    Thank you, Mr. Chairman.
    The Chairman. Thank you, Senator Casey.
    Senator Young.
    Senator Young. Doctors Collins and Gottlieb, I have a lot 
to cover in 5 minutes, so I ask that you try and be concise 
with these questions. So thank you for your presence here 
today.
    Dr. Collins, you mentioned in your testimony the plans you 
have in implementing the Eureka competitions for a vision in 
Cures, that prize program. When I was in the House of 
Representatives, I put together an amendment to Cures. A 
variant of this became the Eureka prize provision. I know some 
others contributed to that effort as well. It was inspired by a 
neighbor of mine who is a latter day Thomas Edison. He develops 
medical devices in his garage.
    I consulted with eminent economists, healthcare 
professionals, researchers, venture capitalists, angel 
investors, and all sorts of individuals in developing my form 
of prize. The objective was to ensure that we have objective 
rather than highly subjective criteria with respect to what 
those prizes are offered for. My hope--something articulated by 
one of my colleagues here today--was that we would target 
funding according to disease burden.
    When my colleagues consulted with the NIH, they were told, 
no, they don't want to be directed. So it effectively killed 
this effort, which I, frankly, find more meritorious than the 
current provision.
    What criteria do you or others within NIH use to determine 
what areas you're going to be funding, with due acknowledgement 
that we're funding Alzheimer's now? That strikes me as 
meritorious, on first blush. But what criteria do you use?
    Dr. Collins. I appreciate the question. By the way, at 
every Senator's place, this booklet which is published this 
week will walk you through a lot of the responses to that. How 
do we decide where the priorities are? Certainly, disease 
burden is a huge part of that. Let me be very clear about that. 
At the same time, scientific opportunities don't always happen 
at the same pace in the same areas, and when you see an 
opportunity that's particularly ripe for investment, we don't 
want to miss that.
    With the prize mechanism, we just put out a request for 
ideas about prizes for Alzheimer's Disease--talk about an area 
of high disease burden. We're looking forward to seeing what 
that will look like. We have a prize right now that's waiting 
for responses--and it's stirring up a lot of interest--in 
antimicrobial resistance, coming up with a test that will tell 
you within 4 hours----
    Senator Young. All the criteria are located in that book 
you just held up? Is that the case?
    Dr. Collins. It will go through quite a lot of it. If you 
need more information, I can supply it.
    Senator Young. Okay. I'll be scrutinizing that, and I thank 
you for that, for publishing that information. Do you include 
or do you plan on including the private sector or outside 
stakeholders, like some of those I mentioned, as we move 
forward in reviewing proposals and in designing prize 
competitions?
    Dr. Collins. Absolutely. Yes in both cases. Our review 
panels, especially for high-technology efforts--we populate 
those with people from the private sector who have that 
expertise. Certainly, in prize competitions, right now we want 
to see what people think in all sectors about an Alzheimer's 
prize.
    Senator Young. Last, do you allow in your prize 
competitions or have any plans to offer in-kind benefits? By 
that, I mean the ability for a garage investor or a researcher 
to use lab space at the NIH, or to use equipment that we, the 
taxpayers, have paid for, or to offer technical assistance to 
those that need it?
    Dr. Collins. Yes. I think we've done that, and, actually, 
in a couple of the small project prizes where we're 
particularly asking students, undergraduates, who have a great 
idea, to be able to apply, and they may not have access to the 
equipment, we are trying to be very flexible on that.
    Senator Young. Well, thank you. It sounds as though the 
career NIH folks that were telling Members of Congress that our 
idea was not thought well enough perhaps were on the right 
track.
    Dr. Gottlieb, pharmaceutical development today frequently 
involves what's been called shooting in the dark, making key 
decisions that impact a development program's success with very 
limited data. For example, decisions including indication 
selection, dosage endpoints, and inclusion-exclusion criteria, 
you might say are made sub-optimally because the data that 
informs such decisions lies in inaccessible siloes, at least 
inaccessible to most stakeholders. This contributes 
significantly to higher R and D costs and longer timelines. 
Now, the FDA already has much of this data, this otherwise 
siloed information.
    My question for you is: Has the FDA taken any steps in 
aggregating healthcare data across siloes to improve the 
pharmaceutical development process? If not, would the FDA be 
willing to analyze the data it collects to provide further 
scientific insight back to the research community to accelerate 
and de-risk biomedical innovation?
    Dr. Gottlieb. I appreciate the question, Senator. It's a 
complex one, and I'd be delighted to follow-up with you on it. 
But the bottom line is that there are situations--first of all, 
we're going to be taking some steps very soon to make more data 
from the clinical portion of the review from approved 
applications public where they can be aggregated into the kinds 
of datasets that you speak of. There are situations where we 
develop our own proprietary datasets from data that we glean 
across applications to make decisions, particularly around drug 
safety. But those datasets remain proprietary to the FDA 
because that information is commercially confidential.
    We are looking at how we could make these datasets public 
in a de-identified way without appropriating anyone's 
intellectual property around their own data, because my belief 
is if we're making regulatory decisions on the basis of 
aggregated data that isn't accessible to the public, that's 
probably something we should try to address. So this is a very 
complex area that we're actively working on. It'll suffice to 
say we are trying to move in the direction that you suggest. 
There are legal complexities associated with it.
    The Chairman. We're out of time. Maybe you could----
    Senator Young. I look forward to working with you.
    The Chairman. Thank you, Senator Young.
    Senator Bennet.
    Senator Bennet. Thank you, Mr. Chairman. I want to also 
congratulate you and Senator Murray on this 1 year 
anniversary--one more reason to be happy to be on this 
Committee.
    Dr. Gottlieb, I just wondered if you could give the 
Committee a little bit of an update on where you are with the 
implementation of the Med Tech Act, the bill that Senator Hatch 
and I worked on together.
    Dr. Gottlieb. Well, I appreciate the question, and I'll try 
to be brief. We just announced major components of 
implementation of some of those provisions today. So we 
continue to move forward with this on schedule. I think that 
it's a good example of what we're trying to do in this space. 
It's a good example of what we're trying to do generally with 
Cures, where we're taking the provisions that Congress outlined 
and trying to take the spirit of what Congress set out to 
achieve and trying to go beyond that.
    For example, Congress set out to create a more efficient 
process for the review or to exclude certain decision support 
tools used by clinicians. In the announcement we made today, 
we're also going to exclude certain decision support tools, 
digital tools that are used by patients as well as--as long as 
they meet certain parameters, and that's an attempt by FDA to 
try to take the spirit of what Congress set out to do and 
extend it a little bit.
    Senator Bennet. What sorts of things do you expect to see 
sort of sooner rather than later in terms of new devices for 
patients?
    Dr. Gottlieb. I think one area of development that we 
haven't seen as much of is in the area of decision support 
tools, where there's tools that could take information and help 
support decisions without making a decision for the clinician 
or the patient. I think, in part, there's a lot of reasons why 
we haven't seen as much innovation in that space as you would 
have thought, but regulatory ambiguity probably played a role 
for a period of time.
    FDA always intended to exercise enforcement discretion in 
this space. Congress expressly outlined that in Cures, and so 
this provides us the opportunity to put out guidance that 
creates some really bright lines and some parameters around 
what does and doesn't cross the line and what are the 
obligations of sponsors, even those who are excluded from 
active regulation, to make sure we're continuing to look at the 
safety of those products or collect information where things 
can go wrong.
    I am hopeful that we're going to see more innovation in 
this space, tools that could sit on top of the electronic 
health records, for example, and help physicians make decisions 
from that information.
    Senator Bennet. I appreciate your focus on it. I also 
noticed, unrelated to that, that the FDA approved the first 
breakthrough designated diagnostic test to detect genetic 
mutations for cancer. That was an approval that came through, I 
think, the new breakthrough therapies--or not breakthrough 
therapies, but breakthrough device section that we wrote for 
the bill--in the bill last year. I was interested to see that 
at the same time that happened, there was a simultaneous 
decision by CMS to also cover the diagnostic test.
    I wonder if you could share with the Committee how you and 
CMS conducted these parallel reviews and whether we can expect 
to see this sort of coordination in the future.
    Dr. Gottlieb. Well, I think you can, Senator, and this is 
an example of a test that was a laboratory developed test that 
voluntarily came through the regulatory process. We were able 
to review it in 6 months under the breakthrough designation--
the first, as you said, breakthrough designated product to 
receive FDA approval--and we worked with CMS to have in place 
simultaneous coverage at the same time.
    We think going forward this is a panel of cancer markers 
that will help guide the treatment of cancer patients and help 
guide the prescription of therapy. This is an area of a lot of 
innovation right now, and what CMS said in their policy--and 
I'll let them articulate it more clearly--is that panels that 
come through FDA for voluntary approval now will automatically 
receive coverage, a national coverage determination. So it's a 
powerful incentive, I believe, for more such tests to try to 
come through the regulatory process, and we can provide, I 
hope, a greater assurance of the effectiveness of it.
    Senator Bennet. I think that's a big step forward, and I 
can tell Dr. Collins agrees. So thank you.
    Dr. Gottlieb, the last question I have--and I only have a 
minute left. Senator Rubio and I last year worked on the RACE 
Act for pediatric cancers, and I know you guys put out some 
guidance recently on developing drugs in rare pediatric 
diseases. I wonder if you could expand a little bit about that.
    Dr. Gottlieb. We did, Senator, and we're going to have more 
to say on this area. But what we did yesterday was finalize 
some parameters and some guidance that we had in draft form 
that tries to look at very rare pediatric cancer, so this is--
pediatric diseases, excuse me, mucopolysaccharide diseases--
trying to outline a more efficient process for developing those 
products. We might not have to rely as much on placebo trials 
and might be able to use modeling assimilation to represent the 
experience of the placebo arm and also allow sponsors to 
collaborate to try to test multiple drugs in the same clinical 
trial.
    The reason why these kinds of accommodations, I think, are 
important in this setting is because it's very hard to enroll 
patients in these very rare diseases where you literally might 
have just dozens of patients who have a disease who are 
eligible to be enrolled in clinical trials. Tying to allow 
sponsors to collaborate and look at ways where you don't have 
to randomize some of those patients to placebo can facilitate 
more efficient development.
    Senator Bennet. Mr. Chairman, I'm out of time, but I didn't 
thank the witnesses for their great service to this country, 
and I deeply appreciate it.
    The Chairman. Thank you, Senator Bennet.
    Senator Collins.
    Senator Collins. Thank you, Mr. Chairman.
    Dr. Collins, I'm always glad to see you, and I still claim 
you as my cousin regardless of the facts.
    [Laughter.]
    Dr. Collins. I accept.
    Senator Collins. Thank you. The State of Maine is doing 
some really exciting medical research, and I have visited a lot 
of the labs and medical institutes that we have in our state. 
The Maine Medical Center Research Institute is conducting 
cutting edge work that researchers in Maine have underway to 
develop medical treatments for chronic diseases. In September, 
one of the researchers with whom I met, Dr. Leif Oxburgh, and 
his team at Maine Medical Center received an award through the 
NIH Regenerative Medicine Innovation Project. Using adult stem 
cells, Dr. Oxburgh is working to develop novel therapies for 
chronic kidney disease, which is very exciting.
    Regenerative medicine also holds great potential for 
understanding aging and reversing diseases like macular 
degeneration. I understand that the Chairman has already 
introduced Doug Oliver. But he, too, is from the State of Maine 
and grew up only 11 miles from where I did, and he shared his 
compelling story about losing and regaining his sight through 
regenerative therapy.
    MDI Biological Laboratory in Maine is leading the 
development of such therapies that hold significant potential 
for slowing the changes that occur with aging and the diseases 
of aging. What especially can we do to support research into 
biological aging?
    Dr. Collins. What a great question, and thank you for 
pointing out a number of the applications to regenerative 
medicine. As we are gathered here this morning, there's an 
intense discussion going on at a hotel in Bethesda sponsored by 
FDA and NIH jointly on this topic of regenerative medicine, 
with several hundred people in the room, talking about 
applications to kidney disease, to heart disease, to aging, to 
such things as rare diseases, common diseases, the whole 
landscape, and it is enormously exciting to see how that's 
talking place. When I spoke yesterday, I even forecasted if we 
do this in the way that I think we could, we could cure, not 
just treat, but cure a disease like sickle cell in the course 
of the next 5 years.
    With regard to the question about aging, we are learning a 
lot about what that process is. I'll just mention one example--
otherwise, I'll go into a long lecture--and that is that as you 
age, there's a certain category of cells that are no longer 
able to keep going. They become senescent, but they don't 
completely exit the stage. They're still there, and it turns 
out that they're not good actors. They're actually making the 
healthy cells around them not so healthy.
    If we could figure out, as we've already done in mice, how 
those senescent cells could basically be told, ``Okay, you're 
done now,'' it could very significantly slow down the normal 
process of aging with all that that entails in terms of frailty 
and chronic disease. This is a pretty exciting new development.
    Senator Collins. I think it is, also, and I remember 
visiting Harvard University and talking with researchers there 
about Alzheimer's Disease, and they're also looking at the 
possibility of turning proteins back on to restore cells that 
have been lost and neurons that have been lost.
    Dr. Collins. Enormous excitement about all of those 
alternatives, as well as identifying drug targets that we just 
didn't know about before by very careful systems biology 
approaches to understanding how networks in the brain work in 
normal individuals and those who are at risk for Alzheimer's. 
We have a partnership with industry that you may have heard 
about called the Accelerating Medicines Partnership, which is 
advancing this at a pace that I wouldn't have thought possible 
a couple of years ago.
    Senator Collins. That brings me to my question for you 
about that program. Which aspects of the Accelerating Medicines 
projects do you find most promising?
    Dr. Collins. Well, for Alzheimer's, there are two areas 
that we're really pushing. One is biomarkers. We really need to 
find out what are the indications that a therapy is working 
without having to wait 10 years to find out whether it was, in 
fact, protective against the development of cognitive decline, 
and there's a lot going on there with various types of imaging 
for tau, for instance, one of those proteins that's involved in 
this.
    The other part is this systems biology, where we're really 
trying to step away from what we know already and ask the 
question: What else is going on in the Alzheimer's brain, and 
how could we use that to develop this next-generation of 
therapeutics, taking advantage of all of the areas that we are 
now learning about to come up with interventions that are going 
to work, and then apply those early before people have already 
begun to succumb to the illness? We've got to start early if we 
want to get a good effective.
    Senator Collins. Thank you very much, Mr. Chairman.
    Thank you, Dr. Collins.
    The Chairman. Thank you, Senator Collins.
    Senator Murphy.
    Senator Murphy. Thank you very much, Mr. Chairman.
    Thank you both for your service. I know it comes at a great 
sacrifice, and, particularly, Dr. Gottlieb is a Connecticut 
resident. I know the sacrifice that you make to serve our 
country. Thank you to both of you.
    Dr. Collins, I wanted to talk to you a little bit more 
about the All of Us Research Program. This is a program that 
designs to build a diverse biomedical dataset for the Precision 
Medicine Initiative. I'm interested in it because one of the 
participating health centers, community health centers, that is 
currently gathering data is based in Middletown, Connecticut. I 
think it's great that you've gone out and worked with community 
health centers, because these centers--you typically serve a 
patient population that is often underserved in biomedical 
research.
    I just want to put that question to you, which is--if you 
could talk about the importance of having FQHCs as part of this 
initiative and whether there are plans to expand beyond the 
current six health centers that are right now part of this 
initiative. The community health center in Connecticut is very 
pleased with their partnership with you on this, and we'd love 
to see more like them get involved.
    Dr. Collins. In my opening remarks, I put up this visual 
image about how it is that we are seeking to enroll 
participants in this very bold, largest ever prospective study 
of health and illness in the United States. We are inviting 
people to participate by a variety of means. But one of them is 
through the community health centers here included in the 
health provider organizations, because we have a very specific 
goal here of having at least 50 percent of the participants in 
All of Us being individuals that are underrepresented 
traditionally in medical research programs.
    The community health centers, who provide care to a great 
number of people, particularly those in lower socioeconomic 
situations, are very excited about being our partners, and 
we're excited about having them as partners. We're starting 
with the six, and glad about Middletown as a place that has 
clearly been very successful in getting this up and going. But 
that is a pilot to see if we can, in fact, enroll many more. We 
aim to launch this project fully next spring. At the moment, 
we're in a beta test. We've enrolled about 12,000 individuals. 
We're learning everything we can about how these moving parts 
can all work together, and it's looking very good.
    Senator Murphy. Great. Thank you, Dr. Collins.
    Dr. Gottlieb, I want to switch topics to another exciting 
development out of the Cures Act. This is the establishment at 
the FDA of the Oncology Center for Excellence, which creates a 
cross-center team to work together on a variety of products to 
treat cancer. Just an update on what you've learned thus far 
from this model, and what do you take into account when you're 
thinking about creating other disease specific offices?
    Dr. Gottlieb. Having gone to college in Middletown, 
Connecticut, I appreciate the shout-out from the Senator.
    Senator Murphy. Thanks.
    Dr. Gottlieb. This is an extremely important effort on the 
part of the agency, so I appreciate your asking the question. 
The Oncology Center for Excellence--what we've essentially 
tried to do is consolidate the clinical portion of the review 
of oncology products into one combined center. So this was 
instrumental in our ability to expedite the review of the CAR-T 
products, for example. By consolidating the clinical expertise, 
we're able to more efficiently look at some of the biologics.
    We've had challenges fully standing it up, and in all 
candor, it's related to fully funding it. We believe that this 
is the future of the agency, though, trying to get these 
consolidated programs in place, and we're looking to other 
therapeutic areas where we can do this. But I think before we 
can progress on to other therapeutic areas, we really need to 
make it work in the oncology setting. So we're looking forward 
to continuing to try to move this program forward.
    Senator Murphy. Great. Another reminder to us that we've 
got to give you the funds to implement this act.
    Quickly, back to you, Dr. Collins. One more question, and 
that is on another part of the 21st Century Cures Act. Senator 
Isakson and I worked on a provision that allows for the CDC to 
collect information on the incidence and prevalence of 
neurological diseases. This was the Advancing Research for 
Neurological Diseases Act that Senator Alexander and Senator 
Murray helped us include in this legislation. Just talk for a 
second about the importance of having this data on neurological 
diseases to research done at NIH.
    Dr. Collins. Well, it's incredibly helpful to know what 
incidence and prevalence is for neurological conditions, 
particularly a condition like Parkinson's, but there are many 
other disorders as well. It is challenging and expensive to do 
that kind of analysis and to do it effectively and to keep it 
updated. As I understand it, while CDC was given the charge to 
do this, at the present time, they do not appear to have the 
funding to carry it out.
    Senator Murphy. Great. All right. You've got another 
advertisement to put the money behind the legislation we 
passed.
    Thank you very much, Mr. Chairman.
    The Chairman. Thank you, Senator Murphy.
    Senator Hatch, a former Chairman of this Committee, 
welcome.
    Senator Hatch. Well, thank you so much, Mr. Chairman. I 
appreciate it.
    I certainly appreciate you two gentlemen. I think you're 
both some of the best public servants I've seen in all of my 
40-plus years in the U.S. Senate, and I'm proud of both of you, 
and I hope you'll just keep doing what you're doing. So I want 
to thank you both here today.
    Dr. Gottlieb, last Congress, I joined Senator Bennet in 
authoring the PATH Act which was included in the 21st Century 
Cures Act and will help advance the development of urgently 
needed new antibiotics for multidrug-resistant infections by 
allowing them to be studied in smaller, more rapid clinical 
trials and, therefore, approved more quickly for the patients 
who need them most. As you know, FDA was tasked with developing 
guidance for industry regarding this limited population 
pathway, or LPAD. Can you please detail the ways in which 
stakeholder input is being solicited and incorporated into the 
guidance?
    Dr. Gottlieb. Thank you for the question, Senator. We plan 
to issue the guidance that you reference in the spring, and 
we've been meeting with stakeholders and other interested 
parties in the development of that guidance, consistent with 
our good guidance practices. So we will have stakeholder 
meetings in the development of any guidance document.
    I'll just say we think that this is an extremely important 
pathway, and we've already had multiple IND meetings with 
sponsors and believe this will be a robust vehicle for trying 
to create new pathways for drugs targeting significant unmet 
medical needs.
    Senator Hatch. Well, thank you.
    Dr. Collins, I was pleased to see that as a result of 21st 
Century Cures the NIH was able to start the Regenerative 
Medicine Innovation Project and that several of the first 
awards from this initiative had gone to research on rare 
diseases. As you may know, I've been a champion of the rare 
disease community for quite some time, and I applaud you for 
also recognizing how vital research in this area truly is.
    Strides in regenerative medicine may prove to be truly 
transformational in the way we understand and possibly even 
treat rare diseases.
    What barriers do you foresee in expanding research into 
this area as the Regenerative Medicine Innovation Project 
continues?
    Dr. Collins. Well, thank you, Senator, for the kind remarks 
at the beginning of your time and also for the question. I 
think this is an enormously exciting time for rare diseases 
because we have tools now that are starting to work. Dr. 
Gottlieb referred a little bit ago to gene therapy. I couldn't 
help but point out today in the New England Journal of Medicine 
a really dramatic advance in hemophilia using gene therapy with 
a viral vector to deliver the gene to the liver of men who are 
affected--and it's men because it's an X-linked condition--with 
really remarkable benefit over the course of many weeks. That's 
just a single example of what's possible in this space.
    I mentioned a little earlier my hopes that we could cure 
sickle cell disease by taking out the bone marrow cells, 
correcting the sickle mutation, putting them back. It's a 
transplant to yourself. It's a gene editing approach, which we 
also find to be very exciting.
    Recently, this terrible disease called spinal muscular 
atrophy, SMA, which results in children who are born, seem to 
be okay, and then develop paralysis and often don't live past 
their first year--now, with a clinical trial recently 
published, some of these kids are making it to their 
prekindergarten and looking pretty good, again by a genetic 
change that's been introduced using either a virus or a gene 
editing strategy.
    I think the big barriers right now is to just push the 
science as hard as we can, and the Cures Bill helps us by 
giving us that kind of inspiration. I'm glad to say the 
barriers with regulation are not the issue right now, working 
with Scott and his colleagues at FDA who also have made rare 
disease a very high priority. Of course, there is this issue 
about investment. Companies may not be so interested in putting 
a lot of money into a very rare disease because the market's 
going to be small, which means NIH has an even stronger 
responsibility to de-risk those projects and push them as far 
down the road as possible.
    One more thing I would say that you did for us in the Cures 
Bill is to make it possible for us to run Phase III trials for 
rare diseases in the Therapeutics and Neglected Disease Program 
in NCATS, which we had not previously had the privilege of 
doing and which we will be using aggressively for this purpose.
    Senator Hatch. Well, thank you. Dr. Collins, one of the 
provisions of the 21st Century Cures was designed to improve 
opportunities for young and emerging researchers. I've heard 
from the University of Utah, which receives, I think, around 
$150 million in NIH grants annually, that they have seen an 
improvement in this area, and for that, I would like to thank 
you and your staff and your work in this area.
    My time is up so I'll just thank you and tell you how much 
I appreciate your willingness to serve in this government and 
how much you really mean to people like us who have worked all 
these years in these areas.
    Dr. Collins. Thank you, Senator.
    Senator Hatch. Thank you.
    The Chairman. Thank you, Senator Hatch.
    Senator Baldwin.
    Senator Baldwin. Thank you, and I want to add my words to 
the others of congratulations for the bipartisan work you led, 
Mr. Chairman and Ranking Member Murray, on the 21st Century 
Cures Act.
    Thank both of you, Dr. Collins and Dr. Gottlieb, for your 
service.
    During the Committee deliberations on 21st Century Cures, I 
regaled the Committee any number of times about being the 
granddaughter of an NIH-funded scientist and how that 
influenced my championing of strengthening our research 
enterprise and support for the NIH. But in my first year in the 
U.S. Senate, in 2013, I had a particularly powerful and 
inspirational meeting with a young man, a high school senior. 
His name is Ian, and he is a bone cancer survivor from Fond du 
Lac, Wisconsin.
    Ian told me that cancer research, no doubt, helped save his 
life, and that's why he wanted to grow up to be a scientist, to 
help others with his disease. But he was concerned that it 
wouldn't be possible for him to break in as a new researcher 
due to his awareness of NIH funding cuts at the time.
    Ian inspired me to author the Next-Generation Researchers 
Act, along with my colleague, Senator Collins, to fight to 
improve NIH opportunities for new and early stage researchers. 
I am proud to report that Ian recently graduated from college, 
where he was helping a researcher at the University of 
Minnesota study the genetics of osteosarcoma, and he is now 
working with a scientist at Huntsman Cancer Institute in Salt 
Lake City, Utah, on pediatric cancers.
    Dr. Collins, I'm encouraged that the NIH has begun to 
robustly implement the Next-Generation Researchers Initiative 
to help support future scientific leaders like Ian as they 
discover cures for cancer and pursue other lifesaving research. 
You announced a new policy this year to issue more awards to 
investigators in the earliest parts of their independent 
research careers to help them sustain or achieve research 
independence.
    I'd like it, Dr. Collins, if you could please describe how 
each institute and center will prioritize awards for these 
early and mid-career investigators and how this will help 
improve and stabilize opportunities for our next generation of 
researchers.
    Dr. Collins. Well, thank you for the question. You're 
touching on a personal passion that I feel and that many of the 
other institute directors do as well. We actually just 
published about a month ago, myself and Michael Lauer and Larry 
Tabak, a description of what this policy is and how we're going 
to implement it, because we passionately agree with you that 
the next generation is really critical for our future, and it 
has been a tough period with the loss in purchasing power that 
NIH sustained between 2003 and 2015. Those first-time, early 
stage investigators were having a hard time getting started, 
and we cannot lose that, and we were starting to.
    Each one of the institutes, depending on where they think 
they can find their flexibilities, are freeing up dollars to 
make it possible for those early stage investigators who 
otherwise would just miss the pay line to actually get funded. 
We started this quite late in fiscal year 2017, but we were 
able to make a whole bunch of awards that otherwise would not 
have happened, and we're not done yet, because we're actually 
trying to see if we can reach back into some of those fiscal 
year 2017 reviews and fund a few more of those.
    We will have a meeting next week of my advisory committee, 
where we have a working group which you would be interested in, 
because it has graduate students and post-docs and junior 
faculty, not just the gray eminences, but the people who are 
really involved in this, and we will have a deep discussion 
about whether we have the right plan here in order to make this 
particular priority really happen.
    Senator Baldwin. I can see I'm running of time, but I want 
to just note--maybe you can answer for the record--that you 
estimate that this new effort to prioritize more awards for 
early investigators would be about $210 million in the next 
year and $1.1 billion over the next 5 years. Does NIH need 
additional resources for this policy to ensure that it fulfills 
its promise and continues to advance all other critical NIH 
efforts?
    Dr. Collins. Very quickly, we are prioritizing this within 
our existing resources, but, of course, we can do more of it if 
the resources are available.
    The Chairman. Before we go to Senator Warren, let me 
recognize Senator Murray.
    Senator Murray. Thank you very much, and I just want to 
thank both of you for your answers, and I will be submitting 
more questions for the record. I have another commitment I have 
to make.
    [The following information can be found on page 51 and 61 
in the appendix:]
    Senator Murray. This has been an excellent hearing, Mr. 
Chairman. I really appreciate it, and we have another one next 
week on the mental health part of Cures. I think it's really 
educational for all of us and appreciate both your efforts, and 
I look forward to continuing to work with you.
    The Chairman. Thank you, Senator Murray.
    Senator Warren.
    Senator Warren. Thank you, Mr. Chairman.
    We've been talking about the Cures Act. It has a lot of 
bipartisan provisions that I'm really glad became law. During 
our recent hearing on gene editing, we discussed new genetic 
privacy protections for research participants that Senator Enzi 
and I have worked on together. Right now, Massachusetts biotech 
companies are benefiting from a provision that Senator Bennet 
and Senator Burr and Senator Hatch and I wrote to try to 
clarify the FDA's authority relating to gene therapies for rare 
diseases, and I could go on. It's a long list.
    But Cures also fell short in a really big way, and that's 
on funding. I led Democrats on this Committee in calling for an 
extra $50 billion for the NIH and the FDA, and Cures did not 
send one single new dollar to these agencies. Instead, it only 
said that future Congressses might spend about 10 percent of 
that amount on NIH and FDA, and I'm glad that so far Congress 
has been increasing NIH funding. But I don't think it's time 
for us to pat ourselves on the back yet over where we are in 
funding the NIH.
    Dr. Collins, let me just go through this a little bit. Does 
the NIH fund most of the grant applications that it receives 
from scientists?
    Dr. Collins. No, we certainly aren't able to do that. We 
fund about 19 percent of those because that's the way it comes 
out after we do the priority scoring and see how much money we 
have.
    Senator Warren. Okay. So out of every 100 applications you 
get, you're funding about 19 of them. Now, is that because the 
other 81 would have been bad investments that would not have 
helped us make biomedical breakthroughs to advance science?
    Dr. Collins. If we look back in history, say, back around 
2000, 2001, we were funding about 30 percent, maybe even 35 
percent, because the funds were more available. We've looked at 
those to see--did a grant that scored at the 25th percentile 
actually turn out to be less productive than one at the 15th 
percentile? The answer is no. We can't really tell the 
difference up to about the 30th percentile. Even though peer 
review is trying to draw distinctions, it's very hard to do so 
in that top third.
    Senator Warren. In other words, if we--roughly, just using 
the numbers you had here--if we doubled, for example, the 
number of grants that we were able to fund, you think there's 
still a lot of good science to be had out there.
    Dr. Collins. I think there would be fantastic science out 
there.
    Senator Warren. Okay. That's powerfully important. I want 
to follow-up, too, on the point that Senator Baldwin made and 
the discussion you all had about researchers in the early part 
of their career. Getting that first NIH grant can make or break 
an academic career. It can be the difference between whether 
the scientist stays in the fight or whether the scientist has 
to leave academic medicine and go somewhere else.
    I just want to ask more about the details here. Where are 
we right now on early career researchers? What percentage of 
the grants are they able to get?
    Dr. Collins. Well, beginning in 2008, we actually 
instituted a policy so that those applicants who came to us for 
the first time as a principal investigator got a bit of a 
boost. They competed against each other, essentially, as 
opposed to against the most experienced ones, which meant, 
effectively, in priority score terms, they got a few extra 
points. But that's not good enough. We are still losing lots of 
those, and their success rates for those early stage 
investigators--we're still well below what we'd want to see.
    Ultimately, we think it would be most healthy if at least, 
say, 25 percent of those applications were going to get funded, 
and that's what we're trying to do with this new initiative, 
the Next Generation Research Initiative, which is named 
specifically for the words that were used in the bill. Thank 
you, Senator Baldwin, for that encouragement.
    Senator Warren. But I understand right now, we've been at 
about 16 percent. Is that right? You're saying at a minimum, we 
ought to be boosting that to about 25 percent.
    Dr. Collins. We've looked closely at every institute's 
successes and tried to figure out how we can get there with 
this new policy, yes.
    Senator Warren. I know that NIH has done what it can in 
this area. But NIH funding is still down about 15 percent of 
where it was a decade ago, back when we had a 50 percent higher 
success rate for the proposals that were coming across 
reviewers' desks. The Cures Act did not solve this problem. 
Frankly, it didn't even come close, and that's why today we're 
reintroducing the National Biomedical Research Act, which 
provides $50 billion in new funding for the NIH and for the 
FDA. I see you're sitting up straighter there, Dr. Gottlieb.
    [Laughter.]
    Senator Warren. This legislation is co-sponsored by 
Senators Sanders, Casey, Franken, Bennet, Whitehouse, Baldwin, 
Murphy, Kaine, and Hassan, all the Members of this Committee, 
as well as several of our Democratic colleagues who are not on 
the Committee. Families across this country are waiting for 
medical breakthroughs, and researchers are waiting for the 
money to fund their work so they can make those breakthroughs. 
It's time for us to step up and put more money into NIH. Thank 
you.
    Thank you, Mr. Chairman.
    The Chairman. Thank you, Senator Warren.
    Senator Hassan.
    Senator Hassan. Thank you, Mr. Chair, and I'll add my 
thanks to you and the Ranking Member for this hearing and for 
your work on the Cures Act.
    To Doctors Collins and Gottlieb, thank you so much for 
being here, and would you please--along with us thanking the 
two of you for your service and leadership, please thank the 
women and men who work with you every day in your agencies for 
the extraordinary work they do on behalf of the people of the 
United States.
    Dr. Gottlieb, I wanted to start with a question or two for 
you. We have discussed the devastating impact that the opioid 
epidemic is having in New Hampshire and all across the country. 
One of the tools in combating the epidemic is medication-
assisted treatment, like buprenorphine. It plays an important 
role in recovery along with access to other services and 
supports.
    Both of you, I think, mentioned in your opening comments 
the possibility that we will develop non-addictive pain 
products, which would help prevent addiction when, for example, 
somebody gets in an accident and is prescribed an opioid and 
then becomes addicted. The 21st Century Cures Act took some 
important steps on patient-focused drug development, including 
requiring guidance on patient experience data.
    Dr. Gottlieb, can you discuss how patient-focused drug 
development initiatives could be used in relation to developing 
new medication-assisted treatment and the development of new 
non-addictive pain treatments?
    Dr. Gottlieb. I appreciate the question. The bottom line is 
they can be a very important tool, and I think the provisions 
that are in the Cures Act are going to help inform how we go 
about thinking of the parameters that we use to encourage the 
development of products, both kinds of products, both non-
addictive alternatives to some of the opioid products, but, in 
particular, medication that can assist people to live lives of 
sobriety.
    We have committed to publish--to develop new guidance 
documents for outlining the pathway for the development of 
medically assisted therapy. We want to create incentives for 
sponsors to come in and try to develop those products, and part 
of that is making sure we have very clear guidelines.
    As part of that, we're going to be looking at alternative 
endpoints that we haven't looked at in the past, for example, 
issues like craving. We know craving is a factor that leads 
people to continue to use opioids, and if that can be an 
endpoint in the trials that we use to assess new products, it 
might provide a more efficient pathway, and that certainly is 
informed by the work we do with patients and looking at 
patient-informed endpoints.
    Senator Hassan. Thank you.
    Dr. Collins, I wanted to talk to you, too, about--you made 
a comment in a response, I think, to Senator Alexander about 
the impact of the Other Transaction Authority that you now 
have. Can you comment a little bit about how that could be 
helpful in the opioid space? You said it would be, but how 
specifically would OTA be useful to the NIH and its work in 
doing opioid disorder research?
    Dr. Collins. The plan that we have put in place, which is 
going to be fleshed out in more detail next week in an intense 
2-day meeting, will involve a lot of rapid action, both to come 
up with new ways to treat addiction, because we need more 
options to treat overdoses that don't respond as well as they 
might to fentanyl, and to develop these new non-addictive pain 
medicines that everybody agrees--that's going to require 
partnerships between academic institutions that have the 
appropriate science skills, with industry that may have 
formulation capabilities or drug development pathways.
    If we have to build that on the process of issuing grants 
and contracts in the traditional way, it's going to take a long 
time. Other Transaction Authority allows us to do something in 
maybe 6 weeks that might have otherwise taken 9 months. We've 
learned how to use this effectively and responsibly for the All 
of Us Program for the common fund, and we think this would be a 
great place for it to be available. We will be careful about 
how to use it, but it could help us a lot.
    Senator Hassan. Well, thank you. Finally, I wanted to talk 
a little bit about our new generation of scientific 
researchers, because both Senators Baldwin and Warren were 
talking about that. Cures took important steps for the next 
generation of researchers by helping to make it more affordable 
for prospective students to pursue their graduate degrees in 
science and engineering. NIH has been responsive to these 
efforts and in September announced a new policy for 
implementing special funding consideration for these graduate 
students.
    In recent weeks, I've heard from a number of graduate 
students, Dr. Collins, who are fearful of how the Republican 
tax legislation, particularly the House version of it, could 
impact their ability to pay back their student debts and 
whether it could even force them to drop out of their programs. 
One particular provision in the House bill would require that 
graduate-waived tuition is taxed with their stipends, a change 
that I've heard from Ph.D. candidates could really impact--one 
wrote, ``This would triple my taxable income and increase my 
yearly taxes by more than $10,000. It would force me to drop 
out of school because I wouldn't be able to afford rent and 
groceries while earning below the poverty line.''
    Can you comment, Dr. Collins, on what you think this 
provision would mean for the future of our young researchers 
and biomedical research?
    Dr. Collins. Well, very quickly, because of the time, these 
are our future graduate students that are learning to be the 
next generation of leaders in science across many disciplines. 
But, certainly, I think of life sciences needing those 
individuals to be the ones who are going to make the next 
breakthroughs. Anything that happens to discourage the best and 
brightest from taking that track or to feel that they can't 
afford to do so is something we should approach with great 
concern.
    Senator Hassan. Thank you very much.
    The Chairman. Thank you, Senator Hassan.
    Senator Whitehouse.
    Senator Whitehouse. Thank you very much, Chairman, and I 
join my colleagues in congratulating you and Ranking Member 
Murray on the success of a year ago. I hope we have more to 
come.
    Dr. Collins, one of the things we got into the Cures Act 
was a request that you reduce the burden of what we call low-
risk sub-recipient monitoring. I just left Brown University's 
Director of Research, who was in the anteroom a moment ago, and 
this was also the University of Rhode Island's request--you get 
things like Brown University and University of Rhode Island 
working together on a project, and the supposed obligation to 
monitor the subcontractors now applies to each of them.
    You have URI monitoring Brown, Brown monitoring URI. 
They're both monitored by you and OMB. Can you help reduce the 
bureaucratic and reporting burden related to sub-recipients?
    Dr. Collins. Senator, we don't particularly enjoy doing 
that kind of low-risk monitoring, either, and we have, in 
fact--thank you to the Cures Bill--put together a proposal of a 
way that we might reduce the amount of low-risk sub-recipient 
monitoring. There are certain situations that maybe don't quite 
meet that, but many of them do, and those are----
    Senator Whitehouse. Please include us in that cycle so that 
we can be helpful in giving advice and making sure that goes 
forward at a good pace.
    Dr. Collins. Be happy to.
    Senator Whitehouse. Dr. Gottlieb, the Cures Act was very 
good at getting FDA to connect the device and the drug sides a 
little bit better, and you've done a lot of training to try to 
connect the two. But the original testimony that we had from 
FDA from both the drug and the device sides was that what you 
really needed was a third pathway for drug-device combinations.
    Would you assure us that if it turns out that the hybrid 
effort that the Cures Act established isn't doing the job that 
you will let us know so we can take a second crack at it 
legislatively?
    Dr. Gottlieb. Absolutely, Senator. This has been a 
challenging area for us over a period of time. We think that 
the provisions in the Cures Act give us a lot of new tools to 
address it. We're going to be implementing those provisions and 
have some guidance pretty soon that we think will articulate a 
better pathway. But if it doesn't resolve the challenges that 
you've identified in the past, I'd absolutely be delighted to 
talk to you about alternatives.
    Senator Whitehouse. Great. Thank you. Just so long as we're 
staying in touch and in the loop and not wasting time if it 
turns out not to be productive.
    Dr. Collins, there have been some very everyday moments 
that are actually very significant. Back in 1876, a gentleman 
called his assistant, Watson, to come into the room, and in 
2012, a lady named Cathy Hutchinson took a sip of coffee--
pretty minor things except for the technology involved.
    ``Come here, Watson, I need you'' was Alexander Graham Bell 
first using the telephone to summon his assistant, and Ms. 
Hutchinson picked up the cup of coffee and brought it to her 
lips through what at Brown University they call the BrainGate, 
which is electrodes in the brain so that by mere thought, she 
could control the robotic arm. The brain technology that NIH is 
funding is terrific. Are you satisfied that you're adequately 
connected with DARPA, which is the BrainGate funding, to make 
sure that everybody is pulling in the same direction?
    Dr. Collins. We are enormously excited about that as well, 
and, yes, we have worked quite closely with DARPA in this whole 
idea about how you could begin, for people who are paralyzed, 
to control a robotic arm to carry out fairly sophisticated 
activities, including the ones you mentioned. This is a big 
part of what the BRAIN Initiative--which involves NIH and DARPA 
and NSF as well as the Department of Energy as well as some 
international partners--aims to do, is to really figure out how 
those 86 billion neurons between your ears do what they do in 
these complicated circuits which we're beginning to take apart 
and understand even better.
    We would like to go from where we are now, which was sort 
of an empirical effort to get this to work, to really 
understand it so well that you knew exactly where to place 
those electrodes to get the maximum sophistication of the move 
of that robotic arm.
    Senator Whitehouse. Last topic. We've just done some good 
bipartisan legislation on plastics in the ocean here in the 
Senate. The U.N. has just issued, I think, a unanimous 
statement of concern about plastics. Plastic, as you know, 
doesn't biodegrade. It just breaks down into smaller and 
smaller and smaller points, and then microscopic creatures can 
consume it, and it begins its track up the food chain.
    Never in human history have we had to experience that kind 
of plastic loading into our diet. It's now found in tap water. 
It's found all over the place. It's obviously going to be in 
our food. Is this something that the National Institutes of 
Health should begin doing some basic research on so that if 
this turns out to be a problem--it's certainly a new experience 
for humankind to have to digest and process that kind of 
microscopic plastic in the food chain--that you're alert to it?
    Dr. Collins. Absolutely. The National Institute of 
Environmental Health Sciences, one of our 27 institutes, but 
the one that's located in North Carolina in Research Triangle 
Park, is already looking at this. I can give you a summary of 
where we currently stand in terms of the research that's being 
conducted.
    Senator Whitehouse. I'd appreciate that. We can do that 
offline and through your staff.
    Dr. Collins. Be happy to.
    Senator Whitehouse. Thank you, Chairman.
    The Chairman. Thank you, Senator Whitehouse.
    Thanks to both of you for being here today. I hope you'll 
follow-up with the memo on regenerative medicine sometime in 
the next few weeks that I can give to Senator McConnell and 
other Senators who are interested in that. You heard several 
Senators mention that today, and you have quite a story to 
tell, I think.
    Also, we'll be interested as we look toward a second 
anniversary of the Cures Act in a year to--especially at how 
we're taking that 10 or 12 years between idea and something in 
the medicine cabinet, something in the doctor's office--how 
we're compressing that, how we're setting priorities, and how 
FDA, NIH, and CMS are working together to do that. I salute you 
for the steps you've already taken, but that would be a very 
promising way to do things, and, really, you have to do that 
more than we. We could do some things in legislation, but that 
we really can't do as well.
    We could order you to do it, but that wouldn't make you do 
it. You have to do what you've already started to do, which is 
to work together to speed that up and still do it in a way that 
provides safety and efficacy.
    Without getting you in the middle, Dr. Collins, I sometimes 
worry that the messages that come out of Washington aren't--are 
heard by the graduate students and the researchers across the 
country, and they worry that we're not funding their work. If 
the President's budget, for example, says one thing, and 
everybody pays a lot of attention to it, and then that really 
doesn't happen, nobody knows it doesn't happen.
    I remember that in President Obama's last year, he actually 
reduced recommended funding--discretionary funding for the 
National Institutes of Health, and he recommended a big 
increase in mandatory funding for the National Institutes of 
Health.
    Now, this isn't too hard for people to understand. This is 
the authorizing Committee. We don't appropriate money, usually, 
or we can't appropriate money, and we have another committee, 
which Senator Murray actually is the Ranking Member of and 
Senator Blunt is the chairman of, and that's the money 
committee. So for us to appropriate, say, $50 billion dollars 
in new funding for the National Institutes of Health is a 
wonderful aspiration, but that's not what we do.
    We decide, for example, whether Dr. Gottlieb should have a 
new breakthrough path for medical devices. If the 
Appropriations Committee were to decide that Dr. Gottlieb 
should have a breakthrough path for medical devices, we would 
be very upset, because we'd say, ``That's our job.'' If we were 
to try to appropriate another $50 billion for you, the 
Appropriations Committee would be very upset because they'd 
say, ``That's our job.''
    Let me ask you this. We have discretionary funding. That's 
the Appropriations Committee. We have mandatory funding, which 
this Committee could do. What's the size of the NIH budget this 
year? What's your total funding?
    Dr. Collins. $34 billion.
    The Chairman. How much of that is biomedical research?
    Dr. Collins. Virtually all of it, and, to be clear, more 
than 80 percent of that goes out to all those institutions all 
over the country that do that research.
    The Chairman. How much of that $34 billion is mandatory 
funding?
    Dr. Collins. I think there's $150,000 in there.
    The Chairman. Almost all of it is money that's supplied by 
the Appropriations Committee----
    Dr. Collins. I'm sorry, $150 million for Type I diabetes.
    The Chairman ----through the subcommittee that Senator 
Blunt and Senator Murray do. Now, 2 years ago, if I'm correct, 
Senator Blunt and Senator Murray recommended and the Congress 
approved a $2 billion increase in funding for the NIH.
    Dr. Collins. Yes.
    The Chairman. Last year, they recommended and Congress 
agreed and the President signed another $2 billion increase for 
NIH.
    Dr. Collins. That's right.
    The Chairman. If I'm not correct, I believe the Committee 
has recommended another $2 billion for the third year in a row. 
The Congress hasn't yet acted. The way we normally do things 
here is once we put something in the budget, we count it for 10 
years. So the first year is $2 billion. That's $20 billion over 
10 years. The second year is $2 billion. That's another $20 
billion over 10 years. The third one, if we do it this year, 
another $20 billion over 10 years.
    Now, that's not guaranteed, but that's usually what we do. 
We put it in the base, and we expect to do it again. With the 
priorities that we have in this Committee and in the 
Appropriations Committee, I expect that to be the case.
    Then, in addition, we did something that was very unusual 
in the Cures Bill, very hard to do. We took $4.8 billion, 
created a hybrid sort of funding that created all kinds of 
consternation with the House of Representatives and with our 
Appropriations Committees, and we gave some special funding to 
the Precision Medicine and the Cancer Moonshot, the BRAIN 
Initiative, and some other things. But the chances of that 
happening again are close to zero.
    The real money that is supposed to go to the National 
Institutes of Health and NIH comes through the Appropriations 
Committee, and they've been doing a tremendous job over the 
last few years, and I say that--I'm a member of it myself, but 
I'll give Senator Blunt and Senator Murray great credit for 
squeezing out of the budget resources which are a good deal 
larger than in the last few years.
    There's nothing wrong with aspiring for more. There's 
nothing wrong with looking back 15 years and saying that if we 
had gone up at the same rate we had been going up, it would be 
even higher today. But I think it's important for researchers 
across the country to know that this Congress in a bipartisan 
way for the last 3 years has been extraordinarily committed to 
significant increases in funding for the National Institutes of 
Health, and I think it's made a difference.
    Dr. Collins. Senator, I really appreciate your taking the 
time to explain all that, because I think there are people 
watching who are wondering how these decisions get made and 
where we are. Certainly, there have been a lot of anxieties in 
the biomedical research community, particularly from young 
investigators, about what is going on and what's the likelihood 
of a pathway.
    You have pointed out that there's a great deal of reason to 
be excited and optimistic about a career in biomedical 
research, first of all, because the science now is so 
incredibly promising and exciting, but, second of all, because 
the support, as you've outlined, has been on the upward 
trajectory, with 2 years already with this $2 billion increase 
already happening and a significant promise that it may happen 
for the third. If that were to be the case, that would be about 
a 20 percent increase for NIH over the course of 3 years, which 
is a very encouraging sign.
    Again, I'm grateful that in this era where so few things 
seem to be bipartisan, medical research continues to be so, and 
much credit to you and your colleagues for keeping that alive.
    The Chairman. I'll ask one last question of Dr. Gottlieb 
and you. With all this excitement and these breathtaking 
biomedical advances, do you see any--as you talk to high school 
students or college students, do you see any increase in an 
interest in biology?
    Dr. Gottlieb. I don't talk to high school and college 
students that much. I will tell you that--my girls are eight 
and four. I think that there is an increase in excitement among 
those training in medicine right now about what the future 
holds. I will affirm that. I have a lot of contact with 
residents and medical students, and I see an increased 
excitement about what they're going to be able to accomplish 
over the course of their careers that I couldn't accomplish 
over the course of my medical career.
    The Chairman. Dr. Collins.
    Dr. Collins. Well, certainly, when I go out to universities 
to give a talk and meet with students--and I always do that. 
That's the best part of any visit to an academic center, is to 
say, ``I want a chance to meet with the graduate students and 
the post-docs, and I don't want anybody else in the room, 
because I really want to hear from them.''
    I have heard a lot of anxiety in the last couple of years, 
and I'm trying to reassure people that things are looking much 
brighter than they think they are. That sort of sense out there 
of trouble is probably beyond what it maybe ought to be 
considering the path that we're on. But, boy, do I hear 
excitement about the scientific opportunities.
    If you can quickly switch to that topic, then the spark 
goes into the conversation, and the eyes light up, and this 
graduate student tells you about the experiments they're doing 
that week and how excited they are about what they can do, 
because there are things that a single student can do right now 
that might have taken a team of 10 people or 5 years to do.
    The technology has come along so quickly and the ability to 
use big data and computational approaches. This is the golden 
era, and if anybody really wants to have a great time in 
science, they should come and join us.
    I hope Ian, whoever that is, that Senator Baldwin was 
talking about will be one of those as soon as possible, because 
we need this. This is our future. We want the best and 
brightest to join us so that this can happen.
    The Chairman. Well, thanks to both of you.
    The hearing record will remain open for 10 days. Members 
may submit additional information for the record within that 
time if they would like.
    Our Committee will meet again next week on Tuesday, 
December 12th, at 10 a.m. for a hearing titled, The Cost of 
Prescription Drugs: An Examination of the National Academies of 
Sciences, Engineering, and Medicine Report, Making Medicines 
Affordable, a National Imperative. This is the third in our 
hearings on drug prices, which has been requested by both 
Democratic and Republican Members of our Committee.
    Then next Wednesday, we have our oversight hearing on the 
mental health aspects of the Cures Act.
    Thank you for being here today. The Committee will stand 
adjourned.
    [Additional Material follows:]

                         QUESTIONS AND ANSWERS

Responses by Francis Collins to questions from Senator Murray, Senator 
Cassidy, Senator Collins, Senator Roberts, Senator Warren, and Senator 
                               Whitehouse

                             Senator Murray
    Question 1. In the 21st Century Cures Act, I was also proud to 
champion provisions to improve the inclusion of historically 
underrepresented populations--including women, racial and ethnic 
minorities, children, and seniors--in clinical research. These 
provisions include requiring NIH to report on the inclusion of these 
populations in NIH-supported research.

    In each institute or center's strategic plan, Section 2031 requires 
the directors of the national institutes and national centers within 
NIH to include details on how it accounts for women and minority 
populations in clinical research to reduce health disparities after 
consulting with the National Institute on Minority Health and Health 
Disparities and the Office of Research on Women's Health.

    In the NIH Triennial Report (formerly biennial), Sections 2032 and 
2038 require the NIH to include or identify:

      Study populations by demographic variables, including 
biological and social variables and relevant age categories, such as 
pediatric subgroups.
      The number of women as well as the number of minority 
groups included as subjects, and the proportion of subjects that are 
women or members of minority groups, in any project of clinical 
research conducted during the applicable reporting period, 
disaggregated by categories of research area, condition, or disease, 
and accounting for single-sex, single-race, and single-ethnicity 
studies.
      For the applicable reporting period, the number of 
projects of clinical research that include women and members of 
minority groups and that have been completed during such reporting 
period and are being carried out during such reporting period and have 
not been completed.

    In the agency's assessment of research priorities, Section 2038 
requires NIH to publicly post and assemble data on study populations of 
clinical research at each national research institute and centers, 
specifying the inclusion of women, members of minority groups, relevant 
age categories (including pediatric subgroups), and disaggregating the 
data by research area, condition and disease category.

      a. Could you provide an update on NIH's progress in implementing 
these provisions and the agency's plans to make this reporting required 
for all studies?

    Answer 1. NIH is committed to supporting clinical research that 
benefits individuals of all sexes/genders, races, ethnicities, and 
ages. Appropriate inclusion of research participants is essential to 
ensuring that NIH is supporting sound science that will ultimately 
inform clinical practice to the benefit of all who are affected by the 
disease or condition under study.

    NIH has longstanding policies to ensure appropriate inclusion of 
women, minorities, and children in its supported clinical research 
studies. For more than two decades, NIH has collected data on the 
distribution of study participants by sex/gender race, and ethnicity, 
with aggregate data available online. \1\ In addition to continuing 
these procedures, NIH has taken the following steps to implement 
inclusion reporting-related provisions of the 21st Century Cures Act:
---------------------------------------------------------------------------
    \1\  https://report.nih.gov/recovery/inclusion--research.aspx

      In August 2017, the Directors of NIH Institutes and 
Centers (ICs) were informed that all IC strategic plans must account 
for women and minorities as well as be focused on reducing health 
---------------------------------------------------------------------------
disparities.

      On December 19, 2017, NIH announced a revised Policy and 
Guidelines on the Inclusion of Individuals Across the Lifespan as 
Participants in Research Involving Human Subjects. \2\ The policy, 
developed after significant input from experts and the public through a 
Request for Information \3\ and workshop \4\, requires all applications 
submitted for due dates January 25, 2019 or later that propose research 
involving human subjects to address inclusion of individuals across the 
lifespan (including children and older adults) and provide de-
identified individual-level data describing participant age, sex/
gender, and race/ethnicity in progress reports.
---------------------------------------------------------------------------
    \2\  https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-
116.html
    \3\  https://grants.nih.gov/grants/guide/notice-files/NOT-OD-17-
059.html
    \4\  https://report.nih.gov/UploadDocs/NIH percent20Inclusion 
percent20Across percent20the percent20Lifespan percent20Workshop 
percent20Summary percent20Report percent20--FINAL--508.pdf
---------------------------------------------------------------------------
      NIH is enhancing its electronic systems to accept de-
identified individual-level data on sex/gender, race, and ethnicity 
(functionality expected this summer). Leveraging data that many 
investigators are already collecting in a format consistent with the 
way these data are typically obtained and stored is expected to 
maximize analytic flexibility while minimizing administrative burden.

      The Human Subjects and Clinical Trials section of the NIH 
application forms has been updated to consolidate human subjects, 
inclusion enrollment, and clinical trial-related information in one 
place, and expand the information required for proposed clinical 
research studies. \5\ Among the changes are structured data fields that 
capture the expected age range of participants. Beginning January 25, 
2018, investigators submitting competing applications that include 
research involving human subjects are required to specify the minimum 
and maximum age of participants in the proposed study.
---------------------------------------------------------------------------
    \5\  https://grants.nih.gov/policy/clinical-trials/new-human-
subject-clinical-trial-info-form.htm
---------------------------------------------------------------------------
      The NIH Office of Extramural Research is developing 
methods to extract data on the inclusion of women and minorities by 
research area, condition, and disease category for each IC. These data 
will account for single-sex, single-race, single-ethnicity, completed, 
and non-completed studies. Further, these data are expected to be 
published in the next NIH Triennial Report published online.

    NIH looks forward to the availability of additional data on the 
diversity of participants in clinical research studies. These steps 
will help us better understand the distribution of participants in our 
clinical research, and how interventions work in their intended 
populations. These better data will allow us to make more informed 
decisions going forward and improve the health of all citizens.

    Question 2. I was pleased to see that NIH formed a Child Enrollment 
Scientific Vision Working Group (CESVWG) to support the inclusion of 
children in the All of Us Research Program as part of the Precision 
Medicine Initiative, which the 21st Century Cures Act authorized in 
Section 2011.

      a. Can you provide an update on the status and expected release 
date of the report from the CESVWG, as well as information on NIH's 
plans for subsequent efforts to oversee the inclusion of children in 
the All of Us Research program after CESVWG sunsets?

      b. Do you intend to have a specific funding opportunity focused 
on pediatric enrollment to support an adequate sample size, 
particularly for conditions such as pediatric rare diseases?

    Answer 2, a., b. The Child Enrollment Scientific Vision Working 
Group (CESVWG), an expert working group of the All of Us Research 
Program Advisory Panel, first convened in the summer of 2017 and 
completed its work in late 2017. The final report of the working group, 
posted publicly on January 18, 2018, describes the types of research 
that All of Us is uniquely positioned to enable through the enrollment 
of children. All of Us is now considering the information gathered by 
this working group with a focus on maximizing the utility of the 
research program on a wide range of pediatric research opportunities in 
the near-, medium-, and long-term. There are several program 
modifications that will need to be made prior to enrolling children, 
including changes to the initial research protocol. The consortium, 
comprised of All of Us NIH staff, awardees, and partners, is actively 
working on all components of the program (engagement, consent, 
assessments, return of information, etc.) to identify pediatric 
alternatives to the current adult versions. As All of Us considers the 
steps it needs to take to include children, the Program will make 
decisions about any funding opportunities.

    Question 3. Section 2034 of the 21st Century Cures Act calls on NIH 
and other entities across the executive branch to review policies and 
regulations with the objective of reducing administrative burden for 
researchers.

    In October, the Federation of American Societies for Experimental 
Biology (FASEB), the Association of American Medical Colleges, the 
Council on Governmental Relations, and the National Association for 
Biomedical Research issued a report with recommendations for reducing 
regulatory burden while maintaining animal welfare.

      a. Do you plan to incorporate any of the recommendations from 
this report in your review and analysis of regulations and policies 
regarding the care and use of laboratory animals, as required by 
Section 2034?

      b. What is NIH's plan to seek stakeholder input on reducing 
regulatory burden for the research community, especially regulations 
related to use of animals in research?

    Answer 3, a., b. NIH has undertaken many efforts in recent years to 
clarify and reduce administrative burden associated with animal care 
and use to the extent possible under current mandates. Section 2034(d) 
of the 21st Century Cures Act specifically requires that the NIH in 
collaboration with the United States Department of Agriculture (USDA) 
and the Food and Drug Administration (FDA) complete a review of 
applicable regulations and policies for the care and use of laboratory 
animals and reduce administrative burden on investigators. The NIH 
Office of Laboratory Animal Welfare, USDA Animal and Plant Health 
Inspection Service--Animal Care, and FDA established a working group in 
February 2017 to address the requirements of the Act.

    The working group will review applicable regulations and policies 
for the care and use of laboratory animals as well as reports and 
surveys recommending approaches to reduce regulatory burden on 
investigators, while maintaining the integrity and credibility of 
research findings and protection of research animals. This includes 
considering the October 2017 recommendations from the Federation of 
American Societies for Experimental Biology, the Association of 
American Medical Colleges, the Council on Governmental Relations, and 
the National Association for Biomedical Research.

    Further, the group will use several approaches to consult with 
stakeholders on reducing regulatory burden for the research community. 
For example, NIH will solicit input with a Request for Information 
(RFI) in the NIH Guide for Grants and Contracts. The RFI will be 
announced in the Federal Register and through other media. The USDA and 
FDA will use communications with their stakeholders to alert them to 
the RFI as well. All three agencies will carefully consider the 
responses in preparing a report on actions to be taken by the agencies 
and the impact on relevant stakeholders.

                            Senator Cassidy
    Question 1. What types of guidance and regulatory reform are needed 
to ensure non-pharmacological interventions are better utilized for 
pain management?

    Question 2. What are some of the barriers that exist to utilizing 
physical therapy and other non-pharmacological treatments for pain 
management?

    Answer 1 and 2. There are numerous barriers to integrated pain care 
that incorporates non-pharmacological treatments for people with 
chronic pain. The 2011 Institute of Medicine (IOM) Report: Relieving 
Pain in America identified major barriers as institutional, 
educational, organizational, and reimbursement--related and noted that 
the greatest challenges are in the primary care setting where most pain 
management occurs.

    The IOM report considered provider training in pain management 
across many disciplines to be inadequate, based on national surveys of 
professional schools' pain curricula. Lack of training coupled with the 
complexity of pain often results in patients not receiving appropriate 
referrals for multidisciplinary care despite evidence that non-
pharmacological approaches are effective for many pain conditions. Many 
primary care settings do not have interactions/access to facilities 
that provide non-pharmacological treatment options. This situation is 
more acute across vulnerable populations in rural areas and in 
communities with limited resources where no such options exist. Poor 
public awareness of pain and treatment options, the stigma associated 
with pain, and the reliance on pharmacological management, often 
prevent patient-provider communication of individual treatment needs.

    Both providers and payers are concerned that the evidence base for 
best clinical practice in pain management is weak and so not helpful in 
determining practice guidelines and coverage policies. For those non-
pharmacological treatments with evidence of efficacy, dissemination and 
implementation of these clinical practices has not been effective in 
reaching the patients. Until recently there was no broad analysis of 
published evidence to show what non-pharmacological treatments are 
effective for different pain conditions. In 2017, AHRQ completed a 
systematic review of the literature, describing in detail the evidence 
base for non-pharmacological treatment approaches for five common pain 
conditions. This comprehensive review is intended to help develop and 
disseminate practice guidelines. It also provides a resource for payers 
to structure their coverage policies and processes for integrated pain 
care.

    Many organizational barriers to access to non-pharmacological 
treatments are driven by current reimbursement policies of public and 
private insurers. An extensive survey of coverage of pharmacological 
and non-pharmacological treatment for low back pain by 50 state 
Medicaid, Medicare, and private payers found inconsistent to no 
coverage for many non-pharmacological treatments, while most analgesics 
were universally covered with fewer pre-authorizations, restrictions, 
and lower co-pays.

    Interviews with key informants revealed a relative emphasis among 
plans on reducing opioid prescribing rather than increasing coverage 
for non-pharmacological treatments. The study revealed that 
determination of coverage of pharmacologic and non-pharmacologic 
therapies are separate process, suggesting that plans do not integrate 
coverage in the context of multimodal, comprehensive treatment for 
pain. Only one plan fully integrated non-pharmacological therapies into 
step therapy requirements for opioid initiation.

    Knowledge barriers still exist. Pain is variable, affects people 
differently, and patient responses to treatment are unique. We lack 
adequate understanding of pain mechanisms, individual risk factors for 
who is likely to develop chronic pain, and therefore need further 
research to guide tailored treatments.

    Question 1. Dr. Collins, in our hearing you mentioned that Congress 
had the responsibility to set NIH funding levels for particular 
institutes. As you know, your agency, working with other parts of the 
Administration, also has a role in that process by requesting certain 
funding levels in the President's yearly budget request to Congress.

    To what degree do you use your discretionary funding request to 
increase funding for institutes such as NIDA which are addressing the 
societal impact of addiction?

    Answer 1. The annual President's Budget reflects the 
Administration's fiscal policy goals for the entire Federal Government, 
and NIH develops its request in close coordination with other divisions 
within the Department of Health and Human Services and with the Office 
of Management and Budget. Within that framework, NIH pursues its 
highest research priorities through strategic investments and careful 
stewardship of appropriated funds. NIH activities that are considered 
part of the National Drug Control Budget, which includes the entire 
NIDA budget and part of the NIAAA budget, receive special attention in 
a section of the Overview Volume of the NIH congressional 
Justification.

                            Senator Collins
    Question 1. In 2013, Congress approved the National Pediatric 
Research Network Act (NPRNA). As you know, the law provides 
authorization for a nationwide network of research consortia to conduct 
basic and translational pediatric research. Last year, as part of the 
21st Century Cures Act, Congress included language to drive forward 
implementation of that network. I have been informed that NIH believes 
the IDeA States Pediatric Clinical Trials Network constitutes 
implementation of the NPRNA. Notwithstanding the important merits of 
the IDeA States program, I have heard concerns as to whether it 
fulfills the statutory intent of the NPRNA, which is to create a 
nationwide network of investigator-initiated and multi-institution 
pediatric research partnerships.

    For example, researchers in my State of Utah (and in 26 other 
states) are not eligible to apply for this particular program because 
Utah is not an IDeA state. The NPRNA was envisioned as a national 
network where each consortium would receive funding for shared core 
research infrastructure for a coordinating central academic center and 
auxiliary sites, bringing together top experts and patient populations 
wherever they may be. Proposals for these pediatric research consortia 
would be reviewed and scored via the NIH peer review process. What 
actions has the NIH taken to date, and what actions are planned in the 
coming months, to further implement the NPRNA?

    Answer 1. Pediatric research has been and continues to be an NIH 
priority. The NIH's strong basic research portfolio provides the 
foundation for pediatric research in a variety of scientific areas. In 
Fiscal Year (FY) 2017, the NIH funded approximately $4.1 billion in 
research grants and projects directed specifically at pediatric 
research, an increase of $220 million over fiscal year 2016 spending. 
The Eunice Kennedy Shriver National Institute of Child Health and Human 
Development (NICHD) funds the largest portion of pediatric research 
among the 27 NIH Institutes, Centers, and Offices (ICOs), taking a 
leadership role in many pediatric research efforts that involve trans-
NIH collaborations. However, all of the ICOs support various aspects of 
pediatric research, such that the NICHD alone accounts for only 18 
percent of the total NIH support for pediatric research. This reflects 
the breadth of the research portfolio at the NIH dedicated to improving 
the health of children everywhere.

    The NIH intends to meet the goals of the National Pediatric 
Research Network Act through four networks: the Environmental 
influences on Child Health Outcomes (ECHO) program IDeA States 
Pediatric Clinical Trials Network, the Pediatric Trials Network, the 
Neonatal Research Network, and the Rare Diseases Clinical Research 
Network.

    The IDeA States Pediatric Clinical Trials Network (ISPCTN) provides 
medically underserved and rural populations with access to state-of-
the-art clinical trials, apply findings from relevant pediatric cohort 
studies to children in IDeA State locations, and build pediatric 
research capacity at a national level. Funding for this new network 
also supports professional development of faculty-level researchers and 
their support teams in the conduct of clinical trials research. The 
awards are a component of the ECHO Program, which is investigating how 
exposure to a broad range of environmental factors in early 
development, from conception through early childhood, influences the 
health of children and adolescents. It is important to note that the 
ISPCTN funds research centers in states where there was little to no 
pediatric research capacity prior to its creation.

    ISPCTN consists of multiple institutions arranged in a ``hub and 
spoke'' model, with each of its 17 clinical sites in a separate IDeA 
State and its central Data Coordinating and Operations Center located 
at the University of Arkansas for Medical Sciences. ISPCTN uses this 
network model to foster collaboration, coordination, and sharing of 
resources not only within the Network but also to partner with other 
NIH networks focused on pediatric biomedical research to increase 
representation of children from beyond the IDeA States.

    The Pediatric Trials Network (PTN) is comprised of over 100 
clinical research sites across the United States with over 7,000 
children enrolled. The PTN provides evidence for the formulation, 
dosing, efficacy, and safety of medications and medical devices in 
infants and children. The PTN conducts pediatric clinical drug trials 
in a variety of therapeutic areas, including but not limited to 
cardiovascular diseases, cancer, infectious diseases, gastroenterology, 
respiratory diseases, neonatology, and medical devices. Current studies 
include research on the pharmacokinetic and pharmacodynamics properties 
of antipsychotic drugs in children and adolescents, a study on the 
effectiveness of sildenafil to decrease the risk of pulmonary arterial 
hypertension in preterm infants, and research on the pharmacokinetics 
of methadone to treat opioid withdrawal in children.

    The NIH also supports a national network focused on neonatal 
research. The Neonatal Research Network (NRN) is a collaborative 
network of neonatal intensive care units across the United States, 
comprising 18 clinical centers and a data coordinating center. Focused 
on newborns, particularly extremely low-birth-weight infants, the NRN 
conducts clinical trials and clinical studies in such areas as sepsis 
and other infections, bronchopulmonary dysplasia and other lung 
conditions, and necrotizing enterocolitis, a condition in which the 
intestines lack oxygen or blood flow.

    Finally, the NIH prioritizes research into rare diseases that 
affect children. The Rare Diseases Clinical Research Network (RDCRN) 
program, led by the National Center for Advancing Translational 
Sciences (NCATS) in collaboration with other NIH Institutes, is a model 
designed to advance medical research on rare diseases. The RDCRN 
currently includes 100 institutions and clinical sites in 33 states 
examining over 6,000 children each year. Several of the Rare Diseases 
Clinical Research Consortia (RDCRC) focus on or include rare diseases 
that affect children, including brittle bone diseases, mitochondrial 
diseases, immune deficiencies, Rett syndrome and Rett-related 
disorders, sterol and isoprenoid conditions, urea cycle disorders, 
genetic disorders of mucociliary clearance, developmental 
synaptopathies, and lysosomal storage diseases, among others.

    Collectively, these networks support research capacity across the 
United States to address unmet pediatric research needs. NIH fully 
expects these networks to continue to expand and will continue to seek 
out partnerships with all stakeholders and other pediatric research 
consortia.

                            Senator Roberts
    Question 1. In your written testimony you mention efforts underway 
to ``cut the bureaucratic red tape that slows the process of science.'' 
Can you provide more detail on how NIH is working to reduce 
administrative burdens on medical researchers?

    Answer 1. For decades, NIH has focused on reducing administrative 
burden in various ways including but not limited to, leading efforts 
within the Federal Demonstration Partnership (FDP) and supporting 
efforts coordinated by the White Houses' Office of Science and 
Technology Policy. The NIH Director, Dr. Francis Collins, co-chairs the 
National Science and Technology Council's Committee on Science (CoS). 
Further, NIH co-chairs a CoS interagency working group, called the 
Research Business Models Working Group, that aims to improve 
coordination and collaboration among Federal research agencies to 
streamline requirements for the extramural research community.

    In response to the fiscal year 2015 omnibus report language, NIH 
engaged and actively participated in a collaborative effort to address 
the issue of administrative burden with the ad hoc committee of the 
National Academies of Science. This group studied Federal regulations 
and reporting requirements with specific attention to those directed at 
research universities. The resulting report, ``Optimizing the Nation's 
Investment in Academic Research: A New Regulatory Framework for the 
21st Century'' was issued in two parts. Part I focused on regulatory 
issues identified as of most pressing concern to the research 
community, while Part II contains the analysis of topics that adversely 
affect the Nation's ability to optimize its investment in academic 
research.

    The report recommended existing Federal policies and processes be 
harmonized across agencies, such as by using a uniform format for grant 
proposals and research progress reporting. It also recommended reducing 
the regulatory burden associated with policies for human subjects' 
research, animal care and use, monitoring of sub-recipients, reporting 
of financial expenditures, and disclosure of financial conflicts of 
interest. In addition, the Committee recommended that Congress 
establish the Research Policy Board (RPB), which would serve as a 
public-private forum for discussions relating to regulations of 
federally funded research.

    The 21st Century Cures Act required research funding agencies 
modify and harmonize regulations and policies with similar purposes to 
minimize administrative burden to the greatest extent possible, all 
while maintaining responsible oversight of federally funded research. 
Further, the RPB was required to be established to provide Federal 
Government officials with information on the effects of regulations 
related to Federal research requirements.

    NIH has implemented several of the 21st Century Cures Act 
provisions, including eliminating Paperwork Reduction Act requirements 
for scientific studies, and automating the issuance of certificates of 
confidentiality as a ``term and condition of award'' for awards 
involving human subjects so NIH-funded researchers no longer need to 
request one. Further efforts to streamline applications for clinical 
trials, effective for due dates on or after January 25, 2018, include a 
structured data form for human subjects research fields that eliminates 
duplicate information entries. In addition, NIH and FDA partnered 
together to develop a clinical trial protocol template \6\ with 
instructional and example text for NIH-funded investigators to use when 
writing protocols for phase 2 and 3 clinical trials. NIH developed a 
simplified application appendix \7\ to rectify inequities in peer 
review that arise from submission of inappropriate or excessive 
appendix materials.
---------------------------------------------------------------------------
    \6\  NIH and FDA Release Protocol Template for Phase 2 and 3 IND/
IDE Clinical Trials
    \7\  Updated Appendix Policy Eliminates Clinical Trial-Related 
Materials for NIH/AHRQ/NIOSH Applications Submitted to Due Dates on or 
After January 25, 2018
---------------------------------------------------------------------------
    NIH continues to work with HHS to decrease burden involved in 
financial conflict of interest reports, reducing audit burden by 
raising the threshold, waiving the requirement for subrecipient 
monitoring when the subrecipient is in good standing, and simplifying 
and harmonizing animal care regulations.

    NIH is partnering with ORCID \8\ to enable scientists to include 
additional data fields useful to maintain and update biosketches and 
CVs across multiple platforms. ORCID is a not-for-profit organization 
that assigns unique persistent identifiers to researchers that supports 
automated linkages between researchers and their professional 
activities with the goal of helping people find information and to 
simplify reporting and analysis. NIH's eRA Commons, an online interface 
where signing officials, principal investigators, trainees and post-
doctoral fellows at institutions/organizations can access and share 
administrative information relating to research grants, is establishing 
a real-time link with ORCID, which allows users to associate ORCID with 
their eRA account. Further, NIH and other funders are collaborating on 
the ORCID Reducing Burden and Improving Impact Tracking (ORBIT) 
project. This effort will expand the ORCID data model beyond 
publications to data elements typically found on a CV, such as grants, 
courses taught, presentations, and other research products. To this 
end, in 2017, NIH developed guidance on how NIH applicants have the 
option, for applications submitted for due dates of May 25, 2017 and 
beyond, to cite interim research products such as preprints in 
applications.
---------------------------------------------------------------------------
    \8\  Teaming with ORCID to Reduce Burden and Improve Transparency
---------------------------------------------------------------------------
    NIH continues to consider ways to address the recommendations to 
reduce the administrative burden associated with Federal research 
funding outlined in the NAS report and 21st Century Cures Act. For some 
of these recommendations, NIH can take action by implementing changes 
to grant policies.

    Because all of the provisions of the 21st Century Cures Act have 
not been fully implemented, it is too early to determine the effect on 
research. However, NIH is diligently working with university faculty 
and research administration staff to ensure that measures implemented 
by NIH to reduce administrative burden are effective.

    Question 2. The Office of Management and Budget has a statutory 
deadline to establish a Research Policy Board to work on this topic. 
Has NIH been engaged with OMB on this priority?

    Answer 2. In 2017, HHS, through NIH, provided technical support to 
the OMB related to the Research Policy Board (RPB). For additional 
information regarding the RPB, we refer you to OMB.

    Question 3. In your testimony, you note that the success rate for 
applicants being awarded NIH grants is below 20 percent. How, or do, 
you see that number improving over the next several years as the 
additional funding from Cures is appropriated to NIH?

    Answer 3. NIH would like to see the success rate for competing 
research project grants increase toward the 30 percent level last seen 
in fiscal year 2003. The additional funding from Cures is a step in the 
right direction, assuming that it supplements rather than replaces the 
regular annual appropriations. The success rate depends on the number 
of new and competing awards as well as the number of grant 
applications. NIH's purchasing power has declined by 16 percent since 
fiscal year 2003, while the number of applications increased by over 50 
percent. Our ability to improve the success rate will depend on the 
total appropriations level going forward. With so many promising 
biomedical research opportunities available today and expected in the 
future, we don't anticipate a significant drop in the number of grant 
applications.

                             Senator Warren
    Question 1. Antibiotic resistant bacteria kill approximately 23,000 
people each year. \9\ According to the CDC, 10 percent of patients 
believe that have had an allergic reaction to penicillin, however, only 
1 percent are actually allergic to penicillin. \10\ The misdiagnosis of 
penicillin allergy can lead to the inappropriate use of broad-spectrum 
antibiotics and increased antibiotic resistance. A 2014 study of 
patients with penicillin allergies showed that ``testing for penicillin 
allergy may result in cost savings, improved patient care, and fewer 
drug-resistant bacteria.'' \11\
---------------------------------------------------------------------------
    \9\  ``Antibiotic Resistance Threats in the United States, 2013,'' 
Centers for Disease Control and Prevention (online at: https://
www.cdc.gov/drugresistance/threat-report-2013/index.html). Accessed 
Dec. 20, 2017.
    \10\  ``Is it Really a Penicillin Allergy?'' Centers for Disease 
Control and Prevention (online at: https://www.cdc.gov/antibiotic-use/
community/pdfs/penicillin-factsheet.pdf). Accessed Dec. 20, 2017.
    \11\  Laurie Barclay, ``Most Patients Misinformed About Penicillin 
`Allergy' History,'' Medscape (April 3, 2014) (online at: https://
www.medscape.org/viewarticle/821429).
---------------------------------------------------------------------------
      a. What research has the NIH conducted on penicillin allergy 
testing?
    Answer a. While the NIH is not currently funding research on 
penicillin allergy testing, it has encouraged the development of 
research proposals in the broader field of drug allergy through funding 
initiatives (see response to Question 1b).

      b. What opportunities for collaboration exist between the NIH and 
other Federal agencies to educate patients and providers about 
penicillin allergy testing and the impact this testing has on 
antibiotic resistance bacteria?

    Answer b. The NIH has encouraged the development of research 
proposals on drug allergy through the funding initiatives described 
below. The NIH collaborates with Federal agencies and other partners as 
appropriate to advance research on drug allergy and welcomes additional 
opportunities to disseminate research findings to key stakeholders such 
as scientists, patients, and healthcare providers.

    The NIH held a workshop on drug allergy in 2013 that brought 
together U.S. and international experts in the field of drug allergy as 
well as representatives from the U.S. Food and Drug Administration 
(FDA). The NIH collaborated with the FDA to hold a second workshop on 
drug allergy in 2015. Based on the research agendas developed during 
these workshops, the NIH developed a drug allergy-related initiative. 
This effort includes two companion NIH-wide initiatives titled 
``Serious Adverse Drug Reaction Research'' (PAR-16-274 and PAR-16-275) 
to stimulate new research on drug reactions, including research on drug 
allergy. In addition to these NIH-wide efforts, research on drug 
allergy also has been a focus of the NIAID initiative ``Asthma and 
Allergic Diseases Cooperative Research Centers'' (AADCRCs; RFA-AI-16-
065). The AADCRC program promotes multidisciplinary basic and clinical 
research on the immunological basis, pathobiology, diagnosis, 
treatment, and prevention of asthma and allergic diseases.

                           Senator Whitehouse
    Question 1. The Recalcitrant Cancer Research Act required the NIH 
to develop ``scientific frameworks'' for cancers that have a low 5-year 
survival rate and cause the death of at least 30,000 Americans each 
year. The NIH is currently using those frameworks to guide its research 
priorities related to pancreatic cancer and small cell lung cancer. Has 
any of the funding Congress provided for the Cancer Moonshot Initiative 
been directed to research objectives identified by the scientific 
frameworks?

    Question 2. The NIH is required to report on the actions taken to 
carry out the Recalcitrant Cancer Research Act in each biennial (now 
triennial) report, and is required to report to Congress on the 
effectiveness of the frameworks within 6 years of their initial 
development. Do you commit to fulfilling these reporting obligations?

    Answer 1 and 2. NIH, through the National Cancer Institute (NCI), 
commits to fulfilling all remaining requirements of the Recalcitrant 
Cancer Research Act: to report on actions taken to carry out the Act in 
each NIH biennial (now triennial) report; to update the Pancreatic 
Ductal Adenocarcinoma (PDAC) scientific framework and the Small Cell 
Lung Cancer (SCLC) scientific framework in 2019, 5 years after their 
initial development; and to provide a one-time report on the 
effectiveness of the frameworks within 6 years of their initial 
development.

    The PDAC and SCLC scientific frameworks continue to inform NCI 
research efforts, including the Cancer Moonshot. It is also important 
to understand that NCI conducts such scientific horizon scanning 
efforts on an ongoing basis to help advance cancer research in all 
areas. To identify the most promising ideas from the field, NCI engages 
in a highly collaborative process that draws upon our external advisory 
groups and steering committees, the expertise of NCI program 
leadership, and opportunities to convene expertise via workshops and 
other collaborations to discuss the State of cancer research in many 
scientific disciplines, and to consider new opportunities.

    Several cross-cutting research efforts supported through the Cancer 
Moonshot in fiscal year 2017 stand to benefit pancreatic cancer 
patients and small cell lung cancer patients, these include NCI's Human 
Cancer Models Initiative and related efforts focusing on cancer models 
for translational research; the development of new enabling cancer 
technologies to characterize tumors and test therapies; and enhanced 
data sharing through a cancer data ecosystem that includes NCI's 
Genomic Data Commons. \12\
---------------------------------------------------------------------------
    \12\ https://www.cancer.gov/research/key-initiatives/moonshot-
cancer-initiative/blue-ribbon-panel/https://www.cancer.gov/research/
key-initiatives/moonshot-cancer-initiative/funding
---------------------------------------------------------------------------
    In addition to these cross-cutting efforts, pancreatic cancer was 
the focus of several Cancer Moonshot awards made in fiscal year 2017 to 
establish and support a Consortium for Pancreatic Ductal Adenocarcinoma 
(PDAC) Translational Studies on the Tumor Microenvironment. \13\ This 
initiative aims to implement the Cancer Moonshot Blue Ribbon Panel 
recommendation, considered and approved by the National Cancer Advisory 
Board (NCAB), to advance cancer immunotherapy translational science, 
and the specific goal of the Consortium is to understand the 
interaction between PDAC tumors and their microenvironment to inform 
the design of new immunotherapy and combination interventions. 
Consortium awards were made to research teams at Fred Hutchinson, 
Massachusetts General, Memorial Sloan Kettering Cancer Center, Dana-
Farber Cancer Institute, MD Anderson, and the University of Michigan.
---------------------------------------------------------------------------
    \13\  https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-17-
015.html
---------------------------------------------------------------------------
                                 ______
                                 

   Responses by Scott Gottlieb to questions from Senator Alexander, 
  Senator Murray, Senator Baldwin, Senator Cassidy, Senator Roberts, 
                 Senator Warren, and Senator Whitehouse

                           Senator Alexander
    Question 1. Diagnostic tests can provide rapid, actionable 
information for clinicians to help improve the quality of care provided 
for patients. In many cases, diagnostic tests can be administered 
outside the traditional laboratory setting and at the point of care, 
such as physician offices. As part of 21st Century Cures, FDA committed 
to provide an update of the current FDA guidance on these point of case 
diagnostic tests, referred to as CLIA waived tests, to ensure it 
includes appropriate use of comparable performance between a CLIA 
waived user and a moderately complex laboratory user to meet accuracy 
requirements.

    On November 29, FDA released a draft guidance update to Section V 
the CLIA waiver guidance, how is the agency working with laboratory and 
health care professionals to ensure the guidance provides clarity to 
enable development and availability of CLIA waived tests for patients?

    Answer 1. FDA is committed to working closely with stakeholders to 
ensure the final guidance provides clarity for test developers and 
promotes the availability of CLIA waived tests. FDA held a webinar on 
January 8, 2018 covering the draft guidance update to Section V of the 
CLIA waiver guidance and the related draft guidance to provide 
recommendations for manufacturers seeking to obtain Dual 51O(k) and 
CLIA Waiver by Application for a new In Vitro Diagnostic (IVD) device 
and to clarify current FDA thinking. The webinar also provided an 
additional opportunity for questions and feedback from stakeholders on 
the draft guidances.

    Question 2. On November 30, FDA and CMS released a joint 
announcement approving a next generation sequencing test for use in 
cancer patients and simultaneously proposing a national coverage 
determination to ensure Medicare beneficiaries can access the test.

    What is FDA doing to work with CMS to ensure this proposal does not 
limit access to next generation sequencing testing for patients?

    Answer 2. FDA is working with additional developers interested in 
having their oncopanels reviewed by FDA, which could enhance and expand 
patient access. In addition, on April 13, 2018, the Agency finalized 
two guidances to drive the efficient development of these novel 
technologies. The guidances provide recommendations for designing, 
developing, and validating tests that use the technology, called next 
generation sequencing \1\ (NGS), and will play an important role in the 
continued advancement of individualized, genetic-based medicine.
---------------------------------------------------------------------------
    \1\ https://www.da.gov/medicaldevices/
productsandmedicalprocedureslinvitrodiagnostics/precisionmedicine-
medicaldevices/default.htm.
---------------------------------------------------------------------------
    The first guidance, Use of Public Human Genetic Variant Data bases 
to Support Clinical Validity for Genetic and Genomic-Based In Vitro 
Diagnostics, \2\ describes an approach where test developers may rely 
on clinical evidence from FDA-recognized public data bases to support 
clinical claims for their tests and help provide assurance of the 
accurate clinical evaluation of genomic test results. The guidance 
describes how product developers can use these data bases to support 
the clinical validation of NGS tests that they are developing. These 
public data bases may include resources like ClinGen, which is 
maintained by the National Institutes of Health (NIH). Using FDA-
recognized data bases will provide test developers with an efficient 
path for marketing clearance or approval of a new test.
---------------------------------------------------------------------------
    \2\ https://www.fda.gov/downloads/MedicalDevices/
DeviceRegulationandGuidance/GuidanceDocumentslUCM509837.pdf
---------------------------------------------------------------------------
    The second guidance, Considerations for Design, Development, and 
Analytical Validation of Next Generation Sequencing (NGS)-Based In 
Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected 
Germline Diseases, \3\ provides recommendations for designing, 
developing, and validating NGS-based tests used to diagnose individuals 
with suspected genetic diseases. It describes what FDA would look for 
in premarket submissions to determine a test's analytical validity, 
including how well the test detects the presence or absence of a 
particular genomic change.
---------------------------------------------------------------------------
    \3\ https://www.fda.gov1downloads/Medical/Devices/
DeviceRegulationandGuidance/GuidanceDocuments/UCM509838.pdf
---------------------------------------------------------------------------
    Issuance of these final guidances is based on extensive feedback 
from the public and stakeholders who are developing NGS-based 
technologies, and the guidances serve as a continuation of FDA's work 
creating regulatory efficiencies in the development and review of NGS 
tests. As you note, in 2017, FDA took several actions to streamline the 
development and review of a variety of genetic-based tests--authorizing 
a third-party option for conducting reviews NGS tumor profiling tests 
and making clearance recommendations to FDA, \4\ as well as outlining 
standardized development criteria for carrier screening tests \5\ to 
allow for their marketing without prior agency review. FDA also 
established such criteria for genetic health risk tests and proposed to 
allow their marketing after a one-time agency review.
---------------------------------------------------------------------------
    \4\  https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/
ucm585347.htm.
    \5\  https://www.fda.gov/NewsEvents/Newsroom/
PressAnnouncementslucm583885.htm.
---------------------------------------------------------------------------
    As NGS technologies continue to evolve, FDA remains dedicated to 
adapting our regulatory review capabilities and leveraging our 
authorities to the fullest extent in order to make innovative and 
accurate testing technologies available to patients as efficiently as 
possible.

    The Centers for Medicare and Medicaid Services (CMS) can speak to 
the specifics of the coverage decision, which was finalized on March 
16, 2018.

    Question 3. Is FDA currently considering similar announcements in 
other treatment areas?

    Answer 3. In November 2017, FDA approved Foundation Medicine's 
FoundationOneCDx (F1CDx) test and on March 16, 2018, CMS finalized a 
national coverage determination-that covers laboratory diagnostic tests 
for Medicare beneficiaries with recurrent, metastatic, relapsed or 
refractory, or stage III or IV cancer-as part of the FDA-CMS Program 
for Parallel Review of Medical Devices. Parallel Review is the process 
through which FDA and CMS conduct overlapping reviews of clinical 
evidence to shorten the time between FDA approval of a premarket 
application and CMS granting a national coverage determination for a 
product. F1CDx is the second IVD to be reviewed through the Parallel 
Review Program, which was established as a pilot program in 2011 . In 
October 2016, FDA and CMS announced the Parallel Review program would 
be fully implemented and extended indefinitely.

    Sponsors who are interested in Parallel Review for their product 
can contact the agencies and submit a request that indicates their 
interest in the program. FDA evaluates and responds individually to 
each request, in coordination with CMS. If a request is accepted into 
the program, FDA and CMS concurrently review the clinical study results 
submitted. It should be noted that FDA and CMS independently review the 
data to determine whether it meets their respective agency's standards 
and communicate with the manufacturer during their respective reviews.

    If sponsors in other treatment areas request Parallel Review for 
their device, the agencies will evaluate these requests, and accept 
them into the program if appropriate. FDA and CMS anticipate making 
similar announcements as warranted by product approvals and clearances 
that go through this program.

    Question 4. How will FDA work with labs who currently have approval 
through CLIA programs to maintain the ability to offer their tests 
following this announcement?

    Answer 4. FDA is committed to engaging with any sponsor seeking FDA 
clearance or approval for their oncopanel test. FDA expects that these 
tests will be reviewed within the timelines negotiated under MDUFA IV; 
the Agency met or exceeded its performance goals under MDUFA III.

                             Senator Murray
    Question 1. FDA recently approved Abilify MyCite, which contains 
``an ingestible sensor embedded in the pill that records that the 
medication was taken.'' We understand that this information can be 
transferred to an app on patients' smart phone to track their 
compliance. While this is exciting technology, it raises important 
concerns about patient privacy and patient rights, especially given the 
indication of Abilify for schizophrenia. Congress has clearly directed 
FDA to assure the patient voice is incorporated in the drug development 
and review process through provisions in FDASIA, 21st Century Cures, 
and most recently FDARA, and we seek to understand how the patient 
voice was considered by FDA during the development and approval of this 
device.

      Question a. FDA staff indicated that mental health advocates have 
pressed the agency for additional options. However, this does not 
provide an alternative treatment option but rather a way to track the 
ingestion of a product that was already on the market. Please provide 
any records to suggest that mental health advocates believe it was 
important to have this technology as an option for patients.

    Answer 1. We agree with the patient and treatment communities that 
there should be more treatment options for patients with psychiatric 
disorders, which can encompass a variety of products. We recognize that 
whether one considers Abilify MyCite to offer a new treatment option 
depends on the value one puts on its ability to track ingestion of the 
drug. However, FDA approves products that meet the applicable approval 
standards found in the Federal Food, Drug, and Cosmetic Act (FD&C Act). 
With respect to your request for records, we do not have any records of 
mental health advocates requesting this specific technology as an 
option for patients.

    Abilify without ingestion-tracking technology, as well as generic 
aripiprazole, remains on the market.

    Question b. Please provide the Committee with the statement 
required under Section 569C(b) of the Food Drug and Cosmetic Act (as 
added by Section 3001 of 21st Century Cures) with regards to Abilify 
MyCite.

    Answer b. The referenced provision only applies to new drug 
applications (NDAs) and biologics license applications (BLAs) submitted 
and approved at least 180 days after enactment of 21st Century Cures. 
Since the NDA for Abilify MyCite, was submitted prior to enactment of 
the 21st Century Cures Act, this provision does not apply to the 
Abilify MyCite NDA. However, patient experience data were collected and 
evaluated as part of FDA's review of the application. Specifically, the 
applicant conducted human factors studies that examined how patients 
used the product.

    Question c. Please provide the committee information regarding the 
original device approval for which this drug product is based, 
including its indications for use.

    Answer c. A De Novo Request was granted for the device in 2012 with 
the following indications for use:

    The Proteus Personal Monitor is a miniaturized, wearable data-
logger for ambulatory recording of heart rate, activity, body angle 
relative to gravity, and time-stamped, patient logged events, including 
events signaled by swallowing the Ingestion Event Marker (IEM) 
accessory. The Proteus Personal Monitor enables unattended data 
collection for clinical and research applications. The Proteus Personal 
Monitor may be used in any instance where quantifiable analysis of 
event-associated heart rate, activity, and body position is desirable.

    Question d. How does FDA plan to assess how the drug is used post-
market? Are other any planned collaborations with the National 
Institute of Mental Health, or other organizations to assess how it is 
being used, if at all, by insurers, employers or others to track 
patient compliance?

    Answer d. FDA reviews safety information and other complaints that 
are received after approval, as we do with any drug. The Agency's 
system of postmarketing surveillance uses multiple mechanisms to assess 
risk and identify adverse events. FDA also actively seeks patient 
engagement and provides a variety of opportunities for patient and 
caregiver involvement in the Agency' s work. To date, FDA has no 
projects planned to survey how Abilify MyCite is being used to track 
ingestion.

    Question 2. While the FDA considers the risks and benefits of a 
product to treat a specific indication in approval decisions, the 
agency is, above all else, an agency with the mission of protecting and 
promoting public health. Consideration of broader public health 
concerns in product approvals is consistent with this mission, and this 
practice is now being more widely adopted by the agency in approval 
decisions for opioid products.

    Question a. How does FDA determine which drug and device reviews 
should include a public health assessment?

    Answer 2, a. Protecting and promoting the public health is central 
to the mission of the Food and Drug Administration. As such, public 
health assessments are part of all aspects of our work including review 
and approval or clearance of drugs and medical devices, to the extent 
such assessments are consistent with the statutory criteria applicable 
to such decisions. Teams of FDA experts, including physicians, 
statisticians, chemists, pharmacologists, clinicians, engineers, and 
social scientists conduct unbiased reviews of drugs and devices 
submitted for approval or clearance that include appropriate 
consideration of the expected public health impact of such products. As 
part of the Agency' s public health assessment, experts analyze the 
target condition and available treatments; assess benefits and risks 
from clinical data; identify strategies for managing risks; and 
consider patient input and experience. FDA also relies on Advisory 
Committees to provide independent advice. Committee members include 
scientific and public health experts-such as physician-researchers and 
statisticians-and members of the public, including Patient 
Representatives.

    Question b. Were public health concerns for the mental health 
patient community, such as the possibility of forced treatment by 
insurers, employers, or family members taken into account during the 
approval process for Abilify MyCite? If not, why not?

    Answer b. Yes. In applying the benefit/risk framework to Abilify 
MyCite, FDA considered public health concerns, patient rights, and 
ethical issues. Considering these factors, scientific evidence about 
the product' s safety and efficacy, and all other appropriate 
information, FDA determined that the benefits of Abilify MyCite 
outweighed its known and potential risks for the intended population.

    FDA further determined that addition of the tracking technology did 
not pose any significant risks. The choice to use Abilify MyCite will 
be made by the patient in consultation with his or her physician. 
Patients will work with their physicians to determine whether they want 
the version of the drug that has the tracking technology, and, if so, 
whether to grant access to ingestion tracking information to the 
patient' s healthcare provider or caregiver.

    This drug/device combination with digital tracking is optional. 
Abilify without ingestion-tracking technology, as well as generic 
aripiprazole, remains on the market.

    Question c. Were public health concerns from the eating disorder 
community, including individuals with binge eating disorder and 
bulimia, taken into account during the approval process for the Aspire 
Assist weight loss device, which allows a user to empty their stomach 
contents after eating? Were concerns about contributing to the 
development of these disorders considered? If not, why not?

    Answer c. Yes, FDA considered whether devices to treat obesity 
could contribute to the development of eating disorders and patients 
were monitored for the development of eating disorders at several time 
points during the year-long clinical trial.

    The AspireAssist device is contraindicated in those with, among 
other conditions, diagnosed bulimia, diagnosed binge eating disorder, 
and night eating syndrome. The device design also limits the number of 
patient uses that are possible between office visits and locks the 
device once the limit is reached. Patient perspective, benefits of 
weight loss, risk of adverse events, and the risks of chronic obesity 
were also among factors FDA considered. In addition, CDRH staff have 
met with representatives of the eating disorder community (health care 
professionals and patient representatives from the Binge Eating 
Disorder Association, National Eating Disorder Association, and Eating 
Disorders Coalition) to discuss their perspectives about devices 
intended to treat or manage obesity.

    Moreover, FDA has mandated two ``condition of approval'' studies in 
addition to postmarket surveillance and reporting required for all 
medical devices. One study is assessing compliance with AspireAssist 
therapy and transient weight-loss following the therapy; impact of 
AspireAssist therapy on eating behavior, incidence, duration and 
severity of adverse events (in particular, infection and stoma-related 
issues); and the effectiveness and safety outcomes after device 
explant. The second study is an extended follow-up multicenter, single-
arm prospective, active surveillance study designed to gather long-term 
data on the incidence, duration, and severity of adverse events, weight 
loss, compliance with AspireAssist therapy, impact of AspireAssist 
therapy on eating behavior and the effectiveness and safety outcomes 
after device removal.

    Question 3. Given the proliferation of medical software and app 
technologies, how many inspections of software developers has FDA 
performed this year?

    Answer 3. In 2017, FDA performed 604 inspections of medical device 
establishments with a profile code description including computer 
software. This profile code description indicates that the activities 
performed at the establishment include software development.

    Question 4. According to FDA public data, FDA has not issued a 
warning letter to any software firms this year, which means that either 
all medical apps on the market are approved devices, or fall into 
categories of enforcement discretion or exemption, or that we don't 
have a full grasp of all the products on the market. How is FDA 
assessing currently marketed products to assure that they are compliant 
with the appropriate regulatory frameworks?

    Answer 4. In 2017, FDA issued eight warning letters to 
establishments with a profile code description including computer 
software: Denttio, Inc.; ELJTechGroup B.V; Magellan Diagnostics, Inc; 
National Biological Corp; St. Jude Medical Inc.; TeleMed; Unetixs 
Vascular Inc.; and Video Inc.

    FDA's assessment of marketed products occurs partly through ongoing 
surveillance of the marketplace and, in many cases, patients, 
consumers, health care providers, and others notifying us of a 
potential violation of laws or regulations. For products we know are 
legally marketed, our assessment includes postmarket surveillance and 
taking enforcement action when needed. Medical device manufacturers as 
well as other firms involved in the distribution of devices must follow 
certain requirements and regulations once devices are on the market and 
FDA ensures compliance with those requirements through reports and 
inspections.

                            Senator Baldwin
    Question 1. We need to do more to advance prevention, treatment and 
detection tools for botulinum neurotoxin poisoning, which presents a 
significant risk to human health due to its high toxicity, ease of 
manufacturing, and lack of medical interventions. Development of 
effective treatments and vaccines for botulinum neurotoxins (BoNTs) is 
slow despite recent advances in testing methods using cell-based 
assays. The use of live mice as a so-called animal ``bio-assay'' for 
BoNTs has been the primary tool used by researchers and vaccine 
developers. But, in recent years, many developers are utilizing 
advanced and effective cell-based assays, which reduce costs and 
provide significantly less risk for the laboratory workers handling the 
animals than the legacy mouse assay.

    Question a. Dr. Gottlieb, what information is the Center for Drug 
Evaluation and Research (CDER) and the Center for Biologics Evaluation 
and Research (CBER) providing to researchers and product developers on 
the use and efficacy of cell-based assays for botulinum neurotoxin(s)?

    Answer 1. We welcome and encourage sponsors to engage early and 
proactively with FDA through the appropriate product center. This helps 
us better understand their prospective product(s), provides a mechanism 
to discuss and evaluate innovative laboratory tools that may expedite 
product development, and helps facilitate efficient development 
programs. We encourage this engagement either in the context of 
individual applications or by pursuing qualification of these tools, 
where appropriate, through the process set forth in section 507 of the 
FD&C Act (as added by section 3011 of the 21st Century Cures Act).

    Answer a. Early and proactive engagement with FDA provides 
direction to sponsors, even prior to submission of an Investigational 
New Drug (IND) application, in regards to the design of preclinical and 
clinical studies to assess the safety and effectiveness of each 
product. FDA's feedback throughout all stages of product development is 
intended to help protect human subjects, facilitate consistent product 
manufacture, and help ensure that pivotal clinical studies are designed 
in such a manner that the study results will provide sufficient 
information to allow an evaluation of the product's safety and 
effectiveness.

    It is the responsibility of the sponsor of a new product to 
approach FDA with adequate assay development data for each test method 
it proposes to use during product development. Some sponsors have 
supported approval of their products utilizing cell-based assays for 
routine product testing ( e.g., for potency testing), while others have 
supported approval using animal-based testing. It is the sponsor' s 
prerogative to decide which type of test method it believes will be 
best suited for its product and to provide data to support its use. 
Post-licensure, sponsors have the option to develop replacement test 
methods should they deem a change appropriate. FDA encourages the use 
of state-of-the-art innovations, whenever possible. As long as product 
safety and effectiveness are not compromised, FDA encourages the use of 
tests that are not animal-based. We encourage sponsors to consult with 
us if it they wish to use a non-animal testing method they believe is 
suitable, adequate, validated, and feasible. We will generally consider 
if such an alternative method could be assessed for equivalency to an 
animal test method .

    FDA will continue to look for opportunities to provide more 
information to researchers and product developers on all aspects of the 
drug development process whether through FDA guidance documents, 
workshops, or individual interactions.

    Question b. Will FDA include updated information on cell-based 
assays in the required guidance documents under Section 3011 of the 
21st Century Cures Act?

    Answer b. As noted above, FDA encourages developers of cell-based 
assays to engage with the Agency, including by pursuing qualification 
of these tools, where appropriate, through the process set forth in 
section 507 of the FD&C Act ( as added by section 3011 of the 21st 
Century Cures Act (Cures Act)). To that end, the guidance documents 
that FDA is required to publish under section 301 1 of the Cures Act 
may be useful to developers of cell-based assays who wish to seek 
qualification under that process. These guidance documents must address 
the conceptual framework for qualification of biomarkers, as well as 
the processes and timeframes associated with the drug development tool 
qualification process more generally. However, the Agency does not 
anticipate that the required guidance will address specific tools or 
technologies such as cell-based assays.

                            Senator Cassidy
    Question 1. What types of guidance and regulatory reform are needed 
to ensure non-pharmacological interventions are better utilized for 
pain management?

    Answer 1. FDA continues to support education for all opioid 
analgesic prescribers. The Agency has recently revised and updated the 
FDA Blueprint, ``Opioid Analgesic REMS Education Blueprint for Health 
Care Providers Involved in the Treatment and Monitoring of Patients 
with Pain.'' FDA recently announced plans to expand REMS to require the 
manufacturers of immediate-release (IR) and extended-release and long-
acting (ER/LA) opioid analgesics, intended for outpatient use, to make 
training available to opioid prescribers and other healthcare 
professionals involved in the management of patients with pain. The 
manufacturers will meet this requirement by providing educational 
grants to accredited continuing education (CE) providers who offer the 
training. The training will be based on the FDA Blueprint which 
contains core educational messages for health care providers involved 
in the treatment and monitoring of patients with pain. It also includes 
more information on pain management, including the principles of acute 
and chronic pain management; non-pharmacologic treatments for pain; and 
pharmacologic treatments for pain (both non-opioid analgesic and opioid 
analgesic). The Blueprint section on non-pharmacologic approaches 
(copied below) encourages health care providers (HCPs) to be 
knowledgeable about the range of treatment options available and 
reminds HCPs that not all non-pharmacologic options have the same 
strength of evidence to support their utility in the management of 
pain.

         ii. general principles of non-pharmacologic approaches
    Pain can arise from a wide variety of causes. There are a number of 
non-pharmacologic and self-management treatment options that have been 
found to be effective alone or as part of a comprehensive pain 
management plan, particularly for musculoskeletal pain and chronic 
pain. Examples include, but are not limited to, psychological, physical 
rehabilitative, and surgical approaches, complementary therapies, and 
use of approved/cleared medical devices for pain management. HCPs 
should be knowledgeable about the range of treatment options available, 
the types of pain that may be responsive to those options, and when 
they should be used as part of a multidisciplinary approach to pain 
management. HCPs should also be aware that not all non-pharmacologic 
options have the same strength of evidence to support their utility in 
the management of pain, and some may be more applicable for some 
conditions than others.

    In the last 5 years, FDA has approved at least 10 novel devices to 
aid in the management of chronic or intractable pain. These devices are 
appropriately regulated to assure both safety and effectiveness. FDA is 
exploring whether additional guidance may be helpful in communicating 
our thinking about how to design robust clinical studies and assess 
clinical data from a variety of sources, including real world evidence, 
for pain management devices.

    Question 2. What are some of the barriers that exist to utilizing 
physical therapy and other non-pharmacological treatments for pain 
management?

    Answer 2. Based on our experience in premarket evaluation of pain 
management devices, we believe a barrier to increased use by health 
care providers and patients of such devices is the limited availability 
of data about safety and effectiveness of new pain devices. More robust 
effectiveness data, including evidence from postmarket studies, could 
help remove the barriers to use of new pain devices by clinicians and 
patients.

    Question 3. The effectiveness of a new CNS drug is notoriously 
difficult to measure, because there are often not readily available and 
well-understood biomarkers or patient-reported outcomes/endpoints. 
Section 3011 of the 21st Century Cures Act requires the Secretary to 
establish an improved process for the qualification of drug development 
tools, upon the request of a drug manufacturer, for use in supporting 
FDA approval of a new drug or biologic. The Secretary must develop 
criteria for accepting a qualification package, and may prioritize the 
development of new tools based on disease prevalence, the lack of 
available treatments, and public health priorities, among others.

    Question a. How will you utilize these provisions to close the gap 
for CNS drugs, through developing an expedited process to qualify 
biomarkers and drug development tools?

    Answer 3. For years, FDA has operated a qualification process for 
drug development tools (DDTs), including biomarkers and clinical 
outcome assessments. Section 3011 of the Cures Act builds upon these 
efforts, establishing a new framework governing the DDT qualification 
process. The new provision directs FDA to develop a regulatory process 
to facilitate timely and consistent review of DDT qualification 
submissions and publicly disseminate information about DDTs at certain 
stages of review and following a qualification determination. This 
authority allows the Agency to work with submitters as they develop or 
refine a DDT that, once qualified, can be used across drug or biologic 
development programs for a particular context of use. We hope that this 
will facilitate the development of drugs and biologics in many areas 
where there are patients with serious diseases and unmet needs, 
including CNS drugs. In addition to pursuing the qualification of DDTs, 
we strongly encourage sponsors and drug developers to contact the 
Division of Neurology Products in CDER or Office of Tissues and 
Advanced Therapies in CBER so that we can provide targeted advice 
specific to their drug development programs.

    Question b. Are the qualification of new tools for development of 
CNS drugs a high priority, particularly given the looming burden of 
Alzheimer's Disease facing our country and the fact that CNS drugs 
continually lag in development compared to drugs for other therapeutic 
areas?

    Answer b. FDA recognizes the urgent need for new medical treatments 
for many serious neurological conditions, including Alzheimer's 
Disease. The Agency is working hard to further drug development in this 
area, including issuing draft guidance for industry in February 2018, 
entitled Early Alzheimer's Disease: Developing Drugs for Treatment. 
Moving forward, FDA is eager to work with sponsors who are interested 
in developing DDTs for Alzheimer's or other neurological treatments.

                            Senator Roberts
    Question 1. One new requirement under the Cures Act is for 
manufacturers of an investigational drug to make its policies on 
evaluating and responding to compassionate use requests publicly 
available. Can you provide an update on how effective this new 
requirement has been? Are patients getting the information they need 
and is the process becoming easier to navigate?

    Answer 1. FDA supports the goal of making more information 
available to patients and physicians; however, the Agency does not 
generally receive data regarding compliance with FD&C Act section 561A, 
as established by the 21st Century Cures Act. FDA also does not 
generally receive data regarding patient/physician experience or their 
satisfaction with information they obtain from manufacturers relative 
to expanded access (EA). Therefore, we are unable to provide an 
assessment regarding the effectiveness of this provision.

    We do note, however, that FDA worked with the Reagan Udall 
Foundation (RUF) as they developed their Expanded Access Navigator, 
which became publicly available in July 2017. The RUF Navigator' s 
express purpose is to help patients and physicians navigate the EA 
request process. The Expanded Access Navigator, among other things, 
includes a directory where companies can submit public links to their 
expanded access policies, criteria used by companies to determine 
whether to make a drug available through expanded access, and company/
manufacturer contact information. In addition, FDA has updated its EA 
guidance with information about company responsibilities under FD&C Act 
section 561A. FDA also continues to update its own EA website with new 
information intended to bring clarity and transparency to the EA 
process.

    Question 2. There are many treatments that have additional uses 
that are medically accepted, that doctors can prescribe for their 
patients, and that the Federal Government will even pay for-but FDA 
prohibits the manufacturers, who know the most about their products, 
from discussing those uses under most circumstances. During your 
confirmation, you commit to working with FDA's staff to get up to speed 
on the agency's latest thinking and actions on these matters, and 
providing clarity to manufacturers, payers, providers, and patients 
about acceptable truthful and non-misleading communications related to 
clinical data not already incorporated in a label. What steps do you 
anticipate the FDA taking in this area and what is the timeline for 
such actions?

    Answer 2. FDA is engaged in a comprehensive review of its 
regulations and policies on medical product communications to ensure 
that our implementation of FDA's legal authorities best protects and 
promotes the public health in light of ongoing scientific and legal 
developments.

    In addition, in January 2017, FDA issued two separate draft 
guidances that help provide clarity for medical product companies, as 
well as other interested parties, on FDA' s current thinking and 
recommendations for a few different types of communications about 
medical products. The first draft guidance addressed common questions 
regarding firms' dissemination of health care economic information 
(HCEI) about approved drugs to payers, formulary committees, and 
similar entities; and provided recommendations for sharing certain 
information about investigational products (drugs and devices) with 
these entities. Comments on this guidance raised the issues of 
expanding the HCEI recommendations to devices (an issue on which FDA 
specifically requested comments) and of expanding the recommendations 
on sharing certain information to cover information about unapproved 
uses of approved products, in addition to other important issues.

    The second draft guidance provides answers to common questions 
regarding firms ' communication of information about the approved or 
cleared uses of their products that is not contained in, but is 
consistent with, the FDA-required labeling for the product. The 
guidance provides details about the types of information that could be 
considered consistent with the FDA-required labeling, and FDA's 
recommendations for how firms can communicate this information in a 
truthful and non-misleading way. Comments on this guidance have asked 
for greater clarity around how FDA determines if a product 
communication is consistent with the FDA-required labeling, as well as 
requested additional recommendations for presenting such information in 
a truthful and non-misleading manner.

    FDA currently is working to issue final guidances.

    Question 3. In 2011, FDA issued an Advisory on glass lamellae 
formation in certain injectable drugs. The Advisory noted at the time 
that ``. . . there is the potential for drugs administered 
intravenously that contain these fragments to cause embolic, thrombotic 
and other vascular events.'' Does FDA have plans to update the Advisory 
and if so, what is the expected timeframe for doing so?

    Answer 3. The advisory issued in 2011 outlined the conditions 
associated with a higher incidence of the formation of glass lamellae, 
such as glass vials manufactured under higher heat by tubing process, 
drug solutions at high pH and with certain buffers, storage temperature 
and shelf life, and terminal sterilization. The advisory also provided 
literature references and included recommended actions to help prevent 
the formation of glass lamellae. In addition to the advisory, which 
drew attention to the issue after several recalls due to formation of 
glass lamellae, the Agency also provided the recommendations regarding 
glass lamellae in a Question & Answer guidance for industry on current 
good manufacturing practices (CGMP). \6\ Drug manufacturers can still 
follow these recommendations to help prevent formation of lamellae.
---------------------------------------------------------------------------
    \6\  See Question 11. www.fda.gov/Drugs/
GuidanceComplianceRegulatorylnformation/Guidances/ucm124780.htm.
---------------------------------------------------------------------------
    FDA has met with manufacturers to address design and manufacturing 
for glass products intended for injectable drugs and appreciates 
industry's efforts to address quality issues that may cause safety 
problems associated with use of glass products in the manufacture of 
pharmaceuticals. FDA plans to meet the Omnibus requirement to report on 
this matter to the Committee.

    Question 4. The Director of the Drug Center's Office of Compliance 
recently stated that one out of every four inspections of compounders 
in last year resulted in a recall. How is FDA working to address this 
and ensure patient confidence in compounded medications?

    Answer 4. Compounded drugs present a greater risk to patients than 
approved drugs. For example, because they are not FDA-approved, 
compounded drugs are not reviewed by the Agency before they are 
marketed for safety, effectiveness, and quality. In addition, drug 
products compounded in accordance with certain conditions set forth in 
section 503A of the FD&C Act are statutorily exempt from current good 
manufacturing practice requirements, the quality standard that applies 
to conventional drug manufacturers. Because compounded drugs are 
subject to a lower regulatory standard than FDA-approved drugs, the 
Agency cannot ``ensure patient confidence in compounded medications.'' 
However, reducing the risks associated with poor quality compounded 
drugs that could lead to serious patient harm is a priority for FDA, 
and the Agency continues to dedicate significant resources toward this 
effort.

    By way of background, the 2012 outbreak of fungal meningitis, 
resulting from a pharmacy that shipped contaminated compounded drugs 
throughout the country, led to more than 750 cases of illness and 60 
deaths in 20 states. The tragic proportions of this outbreak were 
mainly attributable to the company's large-scale, multistate 
distribution of an injectable drug intended to be sterile that had been 
prepared under inappropriate conditions. This outbreak, combined with 
FDA's continued concerns based on monitoring pharmacy compounding, 
underscored the need for improvement in compounding practices. It also 
highlighted the need for more robust oversight of compounders, close 
Federal and State collaboration, and a clear legal framework that would 
provide for compounding to meet patients' medical needs, while also 
providing FDA with tools to address unlawful practices that threaten 
public health.

    Since enactment of the Drug Quality and Security Act (DQSA), a 
statute that Congress passed in 2013 after the fungal meningitis 
outbreak, FDA has prioritized policy development to implement the law, 
State and stakeholder collaboration, and oversight efforts. With 
respect to oversight, since enactment of the DQSA and as of January 
2018, FDA has conducted nearly 500 inspections of compounders, issued 
more than 180 warning letters advising compounders of significant 
violations of Federal law, issued more than 70 letters referring 
inspectional findings to State regulatory agencies, overseen more than 
150 recalls involving compounded drugs, and worked with the Department 
of Justice on multiple civil and criminal enforcement actions.

    As FDA has engaged in these inspection and enforcement efforts, it 
has observed increased compliance with certain provisions of Federal 
law applicable to compounding. However, the Agency still encounters 
serious problems, some resulting in recalls of drug products due to 
substandard conditions that could lead to contamination or other 
quality concerns. Further, because the vast majority of the thousands 
of state-licensed pharmacies and physicians that compound drugs in the 
United States are not required to register with the Agency and are 
routinely overseen by the states and not by FDA, the Agency might not 
become aware of a problem, such as substandard production conditions, 
until after it has resulted in harm to patients.

    Any entity that produces drugs, including compounded drugs, is 
responsible for ensuring that it complies with Federal laws such as 
those concerning production standards and drug quality. FDA intends to 
continue to engage in robust oversight of compounding, in collaboration 
with its State partners, and to take action when it identifies 
violations of Federal law.

                             Senator Warren
                 shortages of blood pressure medication
    Question 1. I have heard from multiple constituents in 
Massachusetts who report facing shortages of blood pressure medication, 
including Atenolol. One constituent reported needing to switch 
medications as a result of not being able to obtain her blood pressure 
medication at the pharmacy. Another reported checking multiple 
pharmacies and being told that there was no medication available. News 
reports indicate that this shortage is affecting individuals across the 
country, not just in Massachusetts. \7\
---------------------------------------------------------------------------
    \7\  Sylvia Perez, ``Doctors, Patients Concerned over Shortage of 
Blood Pressure Drug `Atenolol,''' Fox 32 Chicago (November 10, 2017) 
(online at: http://www.ox32chicago.com/news/localdoctors-patients-
concerned-over-shortage-of-blood-pressure-drug-atenolol). Larry Husten, 
``Generic Atenolol in Short Supply,'' MedPage Today (August 10, 2017) 
(online at: https://www.medpagetoday.com/cardiology/cardiobrief/67185).
---------------------------------------------------------------------------
    Four drug manufacturers--Mylan Pharmaceuticals, Sandoz, Teva 
Pharmaceuticals, and Zydus Pharmaceuticals--have reported shortages of 
Atenolol tablets to the FDA. \8\ Based on the most recent information 
reported to the FDA, Zydus Pharmaceuticals is now able to supply 
current customer demand and has increased capacity to support 
additional demand, while other manufacturers reported limited supply or 
backorders.
---------------------------------------------------------------------------
    \8\  ``Atenolol Tablets,'' Current and Resolved Shortages and 
Discontinuations Reported to the FDA (July 26, 2017) (online at: 
https://www.accessdatajda.gov/scripts/drugshortages/dsp--
ActivelngredientDetails.cfm-AI=Atenol/percent2OTablets&st=c&tab=tabs-
1).
---------------------------------------------------------------------------
    Question a. What steps is the FDA currently taking to resolve 
shortages of Atenolol?

    Answer 1., a. As of August I, 2018, all four of these manufacturers 
of atenolol tablets have product available, except for Sandoz, which 
has limited supply. Please reference our webpage for updated supply 
information. \9\
---------------------------------------------------------------------------
    \9\  https://www.accessdata.fda.gov/scripts/drugshortages/dsp--
ActivelngredientDetails.cfm-Al=AtenololTablets&st=c&tab=tabs-1
---------------------------------------------------------------------------
    Question b. Has the FDA received reports of shortages of generic 
blood-pressure medications in addition to Atenolol?

    Answer b. As of August 1, 2018, we have not received reports of 
shortages of generic blood-pressure medications in addition to 
atenolol.

                           Senator Whitehouse
    Question 1. Please describe the FDA's approach in its Software Pre-
certification Pilot Program. If the FDA decides to exempt certain 
software developers from pre-market review, what types of post-market 
controls does the agency envision in this space to protect consumer 
safety?

    Answer 1. For the American people to see the full benefits of 
digital health products, FDA is using the Software Pre-Certification 
Pilot Program to explore a possible regulatory framework that 
accommodates the distinctive nature of digital health technology, its 
clinical promise, and its compressed iteration cycle.

    Under this possible framework, for an organization to be pre-
certified, the organization would demonstrate that it has a culture of 
quality and organizational excellence, providing assurance that the 
organization produces high quality, safe, and effective products. In 
some cases, software that is a medical device (referred to as ``SaMD,'' 
for ``software as a medical device'') developed by a pre-certified 
organization may undergo streamlined premarket review; in such cases, 
the pre-certified organization would submit less information in a 
premarket application than they would today. In other cases, a pre-
ce1iified organization may begin marketing SaMD without a premarket 
submission and immediately begin post-market data collection. We expect 
pre-certified organizations to collect robust real-world data to 
monitor the safety and effectiveness of devices in the field and for 
FDA to have access to this data. FDA expects to retain its existing 
postmarket enforcement tools and to use them as necessary to protect 
public health. Aspects of this program may require additional statutory 
authority.

    FDA looks forward to continuing to collaborate with the pilot 
participants and the public to develop the Software Pre-Certification 
Program. FDA intends for the program, when finalized, to promote the 
public health by supporting the innovation of high quality, safe, and 
effective digital health devices.
                                 ______
                                 
    [Whereupon, at 12 p.m., the hearing was adjourned.]

                                  [all]