- CONTINUING AMERICA'S LEADERSHIP: ADVANCING RESEARCH AND DEVELOPMENT FOR PATIENTS

[Senate Hearing 114-583]
[From the U.S. Government Publishing Office]

S. Hrg. 114-583

CONTINUING AMERICA'S LEADERSHIP: ADVANCING RESEARCH AND DEVELOPMENT FOR
PATIENTS

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

HEARING

OF THE

COMMITTEE ON HEALTH, EDUCATION,
LABOR, AND PENSIONS

UNITED STATES SENATE

ONE HUNDRED FOURTEENTH CONGRESS

FIRST SESSION

EXAMINING CONTINUING AMERICA'S LEADERSHIP, FOCUSING ON ADVANCING
RESEARCH AND DEVELOPMENT FOR PATIENTS

__________

MARCH 24, 2015

__________

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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 BARBARA A. MIKULSKI, Maryland
JOHNNY ISAKSON, Georgia BERNARD SANDERS (I), Vermont
RAND PAUL, Kentucky ROBERT P. CASEY, JR., Pennsylvania
SUSAN COLLINS, Maine AL FRANKEN, Minnesota
LISA MURKOWSKI, Alaska MICHAEL F. BENNET, Colorado
MARK KIRK, Illinois SHELDON WHITEHOUSE, Rhode Island
TIM SCOTT, South Carolina TAMMY BALDWIN, Wisconsin
ORRIN G. HATCH, Utah CHRISTOPHER S. MURPHY, Connecticut
PAT ROBERTS, Kansas ELIZABETH WARREN, Massachusetts
BILL CASSIDY, M.D., Louisiana

David P. Cleary, Staff Director
Lindsey Ward Seidman Deputy Staff Director
Evan Schatz, Democrat Staff Director
John Righter, Democrat Deputy Staff Director

(ii)

C O N T E N T S

__________

STATEMENTS

THURSDAY, MARCH 24, 2015

Page

Committee Members

Alexander, Hon. Lamar, Chairman, Committee on Health, Education,
Labor, and Pensions, opening statement......................... 1
Murray, Hon. Patty, a U.S. Senator from the State of Washington,
opening statement.............................................. 3
Burr, Hon. Richard, a U.S. Senator from the State of North
Carolina....................................................... 5
Cassidy, Hon. Bill, M.D., a U.S. Senator from the State of
Louisiana...................................................... 40
Mikulski, Hon. Barbara A., a U.S. Senator from the State of
Maryland....................................................... 42
Bennet, Hon. Michael F., a U.S. Senator from the State of
Colorado....................................................... 46
Franken, Hon. Al, a U.S. Senator from the State of Minnesota..... 48
Warren, Hon. Elizabeth, a U.S. Senator from the State of
Massachusetts.................................................. 50

Witnesses

Sullenger, Bruce A., Ph.D., Director, Duke Translational Research
Institute, Professor of Surgery, Duke University Medical
Center, Durham, NC............................................. 6
Prepared statement........................................... 7
Borisy, Alexis, Partner, Third Rock Ventures, Boston, MA......... 9
Prepared statement........................................... 11
Mussallem, Michael A., Chairman and CEO, Edwards Lifesciences,
Irvine, CA..................................................... 16
Prepared statement........................................... 17
Coukell, Allan, Senior Director, Health Programs, Pew Charitable
Trusts, Washington, DC......................................... 26
Prepared statement........................................... 28

ADDITIONAL MATERIAL

Statements, articles, publications, letters, etc.:
Response by Bruce Sullenger, Ph.D. to questions of:
Senator Alexander........................................ 54
Senator Isakson.......................................... 55
Senator Collins.......................................... 56
Senator Whitehouse....................................... 57
Response by Michael A. Mussallem to questions of:
Senator Alexander........................................ 57
Senator Isakson.......................................... 60
Senator Collins.......................................... 61
Senator Whitehouse....................................... 62
Response by Allan Coukell to questions of:
Senator Alexander........................................ 62
Senator Isakson.......................................... 69
Senator Whitehouse....................................... 69

(iii)

CONTINUING AMERICA'S LEADERSHIP: ADVANCING RESEARCH AND DEVELOPMENT FOR
PATIENTS

----------

TUESDAY, MARCH 24, 2015

U.S. Senate,
Committee on Health, Education, Labor, and Pensions,
Washington, DC.
The committee met, pursuant to notice, at 10 a.m., in room
SD-430, Dirksen Senate Office Building, Hon. Lamar Alexander,
chairman of the committee, presiding.
Present: Senators Alexander, Murray, Burr, Collins, Hatch,
Cassidy, Mikulski, Casey, Franken, Bennet, and Warren.

Opening Statement of Senator Alexander

The Chairman. The Senate Committee on Health, Education,
Labor, and Pensions will please come to order. This morning,
we're holding a hearing on Continuing America's Leadership:
Advancing Research and Development for Patients. Ranking Member
Senator Murray and I will each have an opening statement, and
then we'll introduce our panel of witnesses. After our
witnesses' testimony, Senators will each have 5 minutes of
questioning.
We welcome Senator Cassidy and Senator Warren to their
usual positions and Senator Franken and Senator Mikulski and
Senator Bennet. A lot of people are here today.
This is the second hearing on a major initiative of this
committee: our effort to examine how we get drugs, devices, and
treatments from the discovery process through the regulatory
process into the medicine cabinets and doctors' offices.
I'd like to begin today by telling a story that illustrates
why we're doing this and why it's important to get a result.
Just last week, Ginger Birnbaum from Chattanooga visited my
office and told me about her 3-year-old son, King. King has
cystic fibrosis, and today there is no medicine to treat his
form of the disease.
King's family must simply treat his symptoms. His older
sister, Virginia, who is 6, helps set up his feeding tube at
night since the disease doesn't allow him to digest and absorb
the nutrients he needs. She walks with her friends to help
raise money, to try to raise funds for research. They left me
with their Christmas card with the children on it.
There is good news for some cystic fibrosis patients. We
heard about it when the President announced his Precision
Medicine Initiative at the White House. There is a drug that
can actually treat the underlying cause of cystic fibrosis in
just about 9 percent of cases.
This drug, the first personalized drug for cystic fibrosis,
was approved in 2012, 3 months after the developer of the drug
submitted to the FDA a new drug application. That's the good
news. The bad news is that it took 15 years from discovery to
the FDA's door. It also took another 3 years from that approval
in 2012 to approve the same drug for children 2 to 5 years old.
The same company is currently studying other therapies for
different forms of cystic fibrosis. If all goes well, King, the
child I was talking about, could have a drug that treats his
form of cystic fibrosis soon.
My question is: What can we do here in Congress to help
shorten that process? Or, if that drug is not successful, what
can we do to shorten the discovery and development process so
that King doesn't have to wait another 15 to 18 years for the
next personalized medicine?
Earlier this month, we heard from Dr. Collins, the head of
NIH, and Dr. Hamburg, the Food and Drug Administration
Commissioner. They provided insights into what NIH and FDA have
been doing to try to improve the discovery, research and
development, and regulatory processes from the government
perspective.
Today, our goal is to hear from the researchers and the
innovators that interact with the NIH and FDA and can tell us,
in their opinion, how this is working and what are potential
solutions.
I've found the best ideas often come from outside of
Washington. The witnesses today are from outside of Washington.
Senator Murray and I have agreed on them. We call this a
bipartisan hearing for that reason, and it represents much of
the biomedical research and development system.
We'll hear from the academic who makes the discovery, from
the venture capital community who funds further development,
and from a company who takes discoveries through the regulatory
process and makes them for patients. We'll also hear from a
group that has been studying how to improve the discovery and
development process, from improving clinical trial efficiency
to creating a more predictable FDA. We plan to hear from
patients and their families, like King, throughout this process
as well.
I'm looking forward to hearing today about how to decrease
red tape and administrative burden. We'll hear about exciting
new technologies. One of our goals is to make sure that the FDA
and others are ready for these technological advancements.
Senator Burr and I released a white paper in January that
looked at the process of getting drugs and devices from
discovery to medicine cabinets, and much of what the report
covered is relevant here today. We found that medical products
take more time and money to discover, develop, and reach
American patients than ever before.
We also found that FDA has struggled to regulate the most
cutting edge medical products. This disparity between the pace
of scientific discovery and FDA's scientific knowledge is
threatening America's position as a global leader in medical
innovation.
We reported that the venture capital community is shifting
investments away from early stage drugs and devices as a result
of increasing regulatory burden and uncertainty. We also found
that countries across the globe have sought to capitalize on
America's shrinking competitive advantage in the biomedical
space.
These are big challenges that are slowing down the process
for getting the cutting edge innovations we are discovering
into the medicine cabinet and the doctor's office. The NIH and
FDA must keep pace with today's cutting edge scientific
advancements.
I'm looking forward to hearing your unique perspectives on
these challenges and others you see as standing in the way of
innovation. I am especially interested in your ideas about how
to solve these problems.
Senator Murray.

Opening Statement of Senator Murray

Senator Murray. Thank you very much, Chairman.
Thank you to all of our witnesses for being here today.
As Senator Alexander mentioned, at our last hearing on
advancing medical innovation, we had the opportunity to hear
from NIH Director Collins and FDA Commissioner Hamburg. They
talked about their agencies' roles in helping drive development
and approval of treatments that save and improve lives across
our country.
At that time, I laid out some principles I will be very
focused on, including supporting NIH and basic investments in
research, finding ways to get patients safe and effective
treatments as quickly as possible, and prioritizing the needs
of women and children in the product development and approval
process, and above all, protecting and upholding the deep trust
that families place in FDA when they reach into their medicine
cabinet or take a trip to the drug store.
It's very clear in my home State of Washington and across
the country that medical innovation is at a critical moment
right now. Researchers and physicians are looking at prevention
and treatment in a whole new way. And medical advances have
changed the way we tackle devastating diseases like cancer,
cystic fibrosis, and many others.
At the same time, the life sciences are helping to drive
economic growth and job creation. I have seen this first hand
in my home State of Washington. According to our State
Department of Commerce, the life sciences sector in Washington
State directly employs 34,000 individuals and indirectly
employs another 57,000, and that's continuing to grow.
Thinking about ways we can continue to advance medical
innovation is both good for families' health and good for our
economy. The HELP committee has a strong tradition of
bipartisan process in this area.
In 2012, for example, we added accelerated approval to
allow the FDA to approve new drugs faster for serious
conditions and unmet medical needs. We also added a
breakthrough designation for promising new drugs so that
researchers can find out earlier whether these treatments are
effective.
These bipartisan successes have made a real difference for
patients and families. While we learned from Commissioner
Hamburg just 2 weeks ago that FDA's drug approval times are the
fastest in the world, we must continue to look for new
efficiencies.
We all know that Congress can't legislate new cures into
existence. If we could, I know we would. But what we can and
must do is give our Nation's biomedical community the right
tools to innovate for patients, now and for generations to
come.
That means making sure that NIH is well-supported, as
Director Collins urged us to do. This also means making sure
that the doctors and scientists at the FDA have all the tools
and resources they need so they can be engaged early in the
development of new products and can help innovators get new
safe and effective treatments to patients as soon as possible.
We also need to expand our use of medical data. We have a
wealth of medical information that, when shared in a timely and
secure way, will help us make sure the right treatments are
reaching the right patients and help us better understand
different groups' unique health needs, including women.
It is important we look at the entire spectrum of medical
innovation, from basic research, through development and
approval, and into the post-market setting.
While we, of course, want to get patients treatments as
quickly as possible, speed cannot come at the expense of
safety. New doesn't always mean better.
As the Institute of Medicine warned us in 2007, a
regulatory culture too focused on speed can seriously damage
public confidence in product safety. We need to ensure we are
both encouraging innovation and upholding the highest standards
of patient and consumer protection.
I'm pleased that today we will be able to hear from key
players in medical innovation, from the private sector to
academia, about the ways you all think we can step up to these
challenges and help more patients and families get life-
changing, lifesaving cures and treatments.
Thank you all for being here and sharing your expertise.
I'm really confident our bipartisan work to advance medical
innovation for patients will be stronger with your input. As
our discussions continue, I'm looking forward to hearing from
patients and advocates who can share insights into the
improvements our communities want to see.
It's so important to me that the perspective of patients
and their families be prioritized throughout this effort. They
are the ones hoping for new cures, searching for better
treatments, and looking to all of us here for solutions. I'm
very hopeful that working together, we can continue the strong
tradition of bipartisan success we have had in advancing
medical innovation and deliver for the families we serve.
With that, I'll turn it back to you, Mr. Chairman. Thank
you.
The Chairman. Thank you, Senator Murray.
I'll introduce three witnesses, and then I'll let Senator
Burr introduce the first witness. The second witness is Mr.
Alexis Borisy. Mr. Borisy is a partner in Third Rock Ventures,
a venture capital firm based in Boston that invests in biotech
startup companies. He has more than 20 years of experience
building and operating innovative science-based organizations.
Our third witness, Mr. Michael Mussallem, is chairman and
CEO of Edwards Lifesciences. He is considered a global leader
in heart valve transplants. The medical device development
process and challenges are distinct from the challenges facing
drug development.
I thank you for being here to share that perspective.
Our fourth and final witness is Mr. Allan Coukell, who
leads the health projects at the Pew Charitable Trust. Mr.
Coukell has led many projects at Pew examining how to improve
medical product development and regulatory processes.
Now I'll ask Senator Burr to introduce the first witness.

Statement of Senator Burr

Senator Burr. Thank you, Mr. Chairman, for the opportunity
to introduce Dr. Bruce Sullenger from Duke University in North
Carolina. As I often remind my colleagues on this committee,
I'm proud of North Carolina's innovative biomedical research
and development. It's good for North Carolina and it's good for
patients across the country. I'm delighted that one of our
leaders in this area is here with us today.
Dr. Sullenger, thank you for taking the time to be with us
to speak to us about the great work you and your colleagues are
doing at Duke, particularly your expertise about how we can
accelerate and successfully commercialize promising concepts
off the research bench that will reach America's patients in as
timely a manner as possible.
Dr. Sullenger is a professor in the Department of Surgery
and the director of Duke's Translational Research Institute at
Duke University Medical Center. For almost 30 years, Dr.
Sullenger has been working on the development of DNA and RNA-
based translational therapies, and he is one of the pioneers in
this field.
Since joining Duke in 1994, Dr. Sullenger has developed an
internationally recognized translational research program and
has served as the director of Duke's Translational Research
Institute since 2007. In this post, Dr. Sullenger leads the
university's efforts in translating scientific discoveries to
uses in a clinical setting. Much of his work has been funded by
the National Heart, Lung, and Blood Institute of the National
Institutes of Health.
Dr. Sullenger received his undergraduate degree from
Indiana University and completed his Ph.D. work at Cornell
Medical Center and the Memorial Sloan-Kettering Center in New
York. Following his Ph.D., Dr. Sullenger studied under Nobel
Laureate, Dr. Thomas Cech, at the University of Colorado.
Thank you, Dr. Sullenger, for being here and probably
representing the next champion of the NCAA basketball
tournament yet to be finished, the Duke University Blue Devils.
Welcome.
The Chairman. An appropriately parochial comment from
Senator Burr. But he may be right.
[Laughter.]
Thank you, Senator Burr, and thanks to the witnesses.
If you can summarize your comments in about 5 minutes,
that'll give Senators more time to have a conversation with
you. Why don't we start with Dr. Sullenger--and good luck in
the NCAA--and let's go right down the row.

STATEMENT OF BRUCE A. SULLENGER, Ph.D., DIRECTOR, DUKE
TRANSLATIONAL RESEARCH INSTITUTE, PROFESSOR OF SURGERY, DUKE
UNIVERSITY MEDICAL CENTER, DURHAM, NC

Mr. Sullenger. Thank you for that introduction, Senator
Burr, and good morning, Chairman Alexander, Ranking Member
Murray and other committee members. I would like to thank you
for the opportunity to share with this committee my perspective
as an academic biomedical researcher working on the front lines
of medical innovation.
In addition to being an innovator and entrepreneur, I help
other faculty at Duke University apply their medical
innovations to human health in my role as director of the Duke
Translational Research Institute. This institute provides
preclinical and early stage clinical trial seed funding and
project management support to build collaborative,
translational research teams.
I was trained really as a basic scientist in one of the
pre-eminent biochemistry labs in the world, Dr. Cech's lab at
the University of Colorado, with a goal of pursuing knowledge
for the sake of knowledge. However, in 1994, I sought a new
career path and focused on what came to be known subsequently
as translational research.
I joined the faculty in the Department of Surgery at Duke
so I could work closely with physicians and surgeons to develop
new approaches to effectively and safely treat the patients
they saw every day. During the past two decades, this
unorthodox career has been incredibly rewarding. Unfortunately,
it has also become increasingly challenging.
With cardiologists, cardiothoracic surgeons, and
neurosurgeons, we invented new ways to deliver rapidly
reversible anticoagulants for the potential treatment of
cardiovascular disease and stroke patients. I work with
surgical and medical oncologists to develop new classes of
compounds to precisely deliver cytotoxic agents to prostate,
pancreatic, and other types of cancers.
Most recently, working with rheumatologists, we invented
novel anti-inflammatory agents for the treatment of lupus,
arthritis, and other chronic inflammatory disorders without
serious side effects. As you can see, we've been very busy, but
there's so much more that we could be doing.
Creativity and ingenuity are not limiting. What is
preventing these ideas from becoming realities is ever
dwindling resources. All of the preclinical work leading to
these medical innovations I described was possible because of
funding by the NIH and its associated Institutes.
With a 20-plus percent decline in the purchasing power of
the NIH budget over the past decade, it has become increasingly
challenging to create a path to move these inventions from the
bench to the clinic. Moreover, it's challenging to move these
inventions from the academic setting to the private sector. It
is difficult to obtain investments from the private sector for
IND enabling or preclinical enabling work such as compound
optimization, preclinical pharmacology, and toxicology and
manufacturing.
I applaud the NIH and Congress for recognizing this
transla-
tional bottleneck and for establishing the Clinical and
Transla-
tional Science Award program and the National Center for
Advancing Translational Sciences to begin to address this
critical issue. In addition, the NHLBI and the NCI and other
institutes at the NIH have established some programs, such as
the NHLBI network for Translational Research Centers for
treating Thrombotic and Hemostatic Disorders, that supports
translation of basic sciences into clinical applications.
These new initiatives are critical for our success and will
be essential if the United States is to remain the
international leader in medical innovation.
Finally, precision medicine, as you mentioned, Senator
Alexander, is the future of medicine. Yet it is a major
challenge to all of us who translate basic science into health
care. This new frontier in medicine combines the information
age, which is upon us, with the ability to look at personalized
genomics to really collect unparalleled intelligence on health
and disease as well as to help us identify what therapies may
help each one of us.
To meet these challenges and opportunities head on, we will
need to reposition and train a new generation of biomedical
researchers that looks very different from the one we have
today. Engineers, physicians, mathematicians, and biologists
will need to come together as a team to effectively combat
disease, disability, aging, and death.
I would suggest there are four tractable issues that we
should work on together. No. 1, is how to train and expand a
biomedical research workforce that is ready to utilize this
genomic and informatics revolution that is underway. No. 2, is
how to rebalance and right-size the support of all phases of
biomedical research as we transition from gathering
intelligence on health and disease through basic research to
rationally using those large amounts of research that we've
obtained to combat disease through translational and clinical
research.
No. 3, is how to reduce the administrative and compliance
burdens upon investigators and academic institutions to reduce
costs and improve productivity. And, finally, No. 4, is how to
further encourage academic institutions like mine to more
effectively engage with the private sector.
Thank you.
[The prepared statement of Mr. Sullenger follows:]

Prepared Statement of Bruce A. Sullenger, Ph.D.

Thank you for the introduction Senator Burr and good morning
Chairman Alexander, Ranking Member Murray and other committee members.
I would like to thank you for the opportunity to share with this
committee my perspective as an academic biomedical researcher working
on the front lines of medical innovation. In addition to being an
innovator and entrepreneur, I help other faculty at Duke University
apply their medical innovations to human health in my role as director
of the Duke Translational Research Institute. This Institute provides
preclinical and early stage clinical trial seed funding and project
management support to build collaborative, translational research teams
(https://www.dtmi.duke.edu/about-us/organization/duke-translational-
research-institute/pilot-program/leadership).
I was trained as a basic scientist in one of the pre-eminent
biochemistry laboratories in the world, Dr. Cech's lab at the
University of Colorado with a goal of pursuing knowledge for the sake
of knowledge. However in 1994, I sought a new scientific path and
focused on what came to be known as ``translational research.'' I
joined the faculty in the Department of Surgery at Duke so I could work
closely with physicians and surgeons to develop new approaches to
effectively and safely treat the patients they saw every day. During
the past two decades, this unorthodox career path has been enormously
rewarding. Unfortunately, it has also become increasingly challenging.
With cardiologists, cardiothoracic surgeons and neurosurgeons, we
invented new ways to deliver reversible anticoagulants for the
potential treatment of cardiovascular disease and stroke patients. I
also worked with surgical and medical oncologists to develop new
classes of compounds that precisely deliver cytotoxic and immune-
modulatory medicines to prostate, pancreatic and other types of cancer
cells. Most recently working with rheumatologists we invented a novel
anti-inflammatory drug for the treatment of lupus, arthritis and other
chronic inflammatory disorders without serious side effects.
We have been busy but there is so much more we could be doing.
Creativity and ingenuity is not in short supply. What is preventing
these ideas from becoming realities are ever dwindling resources. All
of the preclinical work leading to the medical innovations I described
was possible because of funding by the NIH and its associated
institutes. With a 20 percent decline in the purchasing powers of the
NIH budget over the past decade, it has become increasingly challenging
to create a path to move these inventions from the bench top to the
clinic. And moving these inventions from an academic setting to the
private sector has become even more challenging and rate limiting. It
is extremely difficult to obtain investments from the private sector
for IND (Investigational New Drug) enabling work such as compound
optimization, preclinical pharmacology and toxicology studies and
manufacturing. I applaud the NIH and Congress for recognizing this
translational bottleneck and for establishing the Clinical and
Translational Science Award (CTSA) program and the National Center for
Advancing Translational Sciences (NCATS) to begin to address this
critical issue. In addition, the NHLBI, NCI and other institutes at the
NIH have established some programs such as the NHLBI national network
of Translational Research Centers for Thrombotic and Hemostatic
Disorders that supports the translation of basic sciences into clinical
applications. These new initiatives are critical for our success and
will be essential if the United States is to remain the international
leader in medical innovation.
Finally, precision medicine--the future of medicine--is a major
challenge to all of us who translate basic research into health care.
This new frontier in medicine combines the information age with
personalized genomics to collect unparalleled intelligence as to what
makes us sick and what therapies can be tailored to each of us. To meet
these challenges--and opportunities---head on, we will need to
reposition and train a new generation of the biomedical researchers.
This next generation will look very different from the one we have
today: Engineers, physicians, mathematicians, and biologists will need
to come together to effectively combat disease, disability, aging and
death.
To prepare for the coming challenges, I would encourage this Senate
Committee to work with the NIH, FDA, academic community and private
sector to consider four tractable issues:

1. How to train and expand a biomedical research workforce that is
ready to utilize and act upon the genomic and informatics revolution;
2. How to rebalance and right size support for all phases of
biomedical research as we transition from gathering intelligence on
health and disease (basic research) to rationally using the large
amounts of information to combat disease (translational and clinical
research);
3. How to reduce the administrative and compliance burdens placed
upon investigators and academic institutions to reduce costs and
improve productivity; and
4. How to further encourage academic institutions to more
effectively engage with the private sector and clarify the NIH conflict
of interest policy to facilitate such endeavors without restricting
innovation.
References
references regarding these considerations
1. How training should be expanded to create a biomedical research
workforce that is ready to utilize and act upon this emerging
information;
References describing strategies to revise the training of the
biomedical workforce and how team science will be important for
translational medicine.

https://www.aau.edu/WorkArea/
DownloadAsset.aspx?id=15491;
http://www.hhmi.org/programs/med-into-grad-initiative;
https://www.dtmi.duke.edu/about-us/organization/duke-
translational-research-institute/pilot-program/leadership; and
http://www.pnas.org/content/111/16/5773.

2. How to rebalance and right size support for all phases of
biomedical research as we transition from gathering intelligence on
health and disease (basic research) and move toward rationally applying
the large amounts of information being amassed to combat disease
(translational and clinical research);
Breakdown in basic versus applied funding from the NINDS.

http://blog.ninds.nih.gov/2014/03/27/back-to-basics/.

3. How to reduce the administrative and grant writing burden upon
translational investigators and academic institutions to reduce costs
and improve productivity; and
Link to DTRI Project Management and Consultation Office which
offers professions trained in the private sector to act as faculty
extenders and facilitate translational team builders.

https://www.dtmi.duke.edu/research-facilities-and-support/
duke-translational-research-institute-dtri/project-management.

4. How to further encourage academic institutions to more
effectively engage with the private sector and clarify the NIH conflict
of interest (COI) policy to facilitate such endeavors without
restricting innovation.
Links to NIH COI policy and the Duke's approach to complying with
the policy:

http://grants.nih.gov/archive/grants/policy/coi/tutorial/
fcoi.htm; and
http://duke.edu/services/ethicscompliance/coi/fcoi/
index.php.

The Chairman. Thank you, Dr. Sullenger.
We'll now go to Mr. Borisy.

STATEMENT OF ALEXIS BORISY, PARTNER, THIRD ROCK VENTURES,
BOSTON, MA

Mr. Borisy. Good morning, Chairman Alexander, Ranking
Member Murray, and members of the committee. My name is Alexis
Borisy, and I am a partner at Third Rock Ventures.
At Third Rock, our mission is to form, launch, and build
great companies in areas of disruptive science and medicine to
discover and develop new products that will make a meaningful
difference for patients, physicians, and our healthcare system
overall. I applaud this committee for its commitment to
advancing research and development for patients.
Part of what makes life science innovation so successful
here in America is the functioning of the entire innovation
ecosystem from basic research to venture and industry
investment in early discovery through extensive investment in
development and then to commercialization. The development of
modern medicines and technologies from the handoff of basic
research onward is a risky and expensive endeavor, taking over
a decade and more than a billion dollars to deliver a single
new product.
But there can be no question of the reward. Over the past
decades, we have provided medicines and technologies that have
vastly improved the quality and longevity of the lives of
patients.
The current conditions for private investment into life
sciences are strong in many areas, but also difficult in
others. Policy actions have strengthened the investment into
areas such as therapeutics for oncology and rare genetic
diseases, while conditions have challenged other areas such as
devices and diagnostics.
Overall, venture investments in 2014 in the life sciences
has been the highest since 2008. One must note that although
therapeutics venture investments are robust, medical devices
and diagnostics have not fared as well, and first-time
investments into new companies has fallen last year to the
lowest number since 1995. A primary reason for this decline is
the increased time and cost of developing new devices and
diagnostics with an increased uncertainty about reimbursement
once on the market.
Looking forward, I must note that a keystone to ensuring a
robust life sciences industry is a national commitment to
supporting basic research. Our Nation's historical commitment
to life sciences basic research is viewed as a precious jewel
among nations. However, funding for the NIH has been
effectively declining for the past years.
Basic research is the key to unlocking the mysteries of
diseases and providing foundational discoveries that enable the
venture and biopharmaceutical industry to ultimately develop
new medicines for patients. It is a long, expensive, and risky
road from basic research to breakthrough medical products.
Investors and industry are willing to make those investments
and take on those risks, but the investments and risks cannot
be made without the substratum in basic research to start from.
Building from basic research, venture funding is the life
blood of the small biotechnology companies working on
disruptive science. These venture-backed small biotechnology
companies are the life blood of innovative new medicines. The
decision to deploy capital is directly impacted by the
regulatory decisions and behaviors. Better enabling and
encouraging FDA to utilize flexible approaches has had a very
positive impact on venture funding.
The 41 novel new drugs approved last year, in part
reflecting the successes of accelerated approval and
breakthrough therapy designations, is a substantial positive
signal for innovation. Investments in early stage potentially
breakthrough innovation in life sciences follow these signals,
and venture investment in rare genetic disease and oncology
remains very strong and has been increasing.
It is important to note the positive effect that steady
leadership over these past recent years has had at the FDA. I
cannot underscore enough the importance to the venture
community of having stable, long-term leadership at the agency.
It is also important to note the positive effect that policy
initiatives, such as breakthrough therapy, have had and its
successful implementation in some areas.
As a society, while we celebrate these successes, we have
to ask ourselves about what we want to do to improve how we
treat some of the other egregious diseases that affect some of
our citizenry, including obesity, diabetes, Alzheimer's,
depression, antibiotic resistance, as well as many others. As
we examine the successes of the programs I mentioned before, we
should endeavor to learn from the flexible and modern
approaches utilized under those programs and work to apply them
more broadly across therapeutic areas.
Recent ideas such as approval based on identified
subpopulations in Europe's adaptive licensing pilot could serve
to modernize our current system. Limited population approval
could make a significant difference, not only for antibiotic
resistance, but for many subpopulations of disease.
We need to incorporate the perspective of the patients
closely and make sure that we are examining the right benefits
and risk tradeoffs. These approaches could serve to ensure that
the right drugs are getting to the right patients in a much
more effective manner.
Thank you for the opportunity to provide my testimony.
[The prepared statement of Mr. Borisy follows:]

Prepared Statement of Alexis Borisy

Chairman Alexander, Ranking Member Murray, and members of the
committee, my name is Alexis Borisy, and I am a partner at Third Rock
Ventures. Our firm's mission is to build great companies that discover
and develop products that make a difference for the patients we serve.
Our work focuses on forming, launching, and building innovative
companies in areas of disruptive science and medicine, and matching
that to the right business and strategy. We work to advance pipelines
of discovery projects to the clinic and develop new products that will
make a meaningful difference for patients, physicians, and our
healthcare system overall. I personally have over 20 years of
experience in building and operating innovative science-based companies
and currently am chairman of the board and co-founder of NASDAQ-listed
foundation medicine, chairman of Warp Drive Bio, director for Blueprint
Medicines, which I co-founded, and director for Editas Medicines and
Revolution Medicine. I also serve on the board of the National Venture
Capital Association and was formerly on the board of the Biotechnology
Industry Organization.
I applaud this committee for its commitment to advancing research
and development for patients. Our understanding of diseases and how we
develop medicines has advanced tremendously over the last 20 years.
With over 3,400 medicines in development and over 2,000 public and
private companies in the United States, the promise of this industry
for our society is great.\3\ We have the potential to transform how we
treat patients with life-threatening and chronic diseases, a goal that
not only would improve the lives of patients and their families, but
create new solutions to our Nation's most pressing health care needs.
We must work together to ensure the United States' biopharmaceutical
and medical device and diagnostic industries are best equipped to
maintain global leadership and empowered to deliver the next generation
of medicines and therapies.
This hearing is focused on the critical components of fostering
continued investments in research and development and advancing
therapies for patients. America's leadership in this space historically
has led to translation of cutting edge science, medicine, and
technology into products that manage or treat medical conditions that
otherwise would decrease quality of life and productivity for
Americans. There is much that has been done right in the past few years
to encourage this investment into companies focused on breakthrough
science and its application to products. Yet there are also areas of
significant opportunities to improve, and the patients are waiting.
It is important to understand that successful development of new
medicines, devices, and diagnostics is dependent on policies that
support the entire life science ecosystem--beginning with basic
research and ending with providing treatments and therapies to
patients. Disruption or weakening of policies that negatively impact
any part of this ecosystem weakens the entire enterprise. Part of what
makes life sciences innovation so successful here in America is the
functioning of this entire ecosystem, from basic research, to venture
and industry investment in early discovery, through extensive
investment in development, and then to commercialization.
Assuming that a strong foundation of societal investment in basic
research exits, the development of modern medicines and technologies
from that point onward is a capital- and time-intensive endeavor taking
an average of 10 years and $1 billion to deliver a single new drug.\3\
It is also a high-risk endeavor involving finding solutions to complex
scientific and medical problems. However, when successful there can be
no question of the reward. Over the last 20 years we have provided
medicines that have vastly improved the quality and longevity of lives
for patients dealing with diseases such as HIV/AIDS, cancer, and heart
disease.
The current conditions for private investments into life sciences
are strong in some areas but difficult in others, and I will attempt to
exemplify in my comments how policy conditions have strengthened
investment into some of these areas, such as therapeutics for oncology
and rare genetic diseases, while conditions have challenged other areas
such as devices and diagnostics.
In general terms of first-time financings, industries that captured
the highest total of venture capital dollars and deals in 2014 were
software, media and entertainment, and biotechnology. Overall,
investments in 2014 in the life sciences sector, both Biotechnology and
Medical Devices combined, rose to the highest level since 2008 with
$8.6 billion invested into 789 deals. While there was a 29 percent
increase in dollars there was also a 3 percent drop in deals compared
to 2013. Dollars invested into life sciences companies accounted for 18
percent of total venture capital investments in 2014. Venture
capitalists alone invested $6 billion into private biotechnology
companies.
These private investments trends are a result of a positive
regulatory and policymaking environment for the biotechnology and
pharmaceutical arenas, with one particular example being the success of
FDA's Breakthrough Therapy Designation. Medical device and diagnostics
did not fare as well, as venture capitalists invested $2.6 billion in
private medical device companies in 2014, down more than 27 percent
from the 2008 peak of $3.6 billion. Of even greater concern, first-time
investments into medical device companies tell an even starker story.
In 2014, there were only 58 medical device companies that raised their
first round of venture capital financing, the lowest number of
companies since 1995. A primary reason for this decline is the
increased time and cost of developing new devices coupled with an
increased uncertainty about reimbursement once on the market.
the united states must commit to funding discovery
A keystone to ensuring a robust life science industry is a national
commitment to support basic research. Our nation's historical
commitment to life sciences basic research is viewed as a precious
jewel among nations. However, funding for the National Institutes of
Health has been directly or effectively declining for the past several
years with decreased or flat budgets that have not recognized
inflation.\4\ Basic research is the key to unlocking the mysteries of
diseases and providing foundational discoveries that enable the
biopharmaceutical industry to continue to research and ultimately
develop new medicines for patients. It is a long, expensive, and risky
road from basic research to a breakthrough medical product, and
investors and industry are willing to make those investments and take
on those risks, but the investments and risks cannot be made without
the substratum in basic research to start from. Diminished support for
basic research will lead to a smaller pipeline of next-generation
medicines and impede our country's potential to transform how we treat
diseases.
Research dollars provided by the National Institutes of Health to
universities and colleges throughout the country also serve to train
future scientists for jobs of the future. Currently, the U.S.
biomedical research sector supports over 5 million high-paying jobs in
the United States and has tremendous potential for growth.\5\ However,
we must understand that our position as the global leader in medical
science is constantly being challenged, and without a sustained
commitment for scientific discovery, this is not a position that will
be maintained.
enabling adoption of modern approaches to drug, device and diagnostic
development & approval will incentivize investment
Venture funding is the life-blood of the small biotechnology
companies working on disruptive science, and these venture-backed small
biotechnology companies are the life-blood of innovative new medicines.
In fact, a study published in 2010 found that in the United States a
majority of scientifically innovative drugs were discovered or
developed by biotechnology companies.\6\ Large pharmaceutical companies
may take over late-stage development and commercialization of many
small biotech drug development programs.
However, without innovative small biotech companies, many of
today's innovative medicines would not exist, which in turn would not
exist without the early-stage venture capital funding.
The decision to deploy capital is directly impacted by regulatory
decisions and behaviors. Better enabling and encouraging FDA to utilize
flexible approaches reflective of our understanding of the disease and
patient being treated, as well as incorporation of modern approaches to
development and approval, have a positive impact on venture funding.
For example, since the implementation of the Accelerated Approval
pathway in 1992 over 80 drugs have been approved utilizing this
pathway, including 29 to treat cancer and 32 to treat HIV.\7\ This
pathway allows for approval based on surrogate endpoints such as
shrinking tumors or decreasing viral loads indicative of clinical
benefits to patients with a commitment by the company to conduct
confirmatory trials post-market to confirm the benefit. This has
allowed oncology and HIV drugs to enter the public market in a
significantly more effective manner. It is no coincidence that oncology
has been and is projected to be one of the most active and innovative
therapeutic markets.\8\
Likewise, in recent years FDA has shown an increased willingness to
work with companies to develop more effective clinical development
programs for rare diseases. This, along with added exclusivity for
orphan drugs, has led to a significant increase in venture investment
in rare diseases. The results are clear. In 2012, FDA reported that
from 2007 to 2012 approximately one-third of the NMEs (New Molecular
Entities) approved were drugs for rare diseases.\9\ This trend
continued in 2013, when 33 percent of NMEs approved were drugs to treat
rare diseases.\10\ Again, we see that investment in early stage,
potentially breakthrough innovation in life sciences follows these
signals, as venture investment in rare genetic diseases has
significantly increased over the past few years.\11\
We have seen continued commitment from FDA and policymakers to work
on ensuring an effective development and review process. In fact, in
2014, the FDA approved 41 novel new drugs the highest number of novel
drugs approved in the past 10 years. In 2012, the Food and Drug
Administration Safety and Innovation Act (FDASIA) created a new
Breakthrough Therapy designation that provides increased interactions
with FDA to ensure the most effective development and approval
processes for promising new treatments. As of February 2015 there have
been 80 breakthrough designations granted by FDA.\12\ Similar to
statistics for accelerated approval, many of these designations have
been given to oncology and rare disease treatments and therapies.\13\
It is important to note the positive effect that steady leadership
over these past recent years has had at the FDA, and I cannot
underscore enough the importance to the venture community of having
stable, long term leadership at the agency. It is also important to
note the positive effect of policy initiatives such as Breakthrough
Therapy, and its successful implementation in some areas. Currently,
FDA is in the process of implementing these improvements. Ensuring FDA
can hire, retain, recruit and has tools to ensure the organization is
best able to carry out its mission is also critically important.
The benefit of these programs has clearly been mostly realized in
the oncology and rare disease space. Much has been written regarding
the enormous increase in requirements, duration, and expense of
clinical trials.\14\ \15\ \16\ \17\ These increases are especially
acute for drugs designed to treat chronic diseases with larger patient
populations. As a consequence, the cost and regulatory uncertainty of
developing drugs for these populations has been increasing, and we must
ask if there is more we could do to get these potential therapies to
patients.
As a society, while we celebrate the incredible successes, and
indeed we should celebrate these successes, we have to ask ourselves
what we want to do to improve how we treat some of the other egregious
diseases affecting great numbers of our citizenry and long-term health
costs, such as obesity, diabetes, Alzheimer's, and depression among
others, as well as pressing issues such as antibiotic resistance. As we
examine the successes of these programs in terms of number of approvals
for cancer and rare genetic diseases, we should endeavor to learn from
the flexible and modern approaches utilized under these programs and
work to apply them more broadly across therapeutic areas.
The fact is that while there are several examples where FDA has
allowed for the utilization of novel endpoints, advanced tools such as
biomarkers, and non-traditional clinical trial designs, the basis for
such decisions is still poorly understood and inconsistent across
review divisions. Without a more transparent and consistent approach as
to what criteria such decisions are based on, the private sector will
be hesitant to develop or utilize advanced approaches. Guidance from
and involvement of FDA are critical to creating processes for data
collection to support the utilization and adoption of novel endpoints
and modern drug development tools and approaches would incentivize
investment and enable a modern and effective approach to drug
development and review.
However, while there is a lot to be excited about when it comes to
the number of FDA approvals and programs discussed above, when it comes
to chronic diseases with varying stages of progression and severity,
there seems to be an actual reticence to employ modern tools and
approaches. Recent ideas such as approval based on identified
subpopulations, and Europe's adaptive licensing pilot could serve to
modernize our current system.
Limited population approvals could make a significant difference,
not only for antibiotic resistance, but for many subpopulations of
disease. Currently, our regulatory system is based on a philosophy that
more information before approval is better. We must always support the
highest standard of safety, but we must advance to a system that
critically examines information required and determine whether it is
actually informative as to the potential success of the drug in the
real world. Creating approval pathways that enable the development of
drugs for subpopulations of patients in areas like Alzheimer's,
diabetes, and antibiotic resistance could be a game-changer. We need to
incorporate the perspective of the patients closely, and make sure that
we are examining the right benefit and risk tradeoffs. These approaches
could serve to ensure the right drugs are getting to right patients in
a much more effective manner.
From early stage life sciences venture investment perspective, we
know that when we start a company with breakthrough innovations in new
areas of science and medicine it will take a long time to turn that
innovation into a drug that will reach patients and physicians and
improve public health. The reality is the time required to put a drug
on the market is, more often than not, longer than the length of our
investment funds. Thus, when we create a new innovative company in a
new area of science and medicine we are counting on the new medicine
being developed being seen as important and valuable when it is still
in the early stages of development. This is often referred to as the
``proof of concept in the clinic,'' or Phase IIA. At that point, we are
counting on the company and the product being sufficient to either take
the company public on the NASDAQ or to have the company and/or product
acquired by a pharmaceutical or larger biotech company.
The modern approach to regulation that exists now for cancer and
rare genetic diseases allows this to work very well for three reasons.
First, the regulatory process is more interactive, flexible, and
reflective of the disease and patient being treated. Second, the
amount, of time, and size of investment required to fund a company
through ``proof of concept'' is better understood. And, third, the next
steps in our innovation ecosystem, larger companies and public
investors, value the early stage proof of concept data because they
feel more confident about the development and approval process for
these drugs. However, the same cannot be said for diseases such as
obesity, diabetes, and Alzheimer's, where the time, amount of funds,
and regulatory requirements are greater and there is less understanding
about how to utilize modern tools and approaches. Without improving
these processes, it is very difficult to imagine how early stage
investment can occur in such important areas.
In addition to understanding the criteria needed for FDA to allow
for utilization of modern tools, such as biomarkers and diagnostics--
which are key to advancing personalized medicine by enabling the
ability to diagnostically define subsets of patients suffering from a
disease--there is also a need to provide incentives and clarity for the
development of such tools. This is particularly important for the
development of new diagnostics. It is imperative that regulatory
processes for personalized medicine encourage early collaboration for
the approval of therapeutics and companion diagnostics, as well as the
development of advanced diagnostics in general. Furthermore, the lack
of clarity around approval of advanced molecular diagnostics, coupled
with an enormous lack of clarity on reimbursement for them once
approved, has been making investment into this necessary space to
recognize the vision of precision medicine quite challenging.
A key barrier to the advancement of diagnostic development is the
fact that there are no consistent reimbursement policies for
diagnostics. Last year, Congress passed the Protecting Access to
Medicare Act of 2014 which included the Improving Medicare Policies for
Clinical Diagnostic Laboratory Tests provision. This provision is an
important and positive step forward. How transformative depends on
whether the potential benefits of this provision are realized and
implemented in the regulations. There remains substantial uncertainty
in the private and public world of reimbursement for molecular
diagnostics.
This uncertainty continues to hold back investment in breakthrough
personalized medicine innovation that could significantly advance how
we develop drugs and treat patients with critically important diseases
such as Alzheimer's, diabetes, and others. Lack of regulatory clarity
coupled with lack of clarity on reimbursement also limits investment in
medical devices. For both diagnostics and devices, it may take 2-5
years after the product is approved to secure reimbursement. This
uncertainty is a significant factor in limiting investment. A recent
NVCA survey found that regulatory concerns were cited as the No. 1
reason investors were moving away from putting funds into medical
technology companies.
There are two more areas critical to modernizing our approach to
developing medicines and ensuring continued investment in new solutions
that will benefit patients. We must strengthen the ability to integrate
patient perspectives in the drug development and review process. The
ability to provide information about patients' perspectives about their
diseases and what they believe to be benefits or acceptable risks would
help ensure that the medicines being developed are seen as helpful to
the patients they are being designed to treat.
Protection of intellectual property and patents is also paramount.
Patents are the only asset a small company has to attract investment.
If patents are weakened, the already high-risk proposition becomes one
that is too much and investment in this industry will be decimated. We
must ensure that the patent system protects the patent owners, abuses
of the system for sheer monetary gain and not the advancement of
science and discovery should not be supported.
Last, we must ensure that reimbursement policies are determined in
the context of the disease and patient being treated and the impact of
a drug is evaluated over appropriate time lines. With regard to devices
and diagnostics we must make the same policy strides as we have in
other medical spaces. Appropriate Federal investments and a robust and
transparent and predictable process for approvals will allow for
increased private investments. We must not create a system that will
severely diminish investment in the next generation of cures and
treatments.
Thank you for the opportunity to provide my testimony on this
important topic. There are other critical policy areas that have the
ability to impact or weaken the life science ecosystem not mentioned in
this statement, but I would be happy to discuss these areas further
with this committee.
References
1. http://www.phrma.org/pipeline.
2. Copley, Caroline. With biotech hot on Wall Street, VCs look to
Europe for promising companies. MedCity News. August 7, 2013.
3. Adams CP and Bratner VV (2006) Spending on New Drug Development.
Health Economics. 19, 13-141.
4. Federation of American Societies for Experimental Biology.
``Budget Cuts Reduce Biomedical Research.'' http://222.faseb.org/
portals/2/PDFs/opa/5.16.13%20
Funding%20Cuts%202-pager.pdf.
5. Battelle Technology Partnership Practice. ``Battelle/BIO State
Bioscience Industry Development 2012.'' June 2012. http://ww.bio.org/
sites/default/files/vebattelle-bio_2012_industry_development.pdf.
6. Kneller, Robert. ``The importance of new companies for drug
discovery: origins of a decade of new drugs'' Nature Reviews Drug
Discovery 9, 867-82 (2010).
7. FDA. Fiscal year 2012 Innovative Drug Approvals. December 2012.
8. JP Morgan. 2014 Global Biotech Outlook. January 6, 2014.
9. FDA fiscal year 2013 Innovative Drug Approvals. December 2012.
10. FDA. Approved Drugs 2013.
11. Jarvis, Lisa M. Orphans Find a Home. C&EN Volume 91 Issue 19 /
pp. 10-12. May 13, 2013.
12. FDA.
13. Aggarwal, Saurabh (Rob). A Survey of Breakthrough Designations.
Nature Biotechnology 32, 323-30 (2014).
14. Scannell, J.W., Blanckley, A., Boldon, H., and Warrington, B.
(2012) Diagnosing the decline in pharmaceutical R&D efficiency. Nature
Reviews: Drug Discovery 11, 191-200.
15. Avik, R. (2012) The Stifling Cost of Lengthy Clinical Drug
Trials. Manhattan Institute. http://www.manhattan-institute.org/pdf/
fda_05.pdf.
16. Tufts Center for the Study of Drug Development (12 April 2010)
PDUFA V Meeting.
17. Allison M (2012) Reinventing clinical trials. Nature
Biotechnology 30 (1): 41-49.

The Chairman. Thank you, Mr. Borisy.
Mr. Mussallem.

STATEMENT OF MICHAEL A. MUSSALLEM, CHAIRMAN AND CEO, EDWARDS
LIFESCIENCES, IRVINE, CA

Mr. Mussallem. Chairman Alexander, Ranking Member Murray,
and members of the subcommittee, thanks very much for taking on
this important subject. It's very meaningful.
I'm Mike Mussallem. I'm the chairman and CEO of Edwards
Lifesciences. I'm here representing AdvaMed and the hundreds of
thousands of U.S. medical device industry employees who are
passionate about helping patients, and I'm truly honored to
join my fellow panelists today.
We should all be concerned that innovation in the United
States is suffering from a costly, cumbersome, and risk-averse
regulatory system. I'm privileged to lead a company that's been
the world leader in developing and manufacturing heart valve
replacements for more than 50 years.
Our recent experience in a transformational therapy to
replace heart valves has given us a unique perspective on the
current climate. This technology allows a heart team to deliver
a collapsible prosthetic valve into the body via a catheter,
thus avoid cracking the chest, stopping the heart, and a long
and painful recovery.
This is the most extensively studied heart valve, including
an unprecedented four New England Journal of Medicine
publications, that demonstrated a triple win, a substantial and
sustained clinical benefit, cost effectiveness, and
extraordinary quality of life enhancements. Unfortunately, the
United States was the 42d country to get this new technology, 4
years after Europe.
Since then, Dr. Shuren and the leadership of FDA have been
working to improve the regulatory pathway, and they've made
commendable progress in this area, including facilitating early
feasibility trials in the United States, enabling more rapid
approvals of next-generation therapies, and using post-market
registry data to expand patient access. Additionally, this
breakthrough technology benefited from a close collaboration
between FDA and CMS so that when new patient populations were
approved, they were immediately covered by Medicare.
If these techniques and the others in AdvaMed's innovation
agenda could be applied to other technologies more broadly,
that would go a long way toward revitalizing innovation in the
United States.
We see several additional opportunities to remove barriers.
First, FDA's vision to improve the regulatory process must be
accelerated. FDA has recently proposed a number of improvements
to the pre-market clinical trial process and post-market
surveillance. For example, improving the process to incorporate
patients' perspectives on risk tolerance is an important step
in the right direction.
In addition to these regulatory enhancements, we believe
there should be a separate breakthrough technology designation
for transformative therapies to receive preferential regulatory
treatment. We also believe a central investigational review
board could reduce the cost and delays of initiating clinical
trials.
Second, we should strengthen the R&D infrastructure such
that it is second to none. We support steady growth of funding
to the NIH and the National Science Foundation. Additionally,
the SBIR and tech transfer programs can be improved by raising
the amount of funding to better recognize the costs actually
incurred by startup companies.
Third, to encourage innovation, there are a few essential
elements for a robust ecosystem that rewards our unique
American culture of innovation: ready access to capital, timely
and predictable regulatory processes, a reimbursement system
that supports promising therapies as they go through their
iterative improvement process, and a strong intellectual
property protection. In addition, the United States needs to
foster a supportive business environment through tax policies
that encourage the development of high-wage and high-value
industries like the medical device industry.
Finally, no discussion about medical technology is complete
without understanding the true impact that medical advancements
have on patients, and we are fortunate to meet a lot of
patients. Earlier this month, we welcomed more than 100 heart
valve patients and caregivers to Edwards to connect and support
one another and learn how they can use their voice to help
other patients.
I met a woman from Colorado who survived Hodgkin's lymphoma
only to find out that she needed a heart valve replacement.
Thanks to transcatheter heart valve therapy, her radiation-
damaged chest did not have to be opened, and today she is doing
well and back to work as a middle school teacher.
It's patients like these, ranging in age from teenagers to
folks in their nineties, that remind us daily that our work is
personal and impacts people individually. We welcome your
support to remove the barriers to innovation that may delay
patient access to lifesaving therapies developed and made right
here in America.
Thank you.
[The prepared statement of Mr. Mussallem follows:]

Prepared Statement of Michael A. Mussallem

summary
I am here because I am passionate about helping patients. That's
why I and hundreds of thousands of U.S. medical device industry
employees like me come to work each day. We love what we do because it
can have such an amazing, direct impact on the lives of patients.
But the balanced ecosystem that has supported medical innovation in
the United States has been eroded by an increasingly costly and
cumbersome regulatory process, and a risk-averse payment culture. Based
on Edwards Lifesciences' experience in developing and delivering new
therapies to American patients over the last several decades, I am very
concerned that we are seeing an alarming decline in U.S. medical
innovation.
As an innovator, Edwards has the unique opportunity to live and
breathe the current regulatory process on a daily basis. Our experience
with transcatheter aortic heart valve replacement (TAVR), a
revolutionary approach to replacing a patient's aortic heart valve
without open-heart surgery, has provided us a unique perspective on the
current state of the regulatory process. On behalf of the AdvaMed, the
Advanced Medical Technology Association, today I will focus on three
primary areas:

FDA has made improvements to the regulatory approval process over
the past few years. In particular, progress has been made with TAVR
therapies, including early feasibility trials in the United States,
approvals of new generations of TAVR therapies, and the use of registry
data to expand patient access. My testimony will touch on how FDA can
apply these improvements, and other concepts put forward by AdvaMed in
our Innovation Agenda, to provide innovators and entrepreneurs with the
incentives to make investments in new, breakthrough therapies. It will
also acknowledge a robust research and development infrastructure is a
critical component of the innovation ecosystem. Finally, it will
outline ideas on fostering an ecosystem that incentivizes curiosity and
rewards innovators.
At Edwards, patients help remind us daily that our work is
personal. Each heart valve represents a patient and their family, who
otherwise would miss out on both the extraordinary and precious
experiences of their daily lives. We encourage you to ensure that our
healthcare system listens carefully to the patient's voice, and look
forward to continuing to work with you to support a vital U.S.
innovation ecosystem that addresses patients' needs.
______

introduction
Chairman Alexander, Ranking Member Murray and members of the
committee, I am Mike Mussallem, chairman and CEO of Edwards
Lifesciences, based in Irvine, CA, and I am testifying today on behalf
of AdvaMed, the Advanced Medical Technology Association. I am truly
honored to join my fellow panelists today to discuss a path to
revitalizing medical device innovation in the United States.
I am here because I am passionate about helping patients. That's
why I and hundreds of thousands of U.S. medical device industry
employees like me come to work each day. We love what we do because it
can have such an amazing, direct impact on the lives of patients.
Based on Edwards' experience in developing and delivering new
therapies to American patients over the last several decades, I am very
concerned that we are seeing an alarming decline in U.S. medical
innovation.\1\ The balanced ecosystem that has supported innovation in
the United States has been eroded by an increasingly costly and
cumbersome regulatory process, and risk-averse payment culture.
---------------------------------------------------------------------------
\1\ National Venture Capital Association. (2014). NVCA 2014
Yearbook. Arlington, VA: Thomson Reuters.
---------------------------------------------------------------------------
The United States has been the world leader in medical technology
for more than a generation, but our leadership is eroding. Venture
capital investment, especially investment in the early stage ideas that
are the future of innovative therapies, has plummeted--a decline of
almost three-quarters between 1997 and 2013.\2\ While the current FDA
leadership has begun to make dramatic improvements, the regulatory
process remains time-consuming, inefficient, and unpredictable. The
payment environment is far less hospitable to new technology today than
ever before, meaning investment in new treatments is discouraged and
patients are deprived timely access to important new therapies.
Additionally, uncompetitive tax policies disincentivize the location of
R&D and manufacturing in the United States.
---------------------------------------------------------------------------
\2\ PWC and National Venture Capital Association, ``Venture Capital
Investments Q1. 2014--Money Tree Results,'' April, 18, 2014. There was
an increase in 2014 from the low of 2013, but much of the increase was
concentrated in digital health, informatics and self-pay technologies,
leaving potential technological breakthroughs to diagnose and treat
major diseases still starved for resources.
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Over the 35 years I have spent working in medical devices, I have
had the opportunity to be involved with the development of dozens of
innovative therapies. Today, I am privileged to lead the more than
9,000 employees of Edwards Lifesciences, who dedicate their lives in a
very personal way to helping critically ill patients and those
suffering from heart valve disease around the world. We have been the
leaders in heart valve innovation for more than 50 years, starting when
an engineer, Miles Lowell Edwards of California, partnered with a
cardiac surgeon, Dr. Albert Starr of Oregon, to develop the first
commercially available artificial heart valve. I also had the honor of
representing our industry in a number of leadership roles, noteworthy
among them my term as chairman of our trade association, AdvaMed.
It is my experience that successful medical device innovators keep
an unwavering focus on patients. We count it a privilege to serve these
patients, creating and supplying devices and therapies that save,
enhance and prolong lives. We are the toolmakers for clinicians,
working closely with them to develop technologies to address unmet
patient needs. Each new innovation is also a stepping stone that lays
the path to something even better. Innovation is a powerful and
iterative force, and those who are involved in it are never satisfied
with the status quo. It is our passion and mission to keep finding
better solutions to improve human health.
Edwards' innovation story is similar to many companies that have
made medical technology a uniquely American success story. The medical
technology industry is central to the development of devices and
diagnostics that will provide the life-saving and life-enhancing
treatments of the future. Patient access to advanced medical technology
generates efficiencies cost savings for the health care system and
improves the quality of patient care. Over the last three decades
(between 1980 and 2010), advanced medical technology helped cut the
number of days people spent in hospitals by more than half and added 5
years to U.S. life expectancy while reducing fatalities from heart
disease and stroke by more than half.
The industry is also an engine of economic growth for the United
States, generating high wage manufacturing jobs and a favorable balance
of trade. Medical technology is responsible for more than two million
U.S. jobs, including both direct and indirect employment.\3\ Clusters
of innovation in States like California, Texas, Minnesota,
Massachusetts, New York and North Carolina, are responsible for
addressing the world's most serious health challenges, while, at the
same time, serving as a robust economic engine, providing attractive
U.S. jobs and economic growth far into the future.
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\3\ The Lewin Group, ``State Economic Impact of the Medical
Technology Industry,'' June 7, 2010 and February 2007.
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As innovators, we have the unique opportunity to live and breathe
the current regulatory process on a daily basis. Our experience with
transcatheter aortic heart valve replacement (TAVR), a revolutionary
approach to replacing a patient's aortic heart valve without open-heart
surgery, has provided us a unique perspective on the current regulatory
process. As we have navigated the regulatory channels to bring this
therapy to U.S. patients over the last decade, we have taken note of
not only the challenges, but also the forward-looking vision of the
leaders of FDA and CMS to develop opportunities for better
collaboration with the agencies. FDA has learned from the last several
years, and we are already seeing much-needed improvements being made.
We believe opportunities remain to reduce barriers in regulatory
approval and reimbursement that will help promote America's continued
worldwide leadership in the area of medical device development and
support innovation. AdvaMed has proposed a new Innovation Agenda
(attached). Enactment of this agenda can unleash the potential of
medical technology to extend and improve lives, reduce the cost and
burden of disease, and maintain and enhance U.S. scientific and
economic leadership. I know the committee shares these same goals and I
applaud you for your focus on these important issues. Today I will
focus on three primary areas:

1. FDA's vision to improve the regulatory process must be
accelerated.
2. We should strengthen the R&D infrastructure so that it is second
to none.
3. To encourage innovation, we need to address issues throughout
the entire ecosystem.
edwards' unique perspective
Edwards Lifesciences has been at the forefront of an ambitious
effort to impact the lives of patients suffering from a deadly heart
valve disease called aortic stenosis. The Edwards SAPIEN transcatheter
aortic heart valves deliver a collapsible prosthetic valve into the
body via a catheter-based delivery system. The valve is designed to
replace a patient's diseased native aortic valve while the heart
continues to beat--avoiding the need to saw open the patient's chest,
connect them to a heart-lung machine, and stop the heart. Those of you
who have a friend or relative who has had open-heart surgery knows
first-hand how difficult this procedure and its arduous recovery can
be. In fact, it is so invasive that some patients simply cannot have
surgery because the risk of death is too high. Our new heart valve
procedure allows patients to avoid that pain and suffering.
Some patients who receive the SAPIEN transcatheter valves can leave
the hospital and return home the next day. It's extremely gratifying to
hear physicians and patients describe the immediate improvement in
patients' health after TAVR. They can breathe and speak more easily,
their skin transforms from gray to pink as their vital organs once
again receive the oxygen-rich blood they need, and their vibrancy
returns within hours.
Patients receiving the Edwards SAPIEN valve return home with
potential years of good health added on to their lifespan. Extensive
study of this valve--including an unprecedented record of four New
England Journal of Medicine papers--has demonstrated the ``triple
win'': a substantial and sustainable clinical benefit, extraordinary
quality-of-life improvement, and cost effectiveness in inoperable
patients. In fact, the SAPIEN valves are the most studied heart valve
in history. There are more than 3,000 peer-reviewed publications on
transcatheter aortic valve replacement (TAVR). There are also more than
60 cost effectiveness studies and at least 30 publications on quality
of life related to TAVR.
While our experience with SAPIEN and TAVR, transcatheter aortic
valve replacement, has ultimately been successful, it is important to
reflect on its unique and challenging regulatory pathway, including
some key milestones:

In 1999, Edwards began an internal program exploring
transcatheter valve replacement.
In 2002, Professor Alain Cribier performed the first-in-
human procedure of a transcatheter aortic valve replacement in France.
In 2007, the Edwards SAPIEN valve, our first commercial
transcatheter heart valve, received CE Mark for European commercial
sale. The next-generation SAPIEN XT valve received CE Mark 3 years
later.
Before SAPIEN was approved by FDA, CMS took the unusual
step of initiating a National Coverage Determination (NCD) in October
2011.
Four years after obtaining CE Mark in Europe, and after
one of the largest, randomized controlled trials in the history of
medical devices, the SAPIEN valve was approved by FDA in November 2011
for the treatment of inoperable patients, making the United States the
42d country in the world to approve the device.
We received regulatory approval for our second-generation
device in 2014 and are working on getting the third-generation approved
in the United States in the near future.

We are encouraged to see that FDA leadership has taken the initial
device lag experience with TAVR as a catalyst to improve. In fact, the
Agency has made significant progress in bringing newer generations of
TAVR products to patients faster. They have been very actively engaged
with many constituencies in the healthcare system, working to better
understand and improve predictability and shorten the approval timeline
for future generations of transcatheter heart valve devices. In doing
so, the device lag for TAVR has narrowed significantly.
One way FDA has worked to improve the process is to use registry
data to expand patient access. Under the TAVR NCD, CMS requires that
every U.S. patient be enrolled in a qualified prospective registry that
tracks appropriate outcomes data to the patient level. In a remarkable
effort of collaboration between the medical societies, regulators and
other interested stakeholders, the American College of Cardiology (ACC)
and the Society of Thoracic Surgeons (STS) helped build what has become
one of the most robust clinical evidence and quality measurement tools
ever created: the STS/ACC TVT Registry. In an unprecedented step, data
from the STS/ACC TVT Registry for transcatheter aortic valve
replacement procedures were used by FDA in 2013 to help expand the
indications for use of our SAPIEN technology, allowing access to a
broader patient population.
At the same time, through close collaboration between FDA and CMS,
when new patient populations are approved, they were immediately
covered by Medicare. This collaboration took vision and commitment by
both FDA and CMS, and they should be commended for their work. We think
that these novel approaches reflect agency views that take promotion of
public health as seriously as they take patient protection, which as
consumers of the system we should all welcome.
We realize that TAVR is a unique example of a breakthrough
technology that perhaps warrants this kind of attention from FDA and
CMS. If these techniques can be applied to other technologies more
broadly, that would go a long way toward revitalizing innovation in the
United States
fda's vision to improve the regulatory process must be accelerated
As noted through the Edwards transcatheter heart valve experience,
improvements in the FDA device review process can reduce the time and
cost associated with the development and approval of devices and
diagnostics. They can also ensure that the CDRH's stated vision--that
American patients will be the first in the world to have access to new
devices--is achieved, while maintaining the highest standards of safety
and efficacy.
One important area where FDA is heading in the right direction is
through its efforts to better involve patients in the regulatory
process. Specifically, its guidance document and work through the
Medical Device Innovation Consortium, to create a framework and catalog
of patient preference measurement tools, will help regulators and
device sponsors better incorporate patients' perspectives into the
approval process. It is frustrating to Americans to hear that Europeans
have access to innovations not available in the United States. Many
patients have asked me and petitioned our company directly: ``It is my
life; why can't I make the decision?'' The steps that FDA is already
taking to listen to the patient perspective can help adjust the
regulatory requirements to meet patient demands so that American
patients don't feel compelled to seek alternatives.
FDA is taking a number of other initiatives to improve the
regulatory processes to help patients access innovative therapies.
Thanks to the Food and Drug Administration Safety and Innovation Act
(FDASIA), FDA has agreed to improved review and approval performance
metrics tied to dramatic increases in manufacturer user fees, and we
are just beginning to see positive trends in performance. Beyond that,
during the last few years, Dr. Shuren and his team at FDA have outlined
strategic priorities to strengthen the clinical trial enterprise,
striking the right balance between premarket and postmarket data
collection and improving customer service.
Over the past year, a number of guidance documents have been
drafted to provide manufacturers and FDA reviewers more clarity,
including:

Priority review for premarket submissions
IDE and IRB approvals
IDEs for Early Feasibility clinical studies
Balancing premarket and postmarket data collection
Expedited access for certain premarket approval devices

In addition, FDA's expanded efforts to improve device quality and
safety by shifting the focus from the old regulatory compliance
approach to an upfront quality assurance effort through its ``Case for
Quality'' initiative is promising. Finally, FDA's efforts to improve
its regulatory management processes and structure through the
recommendations coming from its Program Alignment Group are an
important step in the right direction. It would be worthwhile for
Congress to spend time assessing how we can move this process forward.
It is important to note the distinction of our industry as compared
with others in the healthcare space. Whether created by large or small
firms, medical technologies are characterized by a rapid innovation
cycle. The typical medical device is replaced by an improved version
every 18-24 months. To fuel innovation, the medical device industry is
research intensive. U.S. medical technology firms spend over twice the
U.S. average on research and development.
Research in our industry means that to support regulatory decisions
for approval and reimbursement of new medical technologies in the
United States, manufacturers are required to gather a great deal of
clinical and economic evidence. Evidence development can be an
extremely costly endeavor at each stage of the process. Focus should be
put on reducing the delay and expense that data collection adds at
every step in the process.
FDA has recently proposed a number of improvements to the premarket
clinical trial process that hold promise, many of which have already
been discussed by the House of Representatives through their 21st
Century Cures hearings. Some of these improvements that we support
include:

Streamlining the investigational device exemption (IDE)
approval process to reduce IDE approval timeframes.
Reducing the legal complexity and inconsistency between
each hospital Institutional Review Board (IRB) through the creation of
a centralized or standardized review process.
Addressing potentially duplicative clinical evidence
through the consideration of surrogate endpoints and greater use of
data developed outside of the United States.

In addition to these actions that FDA has already taken, AdvaMed
has several proposals that would improve FDA's regulatory processes and
support innovation:

The creation of a ``Breakthrough Technology'' designation,
which would clearly identify which specific and innovative attributes
qualify to receive preferential treatment in both the approval and
reimbursement process.
Revitalize the ``least burdensome standard'' for
regulatory review to allow for enhanced reviewer training and the
ability for device manufacturers to use valid evidence from alternative
sources.
Encourage FDA to accept international consensus standards.
Reduce the review burden on FDA and companies by allowing
companies to self-certify certain changes to devices if their quality
system has been certified as capable of evaluating such changes.
Streamline the CLIA waiver process to accelerate the
availability of point-of-care, rapid diagnostic information to
physicians and patients.
Improve the advisory committee process to reduce delays in
product approvals and enhance the fairness and transparency of the
process.
Encourage the development of technologies for rare
diseases and pediatric populations.
Work with FDA to assure that post-market surveillance is
effective and efficient; provides timely, reliable, and actionable
data; minimizes unnecessary burdens on providers and industry; and is
facilitated by smooth implementation of the Unique Device Identifier
program.

We look forward to working with the committee and the FDA on these
proposals.
we should strengthen the r&d infrastructure so that it is second to
none
A robust research and development infrastructure is a critical
component of the innovation ecosystem. This committee appreciates the
important role that the National Institutes of Health (NIH) plays in
advancing science. To continue this work, we support steady growth in
funding for the NIH and the National Science Foundation.
Additionally, the Small Business Innovation Research and Small
Business Technology Transfer (SBIR/STTR) programs can be improved by
raising the amount of funding, allowing larger individual grants to
better recognize the costs actually incurred by startup companies.
Last, we can more effectively tap the vast intellectual resources
of our Nation's universities and academic health centers by providing
Federal technical assistance to establish and diffuse technology
transfer best practices.
to encourage innovation, we need to address issues throughout
the entire ecosystem
It is important to acknowledge that while we take steps to improve
the FDA device review process or strengthen the R&D infrastructure, we
must also look at the innovation ecosystem as a whole to retain our
innovation leadership. There are a few essential elements to fostering
an ecosystem that incentivizes curiosity and rewards innovators who
develop new therapies for patients:

Patient/physician need.
Ready access to capital and supportive economic climate.
Functional/timely/predictable regulatory processes.
Reimbursement system that welcomes novel therapies as they
undergo a continuous improvement process.
Strong intellectual property protection.

Unfortunately, however, for the Nation's medical technology
industry, every part of the innovation ecosystem is under stress. The
danger signs include:

Reduced investment. Venture capital flowing to the medical
device sector is both an essential generator of future progress and an
index of the attractiveness of investing in the development of new
treatments and cures. Venture investment in medical technology declined
by 42 percent between 2007 and 2013. First-time funding for medical
technology startups dropped by almost three-quarters over the same
period.\4\
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\4\ PWC and National Venture Capital Association, ``Venture Capital
Investments Q1. 2014--Money Tree Results,'' April, 18, 2014.
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Movement of clinical trials and first product introduction
out of the United States. For more complex products, the new normal is
to conduct the first clinical trials and product introductions outside
of the United States. Often, patients in other nations get the second
or even third version of a novel treatment or diagnostic while patients
in the United States are still waiting to get the first version.\5\
Among other factors, the decisions to introduce abroad first are driven
by the higher cost and time involved in conducting clinical trials in
the United States; delays and inconsistencies in FDA review; and,
increasingly, uncertainties about coverage and payment. We believe this
trend is bad for patients and for American jobs. Where research goes,
so goes the high-paying research, engineering and manufacturing jobs.
We are encouraged that FDA has made some recent progress in this area
through FDA's Early Feasibility Program, which supports the early-stage
clinical research. Edwards Lifesciences has been among the fortunate
first few companies to benefit from this program through a U.S.-based
early feasibility study of a minimally invasive mitral valve
replacement technology. We are hopeful the program can be expanded to
benefit many other technologies in the future.
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\5\ California Healthcare Institute and Boston Consulting Group,
``Taking the Pulse of Medical Device Regulation and Innovation,'' 2014.
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Increasing difficulty in achieving coverage by public and
private insurers for new medical devices and diagnostics. Start-up
companies are now reporting that one of the first questions investors
now often ask is about the prospects for coverage and payment, while
the previous focus was almost exclusively on the FDA. Public and
private insurers have been raising the evidentiary threshold for
coverage over the last decade. A new study found that in the 10 years
between 2002 and 2012, technologies being considered for national
coverage in Medicare were 20 times less likely to be successful.\6\
When coverage was granted, it was more limited than the FDA approved
indications in 40 percent of the cases.\7\
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\6\ James D. Chambers, et al., ``Medicare is Scrutinizing Evidence
More Tightly for National Coverage Determinations,'' Health Affairs,
February 2015.
\7\ James D. Chambers, et al., ``Factors Predicting Medicare
National Coverage: an Empirical Analysis,'' Medical Care, March 2012.
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Declining U.S. competitiveness. The U.S. medical
technology industry has been the unchallenged world leader for many
years. We still lead, but our continued leadership is threatened as
other countries are anxious to wrest leadership from the United States.
Other countries not only have lower general tax rates but many provide
specific tax incentives, such as ``patent'' or ``innovation boxes''
designed to further reduce rates for domestic development of
intellectual property and manufacturing based on that property, in
order to attract high-wage, high value-added knowledge-based
manufacturing industries.
Shrinking public research infrastructure. The United
States has historically led the world in cutting-edge biomedical
research. Public funding of NIH and our great universities and academic
health centers has been central to the basic and clinical research that
has proven to be the foundation of new treatments and cures. But total
U.S.-medical research effort, as a share of global medical research,
declined by more than one-fifth in between 2002 and 2012.\8\
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\8\ Hamilton Moses, III, M.D., et al., ``The Anatomy of Medical
Research: U.S. and International Comparisons,'' JAMA, 2015;313(2): 174-
189.

I realize that this committee's jurisdiction does not extend to
Medicare, but a true innovation agenda must address both FDA and
Medicare and I urge this committee and the Senate Finance Committee to
consult with each other as you move forward to find ways to promote
innovation. One of the most important of our innovation agenda
proposals--the breakthrough pathway--spans the jurisdiction of both
committees and can only effectively be enacted cooperatively.
the patient experience
No discussion about medical technology is complete without
understanding the true impact medical advancements have on patients--
and we meet a lot of patients.
Earlier this month, we had the pleasure of hosting 50 patients who
participated in our first ever Edwards Patient Day held at our Irvine,
CA headquarters. We brought them there to connect with one another, and
to meet the dedicated team of employees who hand-sew every heart valve,
stitch by careful stitch. Needless to say, it was a very emotional day
for the patients as well as the teams who created their lifesaving
valve.
During Patient Day, we met a woman from Colorado who survived
Hodgkins lymphoma, but found out she needed a heart valve replacement
due to severe aortic stenosis. Since her doctors were not about to
crack open her chest made frail by radiation, she was a candidate to
receive a transcatheter valve replacement. She told us how her new
valve has kept her healthy and allowed her to get back to her life as a
middle school teacher.
We also met a Marine Corps veteran who received TAVR treatment at
the VA in Ann Arbor, and was discharged only 48 hours after his
procedure. His valve was replaced in January, completely recovered,
making the trip from Michigan to Irvine a few weeks ago to share his
story with other veterans and Patient Day participants.
It is patients like these--a Salt Lake City father of 10 and
grandfather to 25 who received a valve replacement as part of a
clinical trial studying the next-generation treatment, and a New York
marathoner who, after heart valve replacement, was able to return to
running--that remind us of the importance of our daily work, and the
chance to bring our ideas out of the lab, into the clinic and to the
patients and physicians that need them most.
These and the tens of thousands of other patients we have had an
opportunity to help remind us daily that our work is personal, and it
impacts people individually. Each heart valve represents a patient and
their family, who otherwise would miss out on both the extraordinary
and precious ordinary experiences of their daily lives.
Our mission is focused and our way forward is clear. I thank
Chairman Alexander, Ranking Member Murray and members of the committee
for the opportunity to testify today, and to share Edwards' experience
in delivering an important new therapy to U.S. patients in need. We
look forward to continuing to work with you to support the U.S.
innovation ecosystem.

Attachment

innovation agenda background
The medical technology industry is central to the development of
medical devices and diagnostics that will provide the life-saving and
life-enhancing treatments of the future. Patient access to advanced
medical technology generates efficiencies and cost savings for the
health care system, and improves the quality of patient care. Between
1980 and 2010, advanced medical technology helped cut the number of
days people spent in hospitals by more than half and add 5 years to
U.S. life expectancy while reducing fatalities from heart disease and
stroke by more than half. The industry is also an engine of economic
growth for the United States, generating high wage manufacturing jobs
and a favorable balance of payments.
But the innovation ecosystem that supports medical technology is
severely stressed. The United States has historically been the world
leader in medical technology, but our leadership is eroding. Venture
capital investment, especially investment in the startup firms that are
the seed corn of the industry, has plummeted. While there have been
recent improvements at the FDA, the regulatory process remains too
time-consuming, too inefficient, and too inconsistent. The payment
environment is far less hospitable to new technology today than ever
before, with the result that investment in new treatments is
discouraged and patient access to new treatments that are developed is
slower and more difficult. The U.S. tax system is uncompetitive and
discourages location of research and development and manufacturing in
the United States, a situation that has dramatically worsened as the
result of the medical device excise tax. The basic and applied public
infrastructure that is critical to long-term advances in the life
sciences is eroding.
To respond to these challenges and rebuild the innovation
ecosystem, AdvaMed proposes a new Innovation Agenda. Enactment of this
agenda will unleash the potential of medical technology to extend and
improve lives, reduce the cost and burden of disease, and maintain and
enhance U.S. scientific and economic leadership. Failure to act will
mean lost lives, unnecessary suffering, reduced job formation, and
diminished economic growth.

The Five Pillars of the Innovation Agenda
----------------------------------------------------------------------------------------------------------------
1 2 3 4 5
----------------------------------------------------------------------------------------------------------------
Improving FDA's regulatory Restructuring Reform the U.S. Improving access Supporting the
processes so that the cost and CMS's coverage tax system to to international maintenance and
time of development and and payment create a level markets by growth of an R&D
approval of devices and processes to playing field, insisting on free infrastructure
diagnostics is reduced and the support starting with and fair trade in second to none.
CDRH mission statement that development of repeal of the medical
American patients will be the new technologies medical device technology and
first in the world to have that improve excise tax--a tax working with
access to new devices is treatment, that is draining foreign
achieved, while maintaining the diagnosis or resources from governments to
highest standards of safety and prevention, and American achieve
efficacy. provide prompt manufacturing innovation-
patient access to jobs and research. friendly
these regulatory and
technologies. payment policies.
----------------------------------------------------------------------------------------------------------------

proposals to implement the innovation agenda
Establish access to breakthrough products

Establish a streamlined, seamless path for FDA approval
and CMS coverage and payment under the Medicare and Medicaid programs
for breakthrough products that make significant improvements in
treatment or diagnosis of life-threatening or irreversibly debilitating
diseases or conditions.

Improve the FDA's regulatory processes

Responding to patient challenges and to rebuild the innovation
ecosystem, AdvaMed proposes a new Innovation Agenda.

Meet and exceed the groundbreaking 2012 user-fee agreement
goals for such key objectives as reductions in total review times and
more frequent and substantive interactions between FDA and product
sponsors.
Revitalize the ``least burdensome standard'' for
regulatory review through enhanced reviewer training and encouraging
the use of valid scientific evidence from such sources as registries,
experience in foreign markets, and peer-reviewed journal articles,
where appropriate, to support safety or effectiveness determinations.
Encourage FDA to accept international consensus standards.
Streamline the CLIA waiver process to accelerate the
availability of point-of-care, rapid diagnostic information to
physicians and patients.
Allow the use of central Institutional Review Boards to
facilitate the conduct of multicenter clinical trials.
Reduce the review burden on FDA and companies by allowing
companies to self-certify minor changes to devices if their quality
system has been certified as capable of evaluating such changes.
Improve the advisory committee process to reduce delays in
product approvals and enhance the fairness and transparency of the
process.
Encourage the development of technologies for rare
diseases and pediatric populations.
Work with FDA to assure that post-market surveillance is
effective and efficient; provides timely, reliable, and actionable
data; minimizes unnecessary burdens on providers and industry; and is
facilitated by smooth implementation of the Unique Device Identifier
program.

Restructure CMS's coverage and payment processes

Enactment of AdvaMed's Innovation Agenda will unleash the potential
of medical technology to improve lives, reduce the cost and burden of
disease, and enhance U.S. scientific and economic leadership.

Establish automatic Medicare coverage of FDA-approved
clinical trials rather than requiring a duplicative and potentially
time-consuming separate Medicare approval process.
Expand coverage of telehealth services, including remote
monitoring, and of disposable, prevention and treatment technologies
used in the home.
Streamline Medicare's process for granting temporary
outpatient and physician payment codes to new technologies and prohibit
Medicare contractors from arbitrarily denying payment for these
technologies.
Require State Medicaid programs to take patient views into
account in making coverage decisions.
Increase the transparency and fairness of the local
coverage determination process.
Improve the new technology add-on payment program to
capture a larger share of important new technologies and set payments
more appropriately.
Establish payment levels more promptly for new
technologies used in the inpatient setting, using the best available
data.
Improve the methodology for establishing payment for
technologies used in the outpatient setting and for updating payments
to ambulatory surgical centers.
Implement ICD-10 this fiscal year.

Reform the U.S. tax system

Repeal the medical device excise tax.
In the context of comprehensive tax reform, create a level
competitive playing field for made-in-America medical technology:

Enact new tax incentives to invest in startup
companies creating new treatments and diagnostics;
Lower the overall corporate tax rate;
Provide incentives comparable to those of other
countries for development and manufacturing of technology; and
Conform the treatment of international earnings to
that of competitor nations.

Improve access to international markets

Work with the U.S. Government to encourage foreign
governments to establish regulatory and payment systems for medical
technology that are fair, transparent, nondiscriminatory and based on
international best practices.
Enact Trade Promotion Authority to negotiate the Trans-
Pacific Partnership and the Trans-Atlantic Trade and Investment
Partnership, and assure that those agreements include provisions that
improve market access for medical technology.
Enforce provisions of existing trade agreements such as
the U.S.-Korea Free Trade Agreement to assure fair access for U.S.
technology products.

Support the maintenance and growth of an R&D infrastructure second
to none

The medical technology industry is central to the development of
medical devices and diagnostics that provide life-saving and life-
enhancing treatments of the future.

Provide steady growth in funding for the National
Institutes of Health and the National Science Foundation.
Improve the Small Business Innovation Research and Small
Business Technology Transfer programs by raising the amount of funding
(in the context of rising NIH and NSF funding), allowing larger
individual grants to better recognize the costs actually incurred by
startup companies.
More effectively tap the vast intellectual resources of
our Nation's universities and academic health centers by providing
Federal technical assistance to establish and diffuse technology
transfer best practices.
Streamline Institutional Review Board activities to reduce
barriers to initiating collection of clinical data on new treatments,
particularly for multicenter trials, without sacrificing protection of
human subjects.

The Chairman. Thank you, Mr. Mussallem.
Mr. Coukell.

STATEMENT OF ALLAN COUKELL, SENIOR DIRECTOR, HEALTH PROGRAMS,
PEW CHARITABLE TRUSTS, WASHINGTON, DC

Mr. Coukell. Chairman Alexander, Ranking Member Murray, and
members of the committee, thank you for the opportunity to be
here. My name is Allan Coukell. I direct health programs at the
Pew Charitable Trusts. We're an independent, nonpartisan
research and policy organization that operates a number of drug
and medical device initiatives.
My testimony today makes three main points. First, the
rising cost of medical innovation is a serious concern with
multiple underlying causes. Second, the FDA has great
flexibility but would benefit from additional tools in some
areas. And, third, the need for robust clinical data is higher
than ever, and there are steps Congress could take to improve
the efficiency of data collection.
We live in a time of exciting scientific and therapeutic
advances, and yet the cost of bringing drugs to market has
risen steadily. To give just one fact, the per-patient cost of
clinical trials jumped 86 percent over 3 years, by one recent
estimate.
Numerous reviews and analyses have shown that the
regulatory environment is not the sole or even the main cause
of declining industry productivity. Nevertheless, it's
imperative that FDA regulation and the other public programs
that support innovation work as efficiently as possible.
Yet we must recognize the challenge. For many drugs and
devices, the clinical effects are subtle. Unless you study a
lot of patients, using carefully controlled experiments to
reduce accidental bias, you can't necessarily tell if they
work. The crucial point is that the size of clinical trials is
driven not by the approval standard written into the law, but
by the difficulty of discerning the effect of treatment.
To my second point about FDA flexibility, there is no one-
size-fits-all requirement for evidence to support drug or
device approval. Drugs can be and are approved based on a
single trial about a third of the time, using historical
controls and so on as suited to that product.
Congress has created a variety of pathways to speed
approvals. For example, 20 percent of novel new drugs last year
came to market through accelerated approval based on surrogate
outcomes. Now, a similar approach has been proposed for medical
devices, FDA's expedited access PMA pathway. If Congress
codifies this program, it should ensure that FDA also has the
ability to remove devices that ultimately are not found to be
safe and effective.
These various mechanisms are especially important for
products that advance care for patients with serious unmet
needs. One area where Congress could facilitate innovation is
the development of a new regulatory pathway for antibiotics.
Senators Hatch and Bennet have introduced the PATH Act which
would direct FDA to approve drugs for specific limited
populations of patients who have life-threatening infections
and few other treatment options or none.
Such resistant infections are on the rise and threaten to
become a public health crisis. A number of key stakeholders,
including public health groups, providers, industry, and
venture capital, support this legislation. Pew asks the
committee to move it quickly and to limit the pathway to
antibiotics.
Let me now turn to my third point, the efficiency of
clinical data collection. My written testimony contains a
number of suggestions, but let me focus here on the potential
for far-reaching change. I'll give you an example of the kind
of study that we should be conducting in the United States but
right now can't, at least not routinely.
A few years ago, investigators in Scandinavia randomized
7,000 patients to two different surgical treatments for blocked
coronary vessels. A traditional trial like this in the United
States would cost hundreds of millions of dollars. This one in
Europe cost $300,000, $50 per patient.
Why was it so cheap? Because the data for the trial were
drawn from a cardiovascular disease registry, a database that
collects information on groups of patients treated for a given
condition. Registries have been used to a limited extent in the
United States, and Mr. Mussallem mentioned that his product, an
innovative heart valve, got an expanded indication based on
registry data in lieu of a clinical trial.
Pew worked with a range of stakeholders to develop a report
on what it would take to make registries cheaper and more
common in the United States. We found that one of the major
barriers is the lack of electronic health record
interoperability. Another is legal confusion between research
and quality improvement. Finally, there's the need for a
sustainable funding model.
Addressing these challenges could put us on a footing to
reduce the cost of innovation, speed approvals, and make better
decisions about performance and cost once the product is on the
market.
In conclusion, Mr. Chairman, medical product innovation
involves partnerships across the private sector, basic science
and academia, the regulatory environment, and the public
programs that pay for new technology. We should continue to
improve the system, recognizing that each part has its role to
play and that patients rely on it.
Thank you, and I'd welcome any questions.
[The prepared statement of Mr. Coukell follows:]

Prepared Statement of Allan Coukell

summary
In addition to touching briefly on FDA operations, my testimony
makes three key points:

The rising cost of medical product innovation is a serious
concern, with multiple underlying causes.
The FDA has great flexibility, but would benefit from
additional tools in some areas.
The need for robust clinical data is higher than ever, and
there are steps Congress could take to improve the efficiency of data
collection.

Since 1950, the Food and Drug Administration (FDA) has approved
more than 1,400 drugs, at a relatively constant annual rate. Numerous
recent approvals demonstrate scientific novelty and exciting
therapeutic potential. However, the inflation-adjusted cost of bringing
these products to market has risen steadily. As numerous reviews and
analyses have shown, the regulatory environment is not the sole, nor
even the principal, cause of this declining productivity.
Nevertheless, it is imperative that FDA regulation and other public
programs that support innovation work as efficiently as possible.
Patients, clinicians, and product developers rely on the FDA's careful
and efficient review of new products.
There is no ``one-size-fits-all'' requirement for evidence to
support drug or device approval. FDA's drug and device centers have,
and routinely use, flexibility in approving new products, including use
of a variety of pathways and mechanisms created by Congress.
One proposed new pathway--the expedited access premarket approval
(EAP) process for medical devices--would support the marketing of new
medical devices based on surrogate endpoints, shorter clinical trials
or other adaptive designs, but its enactment should include mechanisms
to ensure that sufficient data is collected in the post-market setting
and that devices do not remain on the market absent such data.
Another area where Congress could facilitate innovation is the
development of a new regulatory pathway for FDA to approve new
antibiotics for specific, limited populations of patients with life-
threatening infections where few or no treatment options currently
exist.
Senators Hatch and Bennet have introduced the PATH Act, S. 185,
which would direct FDA to create this pathway for antibiotics. A number
of key stakeholders, including public health groups, providers,
industry, and venture capital, support this legislation and we ask the
committee to move this bill quickly.
To facilitate more efficient innovation and better evaluation of
product performance in the pre- and post-market setting, it is
important to address the rising cost of clinical trials and clinical
data acquisition. Clinical trials remain the most reliable source of
unbiased information for evaluating clinical effectiveness and Congress
could help address these costs by facilitating faster trial initiation
through, for example, greater use of central institutional review
boards (IRBs). More far-reaching reforms would increase the use of
clinical registries (databases) as a source of clinical data.
While sponsors have concerns about the speed and predictability of
FDA review, they generally feel that requests for data are appropriate
and the agency makes the correct decision in most cases. There is
general support for increased investment in FDA training and personnel
and in regulatory science.
______

Chairman Alexander, Ranking Member Murray, and members of the
committee. My name is Allan Coukell. I direct health programs at The
Pew Charitable Trusts, an independent, non-partisan research and policy
organization with a number of initiatives focused on drug and medical
device safety and innovation.
Thank you for the opportunity to present testimony on the medical
product development landscape. I will focus today on steps that could
support innovation, with a particular emphasis on the need for robust
clinical data to evaluate product performance both before and after
approval. I will touch, in particular, on drug approvals and Pew's
medical device and antibiotic innovation work, as well as on FDA
predictability.
In addition to touching briefly on FDA operations, my testimony
makes three key points:

Since 1950, the Food and Drug Administration (FDA) has approved
more than 1,400 drugs. Aside from an increase in approvals after the
enactment of the first Prescription Drug User Fee Act (PDUFA), the
number of annual approvals has been relatively constant over this
period,\1\ while the inflation-adjusted cost of bringing these products
to market has risen steadily. As numerous reviews and analyses have
shown, the regulatory environment is not the sole, nor even the
principal, cause of this declining productivity.\1\ \2\ \3\
Nevertheless, it is imperative that FDA regulation and other public
programs that support innovation work as efficiently as possible.
Patients, clinicians, and product developers rely on the FDA's careful
and efficient review of new products.
Pharmaceutical research and development investment in the United
States has remained flat over the past decade, while investments in
medical device and biotechnology, though much smaller, have grown
steadily.\4\ The United States continues to lead the world in many
aspects of biomedical innovation,\4\ \5\ \6\ and recent scientific and
clinical advances are encouraging; however, there are very real strains
in the business models for both drug and medical device development--
and in our ability to manage the associated costs of these products.
fda approvals and flexibility
In approving new drugs, FDA relies on a ``substantial evidence of
effectiveness'' standard established by ``adequate and well-controlled
investigations, including clinical investigations.'' The medical device
standard is similar: ``reasonable assurance of safety and
effectiveness'' based on ``valid scientific evidence.''
There is no ``one-size-fits-all'' requirement for evidence to
support drug or device approval. For example, an analysis by the
National Organization for Rare Disorders found that of 135 drug
approvals for non-cancer rare disease, 45 met traditional data
requirements, 32 reflected ``administrative flexibility'' based on a
previously documented FDA system, and 58 reflected flexibility applied
on a case-by-case basis.\7\ Another recent analysis of all drug
approvals (funded by Pew) found that while FDA generally relied on
randomized clinical trials to approve therapeutics, over one-third of
approvals were based on a single efficacy trial.\8\ This same analysis
also showed that FDA used flexibility with regards to which outcomes
these trials had to measure.
FDA's review of safety and effectiveness data is essential to
inform patients and physicians. For many drugs and devices, the
clinical effects are difficult to distinguish from the normal variation
in outcomes seen in the relevant population of patients. Often, a
drug's effect can only be assessed across large numbers of patients
through careful experiments designed to reduce confounding and
accidental bias. The crucial point is that the size of clinical trials
is driven, not by the approval standard written in statute, but by the
difficulty of discerning the effect of the treatment.
It is important to note that early promise for drugs and devices
may not be borne out as the products proceed through development. A
recent Pew study found that even among medical devices that the FDA had
identified as sufficiently innovative to qualify for priority review
status, approximately one-third were not ultimately approved.\9\ This
shows, again, that novelty and early promise are not always borne out
by more thorough testing.
Several existing mechanisms provide flexibility for the data
collected. The accelerated approval pathway for drugs, which Congress
codified into law in 2012, allows FDA approval based on surrogate--
rather than clinical--endpoints, with the goal of enabling more
efficient premarket studies. In 2014, FDA approved 20 percent of novel
new drugs through this pathway.\10\
Similarly, for devices that treat or diagnose conditions affecting
fewer than 4,000 patients per year, FDA can grant a humanitarian device
exemption, which allows the marketing of a product that is considered
safe and is expected to provide benefits, even if less evidence on
effectiveness is available. The FDA's proposed expedited access
premarket approval (EAP) process for medical devices would also support
the marketing of new medical devices based on surrogate endpoints,
shorter clinical trials or other adaptive designs. The success of this
policy, though, relies on the efficient collection of data--both pre-
and post-market. Congress should explore codifying this program in
statute, and should address some gaps in FDA's authority to accelerate
patient access to new medical devices while still collecting sufficient
information throughout a product's entire life cycle. In particular,
Congress should assess the agency's ability to promptly remove the
approval of devices that ultimately were not found to be safe and
effective.\11\
These programs provide FDA with significant latitude to tailor the
data collected by sponsors and the agency's review process to reflect
the severity of the disease and availability of alternative treatments,
not to mention each product's risks and benefits.
Limited Population Antibacterial Drug Approvals
One area where Congress could facilitate innovation is the
development of a new regulatory pathway for FDA to approve new
antibiotics for specific, limited populations of patients with life-
threatening infections where few or no treatment options currently
exist.\12\ We have an urgent need for new antibiotics. Antibiotic
resistance is rising and there are increasing infections for which we
have almost no treatments. Currently, for the FDA to approve a new
antibiotic the FDA generally requires extensive clinical trials in the
larger population due to concerns about safety risks resulting from
possible use in broader groups. It would be desirable to have a
pathway--twice endorsed by the President's Council of Advisors on
Science and Technology (PCAST) \13\--under which such drugs could
rapidly reach high-need patients while reducing the risks from wider
use of the drug. There would also be clear public health benefits to
limiting the use of new antibiotics effective against drug-resistant
bacteria, to stave off the emergence of drug-resistant strains.
Senators Hatch and Bennet have introduced the PATH Act, S. 185,
which would direct FDA to create this pathway for antibiotics. A number
of key stakeholders, including public health groups, providers,
industry, and venture capital, support this legislation, and we ask the
committee to move this bill quickly.
Patients May Need More Evidence
It is important to note that current approval standards speak only
to efficacy and safety. Stakeholders beyond the FDA--notably patients
and payors--may frequently need additional information to make informed
choices. For a patient, the question may not be whether a drug is
effective compared with a placebo, but whether it is superior to other
existing treatments. Patients and payors alike may seek to evaluate
that information and weigh it against the drug's cost. These are
crucial questions for the individual that are not addressed by the
current approval standard. In addition, drug costs--particularly for
high-cost biologics that make up an increasing share of drug
approvals--are rising faster than healthcare costs as a whole. The need
to sustainably mange health-care spending is likely to drive further
demands for data to assess the value of new drugs and treatments, and
not merely their effectiveness.\14\ For example, one of the Nation's
leading cancer centers recently announced that it would not utilize a
particular new cancer drug because the drug was more expensive than its
competitors, but did not confer additional benefit.\15\
better data at lower cost
To facilitate more efficient collection of evidence in both the
pre-market and post-market setting, it is important to address the
rising cost of clinical trials and clinical data acquisition. Clinical
trials remain the most reliable source of unbiased information for
evaluating clinical effectiveness,\16\ and Congress could help address
these costs by facilitating faster trial initiation through, for
example, greater use of central institutional review boards (IRBs)
instead of multiple local reviews. For medical devices in particular,
trials are currently required by statute to obtain IRB review at each
facility participating in a study.\17\ Removing this requirement could
help streamline the approval of these trials.
Personalized, or precision, medicine has the potential to identify
sub-populations of patients with specific genetic profiles who are more
likely to respond to a particular therapy--particularly in cancer
treatment. To take full advantage of this potential will require
innovative trial designs, which the FDA has encouraged. For example,
the recently developed Lung-MAP trial has the potential to improve
efficiency by allowing simultaneous and sequential comparisons of
multiple drugs (from multiple companies) and stratification of patients
by genotype.\18\
Per Patient Costs and Large Simple Trials
Independent of the size of the trial, per-patient clinical trial
costs have risen sharply. A 2013 survey found that phase III costs rose
by 86 to 88 percent over 3 years (from $25,000 to $40,000 per
patient).\19\ Across all development phases, the increase was 70
percent. The report notes that finding a sufficient number of general
clinical sites is a challenge, but that,

``The biggest driver behind higher vendor costs and site
recruitment issues is an increasingly intense competition for
top-performing investigator sites.''

One source of cost in any trial is the number of data elements that
are collected. Another approach to reducing trial costs involves
``large, simple trials.'' \20\ Such trials have the potential to reduce
costs by simplifying eligibility criteria and reducing the number of
outcomes tracked. No statutory or regulatory barrier precludes adoption
of such trial designs. Rather, a participant in an IOM workshop
described the barrier as risk aversion, with researchers preferring to
collect 100 unnecessary variables than to miss one important one.\20\
Registries
One successful large simple trial randomized patients through use
of an existing cardiovascular disease registry in Sweden. Registries
are large databases that collect information on groups of patients
treated for a particular medical condition. The TASTE trial enrolled
more than 7,000 patients, and--in unprecedented fashion--allowed
investigators to keep track of every patient throughout the course of
the research at a total cost of $50 per patient, or only $300,000 for
the entire trial.\21\ Conducting a traditional study of this size in
the United States would cost hundreds of millions of dollars, if not
more.
Registries have been used to a limited extent in the United States
to expedite patient access to new products. Notably, the FDA has
approved an expanded indication for an innovative heart valve based on
data from an existing registry, in lieu of a randomized clinical trial.
Pew, together with the Blue Cross Blue Shield Association and the
Medical Device Epidemiology Network, convened experts from the medical
device industry, the registry community and government to consider how
to achieve the full potential of registries in a financially
sustainable way.\22\
Several barriers exist to fully achieving the promise of
registries. Despite the dramatic uptake of electronic health
information sources, these systems cannot easily transmit data among
one another. This lack of interoperability, for example, hinders the
ability of registries to extract clinical and outcomes data from EHRs.
Instead, registries must develop the ability to extract information
from the EHR systems at each facility, or require manual entry from
providers. Additionally, many registries have sought clarity on when
their studies are considered research, rather than quality improvement
efforts. This confusion has slowed their use by hospitals and their
ability to make a meaningful contribution.
Post-market Data and Expedited Device Approval
Better post-market data--from registries and other sources--would
facilitate more effective FDA regulation across the total product life
cycle. For example, FDA has proposed an expedited access premarket
approval policy for devices that fill serious, unmet medical needs.
Under this program, FDA would implement a total-product-life-cycle
approach to regulation by accepting more uncertainty on some of the
effects of new products and require the answers to those questions from
post-market studies. As a result, FDA could accept smaller trials and
the use of surrogate endpoints or short followup on patients in the
premarket setting, with additional data collected after approval. This
approach--so long as it remains tailored to only those devices that
will significantly improve the options available for patients with
serious conditions--can help reduce the time to market of new products
without sacrificing the data collected on the products.
``real world'' and post-market data
As FDA continues to implement a total-product-life-cycle approach
to regulation, better post-market controls and data can provide
assurances that any problems not detected by clinical trials are
promptly identified after approval. The FDA may be reluctant to approve
products more quickly if the agency is not confident that safety
problems will be detected in the post-market setting. At present, the
ability to assess product performance based on claims, electronic
health record and registry data is extremely limited (see, for example,
Madigan et al.'s description of varying results depending on the choice
of database).\23\
As previously stated, developing the infrastructure to more
efficiently collect and evaluate such information could substantially
reduce the long-term cost of acquiring clinical data. It may also allow
for evaluation of products across a wider range of conditions and
patient populations. However, it is important to note that building
this capacity will require investment in both infrastructure and
methods development.
Along with the use of registries to gather this information,
systems such as the FDA's post-market surveillance Sentinel Initiative
can provide better longitudinal data on product performance. Sentinel,
a distributed database that includes data from 178 million individuals,
illustrates the potential of real world evidence, but also its
challenges.\24\ The FDA already uses Sentinel to evaluate drug safety,
and Congress instructed the agency to expand this initiative to
devices. However, the Sentinel program relies primarily on claims data,
which lack information on the specific device used in care. If
integrated into claims, the new unique device identifier (UDI) system
can provide that specificity by clearly indicating the manufacturer and
model of the device used. The Centers for Medicare & Medicaid Services
must issue regulations to update the claims form to include this
information so that FDA can utilize Sentinel--in accordance with the
congressional directive--to evaluate device safety.
In addition, a report released last month from a multi-stakeholder
group of medical device safety experts recommended several reforms and
investments to support more robust data on the performance of new
technologies after approval. For example, the National Medical Device
Post-market Surveillance System Planning Board endorsed the inclusion
of documenting UDI in claims to develop better data on the long-term
performance of medical devices. In addition, the Planning Board
recommended the development of a public-private partnership to advance,
oversee and coordinate efforts to evaluate the quality of marketed
devices. Congress should evaluate the Planning Board proposal and
encourage all stakeholders--including FDA, CMS, manufacturers,
clinicians and health plans--to develop a more robust post-market
surveillance infrastructure.
systemic fda challenges
FDA's most important resource is its staff, including physicians,
statisticians, scientists and biomedical engineers that review medical
product applications, data from clinical trials and post-market
information.
A 2012 Pew-funded report from the Partnership for Public Service
(PPS) found several challenges to FDA's hiring, recruitment and
retention of these scientific and medical experts. PPS recommended that
FDA develop targeted recruitment programs to fill its talent pipeline,
invest in career training and leadership development programs, and
implement strategies to reduce attrition rates.\25\
Perhaps the most commonly cited measure of FDA performance is drug
approval time. Recent studies have demonstrated that FDA approves drugs
more quickly than regulators in Europe and Canada.\8\ \26\ Moreover,
median time to approval today is substantially lower than prior to the
implementation of PDUFA goals.\27\ Over recent decades, the overall
success rate for New Drug Applications (NDAs) has been relatively
consistent (averaging 79 percent from 1993-2012), but the share of
drugs approved at the first action date has increased markedly (45
percent over 20 years, but 77 percent in 2011-12).\28\ To a large
extent that is a function of the quality of the applications.\29\ FDA
has some capacity to influence submission quality through its
communication with industry, either during individual meetings or
through guidance documents. According to a recent PwC survey of
industry executives, 78 percent responded that FDA has improved the
quality and frequency of its communications with industry over the last
2 years, and 76 percent responded that the agency provided ``actionable
feedback.'' \30\
Successive FDA user-fee agreements have provided the agency with
resources to facilitate the evaluation of medical products and have
established new FDA performance metrics and formal mechanisms for
interaction between the FDA and sponsors. Nevertheless, a frequently
cited barrier to medical product development is an absence of
predictability in the FDA's regulatory review processes.\31\ \32\ \33\
\34\ As part of negotiations to reauthorize the prescription drug and
medical device user fees through the 2012 Food and Drug Administration
Safety and Innovation Act (FDASIA), both industries highlighted
improving regulatory predictability as a major goal and, in the case of
devices, a ``paramount'' concern.\35\ \36\
Regulatory predictability may be defined as agency decisions that
are not arbitrary, arrived at through transparent procedures,
consistently enforced, and free of bias.\37\ However, discussions about
regulatory predictability frequently lack specificity. Efforts to
assess or improve predictability may be confounded by the complex
scientific and regulatory environment in which drug and device
regulation occurs. Moreover, this environment is not static; no two
products are exactly alike, and the understanding of disease changes
and improves over time, as does the science of evaluating product
performance. And science itself is unpredictable: the act of evaluating
a product may generate information that raises further questions or
undermines confidence in the outcome of a study, thus requiring further
investigation. Fundamentally, regulatory decisions involve value
judgments about the acceptable level of uncertainty in the data used to
assess both safety and efficacy.
An upcoming Pew report summarizes the results of an industry survey
and expert conference with industry and FDA leaders on predictability.
The survey showed concern about FDA processes and timing, but found
that a large majority agrees with FDA's ultimate decisions--saying the
FDA makes the appropriate decision on new medical products ``most or
all of the time.'' In addition, about 62 percent of the respondents
said FDA's data requirements are necessary in ``all or more cases,''
with only 2 percent saying the requirements were necessary in ``very
few cases.''
When probed further, most respondents to the survey as well as
workshop participants expressed concerns regarding the agency's
predictability. Thirty-eight percent of industry respondents said,
based on their personal experiences, that the FDA's regulatory review
process is ``completely or fairly'' predictable (higher among
biotechnology and pharmaceutical professionals and lower among medical
device professionals). The discrepancy among drug versus device
executives was a consistent pattern, perhaps attributable to the
greater diversity of medical devices products and companies and the
breadth of approaches to testing their safety and efficacy, as well as
staffing issues within CDRH, which the division acknowledged.
Overall, 68 percent of respondents said that such unpredictability
discouraged the development of new products. A third (36 percent) said
the agency strikes the right balance between speed and safety. Industry
professionals were divided on the degree to which they believed the
system needs to be fixed. Nearly half (49 percent) believe the agency's
product review systems need a ``complete or major overhaul.'' The same
number said the systems worked ``fine as-is'' or needed only ``minor
modifications.''
It is important to recognize that regulatory predictability is a
broad and subjective term used to describe a variety of issues.
Therefore, attempts to solve ``regulatory predictability'' are less
likely to succeed because the problem itself is not defined precisely
enough. Rather than relying on this broad diagnosis, stakeholders would
be better served to articulate issues regarding, for example,
communications, staff experience, or data accessibility.
To aid in that process, we briefly characterize several of these
commonly cited facets of unpredictability and potential solutions to
address them. These proposals reflect ideas raised by sponsors, FDA
officials, analysts, researchers, and other stakeholders during the
course of our research:

Sponsors sometimes assert that there is often a lack of clarity or
explicit rationale regarding the type and quantity of additional safety
and efficacy data that FDA staff requests. Specifically, several
sponsors asserted that such requests are manifestations of an inherent
and unwarranted ``risk-aversion'' on the part of FDA staff. Sponsors
assert that some officials lack an understanding about how much risk
the agency is willing to tolerate. As they submit documents to the
agency, FDA staff will request additional information to address
possible concerns with a product or learn more about how a drug will
affect patients. Sponsors contend that many of these data requests
would negligibly affect FDA's decisions but are burdensome and
expensive. Similarly, they assert that some data requests are too
academic and not germane to the safety and efficacy of a product.
Current and former FDA officials we spoke with contend that the FDA
must maintain some measure of flexibility when evaluating sponsors'
applications. Over the course of a product's lifecycle new information
may become available--from the scientific literature, from its
regulatory counterparts in other jurisdictions, among other places--
that compels the FDA to look at a sponsor's application in a new light.
Moreover, in the course of reviewing applications from other sponsors
on a similar product, and through post-marketing surveillance
monitoring, FDA reviewers identify potential safety and efficacy issues
with a product class and uses that information to make additional data
requests of sponsors. Because specific reference to other sponsor's
applications is prohibited by commercial confidentiality laws, FDA
staff cannot always be specific about the reasons underlying a
particular data request, leading to sponsor perceptions of FDA
capriciousness or arbitrariness.
To achieve greater predictability, our conference found substantial
support for the suggestion that the FDA should release all documents--
such as Complete Response Letters--that provide information on why the
agency requested additional information or declined to approve a
product. (Complete Response letters are effectively the FDA's
communication to a sponsor of why a product is not approved; currently
the FDA does not release these letters publicly.) That information will
help all companies understand the data sought for certain diseases and
about classes of medical products.
Most respondents (78 percent) suggested that investing in human
resources, such as training staff, would be a ``fairly'' or ``very''
effective strategy for improving FDA's review process, making this the
most popular proposal offered in the survey.
The FDA's centers for drugs and devices both have established a
number of programs and pathways that facilitate earlier and more
frequent interactions between sponsors and agency staff. When meeting
with the FDA about adaptive trial designs or other issues that are not
typical for a standard drug application, sponsors should request the
attendance and input of senior FDA leadership. Such input could provide
needed reassurance to reviewers and assuage their concerns with a
product review.
Inexperience submitting products for FDA review leads to sponsors
maintaining inaccurate expectations about data requirements and agency
processes, ultimately resulting in perceptions of unpredictability when
those expectations are not met. Small companies are especially
susceptible to this problem. A study by Booz Allen Hamilton found that
large companies obtain approval on their original submission 58 percent
of the time, whereas that is true for only 41 percent of small company
submissions.\29\ More recently, a PriceWaterhouseCoopers survey found
that large companies were more likely to avail themselves of
interactions with the FDA; smaller companies were more likely to rely
on guidance.\30\
Sponsors that have not previously submitted products to the FDA for
review may lack an accurate understanding of the data requirements and
agency processes. Moreover, many small companies fail to hire
experienced consultants and regulatory experts to assist with product
submissions. Without this help, companies may submit inadequate or
noncompliant submissions to the FDA.
Other measures provide insights on additional aspects of agency
operations, such as presentations to societies, consortia, industry and
government organizations (around 100 per month for the center for
drugs).\38\ Of particular interest may be issuance of FDA guidance
documents, which serve to communicate the agency's current thinking on
specific topics. The center for drugs, for example, issued 51 draft
guidances in 2014, but only 13 final guidances.\39\ Earlier years
follow a similar pattern. The reasons for this discrepancy are unclear.
It may be that the agency seeks a wide range of input during
development of a draft guidance, which then serves as an effective tool
for communicating with stakeholders. Alternatively, it may be that the
process for administrative clearance deters the agency from finalizing
guidances. Congress could evaluate the balance between finalizing
guidances and the potential opportunity cost of fewer new draft
guidances on other topics, and potentially identify administrative
simplifications that would facilitate finalization. A similar
investigation of the time required to develop and finalize a formal FDA
rule (often several years) might lead to solutions that would support
greater overall efficiency.
regulatory science and public private partnerships
FDA has focused on the need for better tools to inform its
decisionmaking at least since the Critical Path report in 2004, and
more recently through its Regulatory Science strategic plan and
associated initiatives.\40\ The regulatory science rubric is used by
the agency and stakeholders to refer both to the development of tools
and approaches for use by sponsors and to the development of approaches
the agency may use in decisionmaking.
Pew's predictability survey found strong support for investment in
regulatory science as a ``very or fairly effective'' means to improve
the review process.
Mittleman et al.\41\ provide an excellent overview of the
opportunities for precompetitive consortia, noting both their potential
and the need for more investment. They find that these organizations
succeed by bringing together industry, academics, government and
mission-driven non-profits to deliver on separate and shared interests.
However, these organizations require time and resources to produce
results. For example, the Biomarkers Consortium took nearly 2 years of
negotiations to bridge the divergent standards and practices, including
IP considerations, of various stakeholders. That organization has now
initiated 15 projects, with its first completed in 2009. In contrast
with the $2.7 billion European investment in the Innovative Medicines
Initiative, U.S. support of the various consortia has been limited.
While universities and government are not configured to develop
medicines, public-private partnerships have the potential to spur
innovation. For example, Pew's focus on antibiotic development has
shown that there are key scientific questions that could underpin a
resurgence in antibiotic discovery, but are currently the province of
neither industry nor academia. One barrier to progress, or at least to
efficient progress, is that academic scientists may not have complete
information about what avenues have been pursued by other researchers,
particularly those in industry. Even where needs are clear, there are
limits to the ability of current research funding mechanisms to
encourage progress on the most fundamental questions.
Pew has convened experts to identify barriers to scientific
breakthroughs in antibiotic drug discovery and develop a roadmap for
addressing them. That process is ongoing, but initial discussions have
identified factors such as inter-disciplinary expertise, co-location,
common mission/goals, and sustained funding efforts as crucial for
making headway. These are features that may be difficult to capture
with traditional ``bottom-up'' funding mechanisms.
conclusion
The medical products ecosystem continues to produce innovative
products that, in aggregate, benefit Americans and improve health.
Products with the greatest potential to address unmet medical needs
enjoy a variety of advantages that speed development and review. The
FDA, lawmakers, industry, clinicians, patients, venture capitalists,
and other interested stakeholders share complementary goals: ensuring
that patients have access to safe and effective novel medical products
and enabling U.S. companies to stay competitive.
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The Chairman. Thank you very much. Thanks for the excellent
testimony. We'll now begin a round of 5-minute questions.
Dr. Sullenger, the National Academies has done two studies
that show that 42 percent of the investigators' time on
research grants is spent on administrative matters. I asked the
head of the National Academies what he thought might be a
reasonable amount of time. He said it would vary depending on
the grant, but maybe 10 percent.
Congress appropriated $30 billion to the NIH, 80 percent of
which goes to extramural research mostly at universities.
Vanderbilt University did a study in conjunction with a report
that Senators Mikulski, Bennet, Burr and I asked for about
Federal regulation of higher education.
Vanderbilt, based on their figures, would roughly say that
a quarter of all the research dollars that they get goes to
administrative costs. That would be about $125 million out of
$500 million, more or less.
What's your reaction to that? What do you see at Duke, and
what suggestions do you have for reducing that problem? If we
could save billions of dollars there, that would be one place
to get more money for new investigations.
Mr. Sullenger. Thank you for the question, Senator
Alexander. I would say my general impression is it's a similar
number. We're spending increasing amounts of time on regulatory
issues. Some of them don't seem to even pass the commonsense
test, I would say, in some sense.
For example, in my group, we study blood coagulation. We
draw blood from healthy volunteers. But regulatory requirements
for doing that, which doesn't really put anybody at much risk,
is similar to you doing a clinical trial with a new drug. So at
some level, stratifying and applying some commonsense measures
to the regulatory issue would help a lot.
The other challenge with administrative burden goes back to
what the whole group or, at least, the panelists have
mentioned, which is the stress that we have on the NIH funding
system. It means that each investigator is writing many more
grants, going through all the process of administering, doing
the budgets for the grants, et cetera, which takes a tremendous
amount of time.
The math is pretty simple. It's basically that now it's
about half--we have about half the probability of getting a
grant as we did a decade ago. That means to get two or three
grants, we're writing four or eight times as many grants over a
4-year period to get the same amount of support for research.
The Chairman. I understand that. But what is your reaction
to the suggestion that the 42 percent figure, in terms of the
amount of time spent, might be closer to 10 percent? Does that
sound reasonable to you?
Mr. Sullenger. Ten percent may be tough. I think to get
there, what we have to think about--and one of the things we've
tried to do in our institute is to basically borrow from the
private sector some of the strategists they use, to say,

``Could we get sort of professional project leaders
who are much less expensive and much better trained to
do these things to reduce that burden.''

The Chairman. But if we only got it from 42 percent to 20
percent or 25 percent, we're talking billions of dollars of
Federal taxpayer dollars that could be used for research, not
necessarily as a substitute for increased funding, but as one
way to find more dollars.
Mr. Sullenger. I absolutely agree with that. I think that
reducing those burdens is a way to find a big cost savings, and
also let researchers spend their time on what they're trained
to really do, which is to do the science.
The Chairman. I want to stay within my time. Let me ask Mr.
Borisy this question, and others of you may want to talk about
it. Dr. Hamburg said at our hearing that the FDA had a record
number of new drug approvals last year and talked about the
breakthrough therapies program.
She said,

``The past calendar year, FDA approved 51 novel drugs
and biologics, the most in 20 years. Today, FDA's
average drug review times are consistently faster than
other advanced regulatory agencies around the world,
providing Americans earlier access to new innovative
drugs than patients in any other country.''

Any comment on that?
Mr. Borisy. I think those numbers are accurate. If you are
developing a drug in an area that will qualify for accelerated
approval or the breakthrough therapy designation, I think
that's a very productive interaction with the agency. If you
are out of those areas, then there becomes a lot more
uncertainty and a lot higher degree of questions.
The Chairman. Mr. Mussallem.
Mr. Mussallem. Yes, I think those numbers are accurate. I'm
not sure that that experience necessarily translates over to
the medical technology and diagnostics side. By and large,
although those trends are positive and there are some great
moves on the part of leadership in the right direction, there
has not been that sort of trajectory that's going on in
devices.
The Chairman. Thank you. My 5 minutes is up.
Senator Murray.
Senator Murray. Thank you very much, Mr. Chairman.
Mr. Mussallem, let me start with you. Your company has made
some really significant advances in medical device product
development. Your testimony talked about both the regulatory
challenges you face as well as the progress that is being made
at the FDA.
Can you tell us more about how you have seen FDA engaging
with developers and the effect that it's having on the
development of new therapies?
Mr. Mussallem. Yes. I'm very encouraged by what's going on
with the leadership of FDA, particularly on the device side.
Dr. Shuren and company have reached out to the industry and
really tried to advance an agenda that is responsive to the
feedback that they've gotten. Frankly, they've been
disappointed with what's happened in the past, and trends are
going in the right direction.
I do think also that they're managing quite a large
bureaucracy, and it's not so easy to move sort of the day in
and day out bureaucracy at the same pace that leadership is
moving, which is why we encourage that to continue. There's a
particular initiative called MDIC, which is a public and
private partnership, which really gets deeper into regulatory
science which could be a really good example of the way to make
advancements.
Senator Murray. Thank you.
Mr. Coukell, in your written testimony, you discussed
innovative ways to perform clinical trials so that trials are
more flexible and efficient. You stressed that the data
collected through robust clinical trials is critical and
provides patients and healthcare providers the information they
need so they can make well-informed decisions.
Can you discuss in more detail how we can move forward with
innovative clinical trials without compromising the data needed
to help patients and healthcare providers make informed
decisions about their products?
Mr. Coukell. Thank you for that question. I think that the
key point is that the randomized trial has been an essential
tool in figuring out if something works, and we have a legacy
of examples where we didn't do a randomized trial and only
later learned that it was not working or causing harm.
But it has become increasingly expensive to do these
trials. I talked in my testimony about ways that we could get
better at pulling information out of the electronic health
record to do trials. We also need to get faster at the
contracting process, at the consent process, at the
institutional review board process. All of these things could
help streamline trials.
We could use more clinical trial networks to get better at
finding patients. The Scandinavian trial that I mentioned in my
statement enrolled half of all patients getting that particular
procedure. If we could populate our trials faster, just take
advantage of the patients that are already in our healthcare
system now, the time it would take to do a trial--and time is
money--would be so much shorter.
Senator Murray. I've heard from a lot of families in my
home State of Washington about the terrible situation of a
loved one having a disease and there's no treatment available.
I know we all have, which is part of the reason why we in
Congress put in place the FDA breakthrough designation and
accelerated drug approval in 2012.
Can you talk a little bit about how these new authorities
are working to help meet the serious medical needs of patients?
Mr. Coukell. The breakthrough therapy is widely viewed to
have been a success. It's essentially an all hands on deck
approach, where if a new drug is identified as being especially
promising or an especially important advance, the agency puts
everything in service to get that review done faster. It
doesn't change the upstream evidentiary standard. But it does
help get those products to market more quickly.
Senator Murray. One last question for you. We're all about
helping patients. That's basically the backbone of everything
we do. As I mentioned earlier, the perspective of patients and
their families has to be prioritized in the product development
and approval process.
I know you've spent a lot of time examining that issue. Can
you tell us more about how you believe patients can be more
involved in this process?
Mr. Coukell. Senator, I think you're absolutely right. At
the end of the day, what matters is the patient experience, and
that's suitable for some indications and not others. It doesn't
matter too much for a blood pressure drug. But if you were
treating something like arthritis, understanding how it has
actually influenced the patient's life, their function, their
quality of life is really fundamentally the most important
thing.
Those patient-reported outcomes are still challenging to
measure and challenging to know how much of a change matters.
So measurement remains hard. But building those kinds of things
into our assessment of new medical technologies is really
important.
Senator Murray. Thank you. I really appreciate that.
My time is up, Mr. Chairman.
The Chairman. Thank you, Senator Murray.
Senator Cassidy and then Senator Mikulski.

Statement of Senator Cassidy

Senator Cassidy. Implicit in what you were saying is that
different divisions of the FDA have different rates of
approval.
I have something from the Manhattan Institute which shows
that oncology and antiviral has a median time and a mean time
of approval substantially better than that for neurology,
cardiovascular, and renal.
I'm trying to understand why some divisions at FDA do
really well, and others, at least judged by time to approval,
do far less well. Do you have thoughts on that? Because
implicit in your testimony is that people acknowledge that
there's differences--I think you mentioned several times
diabetes and Alzheimer's as being something--I think it was
your testimony--as having delayed approval times.
Any thoughts on that? Can we understand why some divisions
do well and others do poorly?
Mr. Coukell. I think it's a crucial question, and I'm not
sure I have a good answer. Part of it is leadership and
engagement with the stakeholder community. I think that one of
the things that we have seen happening, in particular, over the
past 6 years is this increasing focus on public-private
partnerships to develop the kinds of regulatory tools that we
need to assess----
Senator Cassidy. I see that oncology has like 200 days,
whereas neurology has close to 600, as a median time to
approval by FDA division. Again, your survey seemed to find
that different groups found that, oh, yes, the FDA is working
well, and other groups found that FDA is not working very well.
So if you did a crosstab, would the people that found FDA
working well--would those be the oncologic researchers? And
those that found it working less well--would those be the
diabetes researchers?
Sir, you're shaking your head. You're nodding as if you
agree. Can you comment on this?
Mr. Borisy. Yes. I think you would tend to find those
differences by the different groupings within the agency. Some
of those are people related, cultural related. It is a very
large agency, as was mentioned.
Senator Cassidy. I keep hearing people and leadership. Dr.
Hamburg, for example, has done a great job. We can see all
these improvements. So it tells me that it's division
leadership. It's not necessarily overall leadership. I'm not
putting you on the spot, because I don't want to sabotage any
approvals that you have currently before a division.
[Laughter.]
But I am struck that there must be some sublevel division
that is not working as well, that is keeping needed drugs for
diabetes, et cetera, from being approved in a more rapid
fashion.
Mr. Borisy. I would agree with your statement that there's
been strong senior level leadership, and we need to pay
attention to making sure that we continue to have consistent
senior leadership at the agency going forward. A question is
how can we help the agency from a human resources perspective,
from a--hiring the talent that's necessary throughout the
agency, to be able to take the----
Senator Cassidy. First, let me say somebody's testimony
spoke--and maybe Pew's--as to how we should have people
surveyed, so there should be more training. In another
document, in another hearing, I think I read that the average
person studies for 2 years before they become a reviewer. I'm
thinking, ``Oh, my gosh. If we have more training than 2 more
years, this is a master's.'' The University of Maryland now has
master's training for becoming an FDA reviewer.
At some point, there has to be something besides training
which is a solution. I guess I'm trying to put my finger on
what that training is.
Mike.
Mr. Mussallem. In a slightly related subject, there's a
vast difference between devices and diagnostics inside the FDA,
and it goes on in drugs and biologics. That's just because
there's a different development process, and it deserves a
different regulatory system. Devices are developed with
engineers and scientists working closely with doctors, and then
there's an iterative process in which there's a rapid
improvement that takes place rather than a single entity----
Senator Cassidy. Can I interrupt you because I'm almost out
of time.
Mr. Mussallem. Yes.
Senator Cassidy. I've also noted, again in someone's
testimony--they're jumbled together--that in some cases, there
is a sort of collaborative iterative process. In the other,
they look for guidance, and it's the guidance which is not
quite as useful.
Are there some divisions that are better at giving this
constant communication, and are there others that put out
guidance that is like reading tea leaves and you're not quite
sure? Is that part of what this leadership is about? We need to
understand why FDA works really well for onc and poorly for
Alzheimer's drugs. Do you follow what I'm saying? Are there
some divisions that are better, given this iterative
interactive process and others not?
Mr. Borisy. There are some divisions where the accelerated
approval pathway is more directly applicable to. In other
words, just the diseases and the conditions those divisions are
treating have been under accelerated approval. Then with
breakthrough therapy that is having the clear sense of
Congress, as was legislated in FDASIA, that made a big
difference throughout the agency, not only at the senior
leadership level, but throughout the depth of the agency.
The communication of policy from Congress does have a big
effect on the agency. Different groups have had more experience
with the accelerated approval because the way that's written,
it applies more to some disease areas than to others.
Senator Cassidy. I yield back. Thank you.
The Chairman. Thank you, Senator Cassidy.
Senator Mikulski.

Statement of Senator Mikulski

Senator Mikulski. Thank you, Mr. Chairman. I really want to
thank this panel for a very content-rich testimony.
My interest in this is threefold. No. 1 is to improve the
lives, save the lives of people both in our own country and
around the world, to have clinical products that actually
improve their lives. I'm also interested in the jobs that are
created by having them right here in the United States of
America.
Mr. Borisy, your description of your life and your
companies are very similar to Maryland. We have FDA, we have
NIH, and great institutions at Maryland, and Hopkins, and then,
of course, our vibrant biotech industry. But the other is also
to be able to export products, because if they do have the FDA
approval, we can sell easily abroad, particularly to countries
that don't have the FDA. So that's where I come in.
Let me go to my questions. Much has been said about FDA and
its approval process. My question is this. In the approval
process at FDA, do you feel that not only does it require
leadership, but certainty of leadership, and then certainty of
financial resources? In other words, that FDA really knows what
it's going to get, and it can really count on it, that NIH and
its institute directors, not only the CEO of NIH, the director,
but the institutes.
Do you feel that reliability, certainty, and predictability
of what they will get from the government budget is essential
to both the recruitment, hiring, and kind of the experience
needed in the regulatory process?
Mr. Borisy, you and then Mr. Mussallem.
Mr. Borisy. Yes. Stability at the agency, both in terms of
leadership and resources so that we can have a stable and
predictable regulatory process is very important.
Senator Mikulski. Why do you say that?
Mr. Borisy. In creating innovation, in funding new
companies, which we do at Third Rock, we're embarking on a
journey that's a 10- to 15-year product development cycle that
will cost--the total journey--north of a billion dollars. That
is a long time and a lot of money.
When we start that in the beginning, we're trying to say:
What is the path of that going forward? How much will be spent
when? When will we get to what point? When will we be able to
show things to convince other people downstream that value has
been created?
So much of that interaction is with the agency. Knowing
what those paths will be, knowing how much it will take, and
what the hurdles will be is crucial. If those change
unexpectedly, it makes it impossible to be able to invest that
type of resources over those types of timelines.
Senator Mikulski. Mr. Mussallem.
Mr. Mussallem. Yes. In terms of creating jobs and making a
commitment from the private sector, certainty is very helpful,
and so we ask for a certainty in our regulatory processes. If
you just move upstream from that, the point that you're making,
Senator, about them having certainty in their funding is
certainly aligned with that.
If they have the ability to count on the resources, and
they can make the investments in training to keep up with the
rapid advancements and technology that they're going to be
constantly dealing with in the future, it puts them in a far
better position to be able to deliver what we need from them,
which is an efficient process that really, in a timely fashion,
moves through these processes.
Senator Mikulski. First of all, respect to the people who
work there, because their morale is absolutely important.
There's a whole culture in Washington--let's blame the
bureaucrat, let's not fund them, and then let's complain when
the job doesn't get done--so starting with respect. But
resources can't be like a one-shot deal. It has to have
continuity and stability.
No. 3 is targeted reform. I'm very much interested in the
fact--what you said, Mr. Coukell, which is that one set of
processes costs hundreds of millions of dollars. Using new
techniques could reduce it to like $300,000. That's a stunning
number.
Are you saying that registries would be the answer to all
problems? Or what would be the limitations of registries?
Mr. Coukell. I wish there was a single answer to the
problems.
Senator Mikulski. So do I.
Mr. Coukell. Unfortunately, there isn't. I think that being
able to get better at extracting the information from our
healthcare system, finding patients, putting them into trials,
learning before and after a product reaches market from the
information that's in the electronic health record, and being
able to do it in a more cost effective way would be a very
important contribution. It, unfortunately, won't solve all
problems, and we have to take a broad-based look at other
approaches to reducing the cost of acquiring clinical data.
Senator Mikulski. My time is up. Mr. Chairman and
colleagues, we have a big opportunity, that in this budget
debate we could end sequester, which is very demoralizing and
disruptive. We want disruptive technologies, but not disruption
in resources.
We could also lift the caps. I know there's a big move to
lift the caps in defense, and, of course, we worry about the
threats to America. But there are these other threats that
these men and women have devoted their lives to fighting, the
threats of arthritis, depression, and Alzheimer's and all these
things, and cystic fibrosis.
I think we ought to just lift the caps and end sequester,
it would be a big down payment on what is being recommended
here.
The Chairman. Thank you, Senator Mikulski.
Senator Burr.
Senator Burr. Thank you, Mr. Chairman.
Mr. Coukell, should the FDA be required to use foreign
clinical data as they review and approve new applications?
Mr. Coukell. The short answer, sir, is no. If a trial was
conducted outside the United States, and it was a patient
population that wasn't like ours, or we had reason to believe
the trial was badly conducted, we wouldn't want that to go into
our evaluation of a product.
But should they be able to, and do they use clinical data
that's generated outside the United States? Absolutely.
Senator Burr. They've had that ability since 1997 and
rarely chose to do it. And in cases where applicants have asked
the FDA to use foreign clinical data, because the population
was similar or there was merit to it, the FDA's response has
been we weren't involved in the consultation of how the trial
was designed. Therefore, we can't use the data. Do you call
that cooperative and helpful?
Mr. Coukell. Sir, I served for a couple of years on the
Cardiovascular and Renal Drugs Advisory Committee, and I would
say virtually every product we looked at brought data from both
the United States and outside the United States.
Senator Burr. Mike, the FDA Act of 1997 required the FDA to
eliminate unnecessary burdens that may delay the marketing of
beneficial new products. But the statutory requirements for
clearance and approval remained exactly the same. The goal of
least burdensome requirements was to streamline the regulatory
process and reduce burdens to improve patient access to
breakthrough therapies.
In your opinion, is the letter and the spirit of the least
burdensome provision being applied on a day-to-day basis at the
agency?
Mr. Mussallem. Thank you, Senator. You're onto a very key
point. It's been there. It's been in the background. But my
sense is that least burdensome needs to be revitalized. It
needs to be focused on.
I think of all the new reviewers that have come into FDA as
part of the recent funding from industry. I wonder how much
training they've really had on least burdensome and how to
really bring that to practice. There's something there that's
valuable, and it's one that we should encourage FDA to look at
even more seriously than they do today.
Senator Burr. Thank you.
Dr. Sullenger, earlier this year, the Chairman and I penned
our Innovation for Healthier Americans report in which we asked
the simple but critical question: How can we do medical product
research and development better on behalf of America's
patients?
Based on your experiences across the pipeline, are there
specific proposals or ideas that you would encourage us to
focus on in this committee as we examine that critical
question?
Mr. Sullenger. One of the things that we're very interested
in is how do we educate people to be thinking along those lines
more. Traditionally, I would say most of our science training
isn't focused in this translational space that you're alluding
to, which is how do we take innovation and apply it to help
improve healthcare.
I was fortunate enough that--there have been some pilot
programs along this way. The Howard Hughes Medical Institute
actually had a pilot program of trying to train scientists to
work more at the medical interface. They hoped that the NIH
would pick up that program after they seeded it, and because of
the budget issues, they haven't.
One of the practical things I would recommend is
considering sort of training this next workforce to do exactly
what you're saying, to teach scientists to think at that
interface versus doing pure fundamental basic science. We need
both. Just like we need chemists and chemical engineers, we
need molecular scientists and we need applied molecular
scientists.
Senator Burr. We're in a new area, aren't we?
Mr. Sullenger. Absolutely.
Senator Burr. Mr. Borisy, in your testimony, you note that
medical device and diagnostic venture capital investment was
down 27 percent from its peak in 2008 of $3.6 billion, and that
in 2014, first-time investments in medical device companies
fell to the lowest number of companies since 1995. What do you
believe to be the largest contributing factor to that decline?
Mr. Borisy. It's a very real decline. Actually, in our own
funds, we've made several device investments in our first fund,
and we're now down to one single investment that we're making
out of our current fund. It's a double jeopardy of an unclear
regulatory hurdle, which has been lengthening, coupled with an
unclear reimbursement hurdle.
In both medical devices and diagnostics, after the product
is approved, it conventionally takes 2 to 5 years of hashing
out and debate both with Medicare and private payers to secure
reimbursement. If you increase the regulatory requirements,
which is what has happened over the past decade in devices, but
you have unclarity in how it's going to get paid for, then the
math just doesn't work, and then the investments can't flow.
Senator Burr. Mr. Chairman, if I could just ask one more
question, and it's a hypothetical question for Dr. Sullenger.
Should the FDA be able to regulate anything that I take
from my body, don't alter, and reintroduce into my body?
Mr. Sullenger. That's a good question. I don't know that--I
haven't thought exactly about that. But one of the programs we
look at is bone marrow and cord blood transplant for patients.
And, essentially, it's doing those types of procedures.
We take cord blood at Duke from babies and then re-implant
it to them after they're born, and there is a regulatory
requirement for that. It's less than if we've manipulated or
changed those cells, but there's definitely some regulatory
requirements. I could seek advice from the people doing that at
Duke, but I'm not an expert in it.
Senator Burr. I'd just pose to all of you as we talk about
this different path forward, this different world, that we're
going to be faced with decisions that don't look like the
decisions today. They're not black and they're not white. I
could make a tremendous case today that why should the FDA
regulate what I take from my body and put back in my body, and
I think that the body is the greatest source of cures in the
future. It's just understanding what it is you use and where
you use it.
I thank the Chairman.
The Chairman. Thank you, Senator Burr.
Senator Bennet.

Statement of Senator Bennet

Senator Bennet. Thank you, Mr. Chairman.
Mr. Borisy, just picking up a little bit on Senator Burr's
previous question, a number of years ago, he and I and Senator
Hatch, I think, all heard that venture capital--or from our
bioscience communities that venture capital was no longer
investing in the United States in this area. It was going to
Europe and it was going to Asia. And they came and said, ``Is
there something you can do to help us with that?'' And that
became breakthrough therapies.
I think your testimony today, and the rest of the
witnesses' testimony, is that it's actually been a pretty big
success. I wonder if you could talk about, in very practical
terms, how that has helped your ability to invest here in the
United States.
And, Mr. Mussallem, I'll come to you to talk about your
ideas for the breakthrough therapy technology designation and
what that might look like.
Mr. Borisy, I'll start with you. You described it as
productive interaction with the agency--is what you said around
breakthrough.
Mr. Borisy. In creating a new medical product and a new
drug, it's this long path and more than a billion dollars to
create it. As a venture capital firm--and we are one of the
larger venture capital firms, and we put more money into a
typical investment than most--we might invest $30 million or
$40 million or $50 million into a company. That's only a small
piece along that billion dollar journey.
Getting to a point of clinical proof of concept, where you
clearly know that you've done something important for a
patient, that often is going to cost on the order of $200
million to $250 million. So when we create a company and invest
in a company, we're looking to understand the path of what
partners might join us on that, whether those are larger
companies or whether those are public markets.
Part of what they want to know is: Will we have clarity
that you really have done something that's important? Because
one of the great things of the overall ecosystem here in
America is that if you have shown something in patients, that
it really is doing something that people believe is important,
they'll value that very highly, and that makes this whole set
of equations in this ecosystem work.
Having breakthrough therapy, having accelerated approval,
having those tools so that in the areas where they apply, you
know that with those initial clinical studies and the results
you get, if the science and medicine is good, if the results
are worthy of it, then everybody in the ecosystem values what
has been created.
That makes it possible that those really early stage
investments, when we're investing for things just coming out of
academia and doing that initial work, can be done, because we
don't have to go all the way--the 10 to 15 years to approval.
We can fund it for the 5 years, 6 years to that clinical proof
of concept, and so the equation is solved. On medical devices,
those equations aren't solving right now, because everything is
too unclear.
Senator Bennet. Mr. Mussallem.
Mr. Mussallem. Yes. Mr. Borisy makes great points. Thanks,
Senator. You're onto an important theme. We can take some of
the lessons that have been learned on the drug side for
breakthrough therapies and apply it to the medical technology
and device side.
Today, we don't have that sort of pathway. I would suggest
that an expedited pathway for truly important medical
technologies that are really transformative and breakthrough
should be adopted, and that could make a difference.
You could get bogged down if you try to move every medical
device through that sort of a system. But for the ones that are
most important, there's a big positive that's associated with
that that can make for the kind of policy success that we've
seen on the drug side.
Senator Bennet. Somebody testified--it may have been you,
Mr. Borisy--that the breakthrough sort of--that the message
from Congress had been heard by the FDA, not just at the top,
but all the way through the agency. Can you talk a little bit
more about that, too, as we think about cultural change?
Mr. Borisy. That's a very important point, because when
FDASIA was being passed that authorized the breakthrough
therapy designation, a lot of the arguments or discussion going
on at the time said: Why does this need to happen? The agency
already has these authorities.
Yet we can see that having had that in an act of Congress,
in FDASIA, establishing the breakthrough therapy really has had
a dramatic effect. That goes directly into what I do in new
company creation.
When we think about different areas, when we're just
talking about a breakthrough therapy for medical devices, I
know a lot of thought has been going into anti-bacterial--to
bacterial resistance and also can go into other areas, as has
been mentioned, diabetes, obesity, depression, Alzheimer's,
places where you can say can we create clearly understood
patient populations, precision medicine, the right drug for the
right patient.
If we can get clear pathways so it's limited populations,
where one can understand and deploy the successful lessons of
breakthrough therapy, then that act of Congress really had a
tremendous effect across the agency.
Senator Bennet. Thank you to the panel. I'm out of time.
Mr. Chairman, thank you very much for holding this hearing.
I hope in the coming weeks, as we work together to figure out
what the next generation is, that we'll have the chance to work
together on it. It's very exciting.
Thank you.
The Chairman. Thank you, Senator Bennet.
Senator Franken.

Statement of Senator Franken

Senator Franken. Thank you, Mr. Chairman.
Mr. Mussallem, you mentioned in your testimony here the
Medical Device Innovation Consortium, which kind of started
with the LifeScience Alley in Minnesota, working with the FDA.
When Commissioner Hamburg was here, I asked her how public-
private partnerships like the MDIC help to improve relations
between regulators and the industry. In your written testimony,
you mentioned that Edwards Lifesciences has seen positive
improvement in its dealings with the FDA.
How can we expand the MDIC model to continue to foster the
strong positive relationships between industry and regulators?
And can you describe how it has improved thus far?
Mr. Mussallem. Thank you, Senator. You're onto something. I
may not be an expert here in the statutory limitations in terms
of conversations between regulators and companies, but through
this public-private partnership, we have a chance to have
intimate conversations about regulatory science and how to do
it better and how to have an open and honest dialog about
what's working and what could be better. I think that the
agency and the industry finds this kind of dialog really
refreshing, and there's learning that comes from that.
One of the things most tangible for me is we're working now
on a tool to be able to incorporate the patient's voice somehow
into the regulatory process, because that's been missing in the
past. That's one that comes to life very specifically when you
work on these breakthrough technologies, in particular.
Senator Franken. When I first came to the Senate and
started studying these kinds of issues, I saw the different
culture between the regulators, of course, and the industry,
and this public-private partnership--and this is the first of
its kind--seems to be very helpful.
Mr. Coukell, in your testimony, you discuss several ways to
improve clinical trial efficiency, and one of them is by
streamlining the institutional review board, the IRB process.
My understanding is that under current law, if a medical device
company is testing a device in multiple locations, they need to
get IRB approval in each location where they're conducting the
trial.
You suggested that this process could be centralized in a
single national IRB in order to improve efficiencies. Could you
elaborate on that?
Mr. Coukell. Yes, sir. One of many steps that takes time
when building a clinical trial is going to the institutional
review board to review the trial from a perspective of patient
safety. As you say, for medical devices, now the law requires
that that be done locally. There are examples in other
therapeutic areas of using a single centralized board, and that
is one thing that could speed up the process of standing up a
new trial, if that prohibition on centralizing was removed.
Senator Franken. Thank you. You also talked about the role
that disease and device registries can play in making data
collection more efficient. Mr. Mussallem testified that his
company used a registry, a large data base of patient
information, as a key part of getting one of his products
approved for a new use. You talked about a trial in Sweden
where researchers were able to leverage an existing
cardiovascular disease registry to study a lot of patients for
a fraction of what it would cost in the United States.
What are the barriers to expanding the use of registries in
the medical device approval process?
Mr. Coukell. There are several. One is getting the data
into the database. Right now, for a lot of these registries, it
requires somebody to hand enter it. In some cases, it's taking
more time to enter the data in the registry than it is to
actually carry out the procedure. So if we were better at
pulling that from the electronic health record, or at least
some of the data from the electronic health record, it would
reduce the cost of operating the registry.
We also have to recognize that right now, we're building
them one at a time, and we're doing it in a costly way. We need
a sustainable funding model that will let us operate them at a
lower cost.
Senator Franken. Thank you. I was going to ask Mr.
Mussallem about his opinion on registries, but----
Mr. Mussallem. Just quickly, it's a very powerful tool. It
can really work. Allan said it well. We need not to overreach
for this--try and find really the data elements you really
need, and if you can automatically populate it so you don't
make this another big administrative burden for hospitals.
Our case was a perfect one. It actually takes twice or
three times as long to fill out the registry as it does to do
the case, and that's not helpful. But there are best examples
that can be applied, and this can really be powerful, because
by being able to collect vast amounts of information on all the
patients that are being treated, you can make some very
informed decisions on efficacy and safety, for that matter.
Senator Franken. Thank you.
Thank you, Mr. Chairman. We probably should do a hearing
sometime on electronic medical records. Oh, we just did. I'm
sorry.
The Chairman. We'll do some more. Actually, we're going to
focus more on electronic medical records. Based on that hearing
we had, there's a lot of interest on both sides, and I talked
with the acting director of CMS, who is interested in taking
some steps. That's probably an area that we might work on and
see if we can get a result.
Senator Warren.

Statement of Senator Warren

Senator Warren. Thank you, Mr. Chairman.
Every single Member of Congress I've spoken with says that
they support NIH and they support more medical research. But
medical research takes money, and Congress has done absolutely
nothing to actually get more money into the agency. In fact,
for over 10 years, Congress has been choking off vital funding
for medical research and has reduced the buying power of the
National Institutes of Health by nearly 25 percent.
All of you work in different parts of the American system
of medical innovation. Can you tell me in just a few words how
gutting NIH funding over the last decade has affected your
sector?
Mr. Borisy, could I start with you?
Mr. Borisy. Yes. Our historical investment in NIH has been
absolutely the basis of our life sciences ecosystem and all the
innovation that we have here in this country and is absolutely
essential for the future.
The diminishing of resources that we're facing now--I see
it in two ways that it's affecting. One is going to be long
term. There's obviously great breakthroughs in science and
medicine that have been happening from the investments that
we've made over the past decades. Those are still good right
now.
But those aren't going to be there in 10 or 20 years. It's
a long-term cost to one of the most dynamic sectors of our
economy and also that does so many things for patients.
A second thing, which I will admit in the short term is
beneficial, but is not good for the ecosystem in the long
term--when I'm looking to hire people now, I'm able to hire
people that would have been getting--would have been the new
stars, the rising stars, the people that would be getting the
junior faculty positions. I'm also able to hire people out of
the more senior faculty positions. The best talent that used to
be going into academia, I am now able to hire into the
companies that we're creating.
This is good in the short term for the companies. It's not
good in the long term, because these people, in the past, would
have gone on to amazing academic efforts, which would have
spawned many, many companies, many, many innovations. So you're
seeing that it's a direct effect.
Senator Warren. Thank you. This is very powerful, but I'm
also going to have to ask you to be short if you can.
Mr. Sullenger, could you just add something from your
field?
Mr. Sullenger. Yes. From being on the academic side, it's
been crippling, to be blunt. I would echo several of the things
that my colleagues are saying. Not only are we losing people
from the academic sector to the private sector, but we're
losing them to other countries. Now we're having a loss of our
best and brightest, who are leaving the United States to go to
Asia because they're investing more. It's been crippling, to be
sure.
Senator Warren. Thank you.
Mr. Mussallem, could you add something?
Mr. Mussallem. Yes. I believe NIH funding is a critical
element, and it really has a great return on investment. That
early investment in research answers some key questions that
then causes the private sector, like us, to jump in and move
products to patients, so there's a return on investment. When
you get that early research right and you answer some tough
questions, then you encourage others to follow.
Senator Warren. A critical part of the pipeline.
Mr. Coukell.
Mr. Coukell. In antibiotic development, which is a
particular focus for us, we have a 30-year drought of new
drugs, and we have some basic upstream science questions that
really need to be answered if we're going to jumpstart the
pipeline. There are questions that companies aren't in a
position anymore to address.
Senator Warren. I want to thank all of you. The House
Republican budget and the Senate Republican budget were both
released last week, and both say that they support medical
research funding. But what the Republican budgets actually do
is lower the budget caps that are already crushing our research
agencies, making it likely that agencies like NIH would see
cuts, not increases, under these plans.
Chairman Upton, who is leading the push in the House for
FDA reform, says he cares about research, too, and says that
the NIH needs more funding. But his draft bill, called 21st
Century Cures, doesn't provide a single new dollar from
Congress for NIH, not one dollar. Talk is cheap.
Earlier this year, I introduced a proposal to try to fix
this problem. The Medical Innovation Act would boost the NIH
budget by about 20 percent, and it achieves that increase
without raising taxes, without gutting vital programs, and
without adding to the deficit. More than 30 nonpolitical
doctor, patient, and scientific organizations, like the
American College of Surgeons, the National Women's Health
Network, and the Dana-Farber Cancer Institute, have supported
it.
There's no reason that every Republican, Democrat, and
Independent in Congress shouldn't be able to support it. If
people don't like this idea, then they should bring other
solutions to the table. But let's be clear. It doesn't matter
what Republicans say about supporting innovation if their
budgets actually cut support for NIH. It doesn't matter that
House Republicans put the word, cure, in the name of a bill if
the bill doesn't put one new dollar from Congress into NIH to
help fund those cures.
Something needs to change. Families are losing loved ones
to incurable and untreatable diseases while we do nothing. It
is time for Congress to stop talking about increasing medical
research funding and actually do something about it. People are
counting on us.
Thank you, Mr. Chairman.
The Chairman. Thank you, Senator Warren.
I want to thank the witnesses. Several Senators said as
they left how--as Senator Mikulski said--content-rich the
testimony has been. I want to thank Senator Murray for working
together with me to do this.
I'll ask Senator Murray if she has any further comments to
make, and then we'll conclude the hearing.
Senator Murray. Thank you very much, Mr. Chairman, and I am
very worried about sequestration and budget cuts and the impact
on our ability to make sure our families have the cures that
they are really counting on. We've seen a lot of advances in
medical innovation that have improved the health of families
and helped our economy. So it really is critical that we meet
these challenges that have been outlined today by this
excellent panel, and I really appreciate your input.
Mr. Chairman, I look forward to working with you on finding
bipartisan ways to continue the success we've had in the past
to advance medical innovation.
The Chairman. Thank you, Senator Murray.
These things occur to me listening to what was said today.
Reimbursement is something we need to focus on. The acting head
of CMS mentioned, I believe, that the cost of reimbursing for
hepatitis C grew from a few hundred million last year to $6
billion, a great success, a cure. But that's a lot of money.
Another company told me that while they're losing hundreds
of millions of dollars a year, they're producing a new
breakthrough therapy that will cure a dreaded disease. Its
annual cost is going to be a few hundred thousand dollars.
These are things we want to do. But we have a lot of tough
choices coming up as we think about reimbursement in the
future.
It was important to hear that attention from Congress
matters. The point that the FDA--the breakthrough authorities
that it needed were already in the law, but the fact that the
new law came in seemed to put an emphasis on it. That's useful
to us.
It's important, too, in terms of the funding, on the point
of increasing funding for NIH, there is widespread--well, I'll
just speak for myself. I think we should do that.
It would be poor management not to pay attention to the
National Academies saying that of the $24 billion we spend in
extramural research, mostly at research universities every
year, 42 percent of it goes for administrative costs. If we can
get that down to 32 percent, that's $2 billion or $3 billion
more. That's real money that we're already appropriating, and I
hope we can work together to also do that while we're talking
about increasing the total amount.
Then it's inescapable that if we're looking at our budget,
the side of the budget that has to do with military spending,
cancer research, NIH, is about level funding over the next 10
years, more or less. The side that has to do with mandatory
entitlement spending goes up 86 percent over the next 10 years.
Yet Democrats and Republicans are wary of doing anything about
this.
I've said many times the fact is unless we do something
about this, we'll never be able to do anything about this. It's
going to squeeze out the money that would go for all the things
we're talking about today. That's a spirited discussion that we
can continue to have.
But I would ask, finally, that each of you, after you
leave, if you reflect on anything that you'd like to say to us
in terms of specific steps you'd like for the Congress to take,
I hope you would do that.
I have a little ritual I have to go through at the end
here, and it's written on this piece of paper.
The hearing record will remain open for 10 days. Members
may submit additional information and questions for the record
within that time if they would like.
The next hearing on medical innovation is tentatively
scheduled for April 28th.
Thank you for being here. The committee will stand
adjourned.
[Additional Material follows.]

ADDITIONAL MATERIAL

Duke University Medical Center,
April 28, 2015.

Hon. Lamar Alexander, Chairman,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, DC 20510.

Dear Chairman Alexander: As director of the Duke Translational
Research Institute and professor of surgery at Duke University Medical
Center, I am pleased to submit additional feedback following the March
24, 2015 hearing entitled, ``Continuing America's Leadership: Advancing
Research and Development for Patients.'' I appreciated the opportunity
to participate, and we are grateful for your leadership in exploring
thoughtful and meaningful reform of the National Institutes of Health
(NIH) and the Food and Drug Administration (FDA).
I have attached additional information in support of my written and
verbal testimony in response to the additional queries made by various
committee members. We look forward to continuing to work with the
committee as it continues examining the time and cost currently
involved with the drug and medical device discovery and development
process, and how to better align public policies to support medical
innovation.
If you have any questions or need additional information, please
feel free to contact me at [email protected] or (919) 684-6375
or Catherine Liao in the Duke Medicine Office of Government Relations
at (919) 416-8913 or [email protected].
Sincerely,
Bruce Sullenger, Ph.D.,
Joseph and Dorothy Beard Professor,
Director, Duke Translational Research Institute,
Department of Surgery,
Duke University Medical Center.
______

Response to Questions of Senator Alexander, Senator Isakson,
Senator Collins, and Senator Whitehouse by Bruce Sullenger, Ph.D.
Since many of the queries involve challenges between the academic
and private sectors and difficulties with translating medical
innovations from the laboratory to the community, I have discussed
these questions with Dr. David Robinson, Professor of Finance in Duke's
Fuqua School of Business and Research Director for the Duke Center for
Entrepreneurship and Innovation (https://www.fuqua.duke.edu/
faculty_research/faculty_directory/robinson/). The responses below
incorporate some of Dr. Robinson's thoughts and recommendations.
senator alexander
Question 1. What barriers are there to academic medical centers
collaborating with other private entities, such as drug and device
companies?
Answer 1. We believe that the main impediments preventing academic
centers from collaborating more effectively with private entities are
the rules in place inside the university, especially as they pertain to
conflict of interest and licensing policies. As I mentioned in my
introductory remarks, currently the NIH requires academic institutions
to disclose and mitigate conflicts of interest between faculty and
private entities. Because the safest way to mitigate such conflicts is
to limit such interactions, often policies are established at risk
adverse, academic institutions that serve as barriers that faculty must
overcome if they want to interact with the private sector. Thus I would
recommend that the NIH work with Congress to clarify and simply what is
allowed or even encouraged with regard to such interactions.
University licensing policies can also be a barrier for such
collaborations. To the extent that University Offices of Licensing and
Ventures favor early licensing revenues over long-term business value
creation, they inhibit the creation of new businesses formed around
technologies. To the extent that strategic alliance funding is an
important source of capital for such firms, this in turn inhibits
collaboration between academic medical centers and other private
entities.

Question 2. We do not want to waste time this year, and want to
focus on the areas that have the greatest impact on improving our
biomedical research enterprise. What are the two or three things that,
if done right, would help you accomplish your goals?
Answer 2. In addition to addressing the challenge associated with
conflict of interest described above, I would reiterate three tractable
issues I mentioned in my statement as well as add a fourth that I
believe the HELP Senate Committee should focus upon with the NIH, FDA,
academic community and private sector:

1. To train and expand a biomedical research workforce that is
ready to utilize and act upon the genomic and informatics revolution;
2. To rebalance and right-size support for all phases of biomedical
research as we transition from gathering intelligence on health and
disease (basic research) to rationally using the large amounts of
information to combat disease (translational and clinical research);
3. To reduce the administrative and compliance burdens placed upon
investigators and academic institutions to reduce costs and improve
productivity; and
4. To reduce regulatory uncertainty to release the brakes on
private sector investment in biomedical research. Whether FDA
regulatory waiting times are long or short is secondary in some sense
to whether they are predictable. Anything that increases the
predictability of regulatory oversight would be a welcome change.
Another important dimension to the problem is reimbursement, so more
clarity around the reimbursement process would also stimulate the
development process.

Question 3. In our last hearing, Dr. Hamburg said that the FDA had
a record number of new drug approvals last year, touted the success of
the Breakthrough therapies program, and told us that FDA's review times
for drugs is fastest in the world.
From her statement:

``This past calendar year, FDA approved 51 novel drugs and
biologics, the most in almost 20 years. Today, FDA's average
drug review times are consistently faster than other advanced
regulatory agencies around the world, providing Americans
earlier access to new, innovative drugs than patients in any
other country. In achieving these outcomes, FDA has maintained
its commitment to high standards to protect the public health,
while also exercising regulatory flexibility in order to help
promote medical product development. This flexibility, along
with FDA's work to collaborate with industry, has helped reduce
product development and review times. As a result, Americans
are seeing more products being approved, and in many cases,
they have access earlier than patients anywhere else in the
world.''

Could each of you briefly discuss your thoughts on what she said,
FDA's performance, and where Congress could be helpful?
Answer 3. Please see previous answer on regulatory uncertainty and
the need to reduce it to increase investment in the medical innovation
sector.

Question 4. Could you each talk about how the role of the patient
has changed with new technology, and what policy changes need to be
made to use this new excitement and involvement of patients to move
technologies from discovery through development more quickly?
Answer 4. As I discussed in my testimony, the information age and
the age of precision medicine are now upon us. Laboratory developed
tests that predict patient outcome based upon personalized Omics
information will revolutionize how care is delivered and developed in
this United States in the coming years. Thus the patient and his/her
personal information and individual needs will become increasingly
central to medical care as we move the next generation of medical
innovations to the public. This new direction poses a lot of challenges
for the way we think about oversight. Also, as big data becomes a
bigger part of medical care, there are a number of regulatory issues
that are raised because computers analyzing datasets are increasingly
part of the medical supply chain. This has typically not been something
under the purview of the FDA. The Congress together with the FDA need
to develop policies that will facilitate the proper use of such
information so that it delivers precise medicines to patients as safely
and rapidly as possible as well as informs the next round of discovery
science and innovation to accelerate the invention and development of
future breakthrough medicines and therapies.
senator isakson
Question 1. I understand that some medical device companies have
had challenges with the inconsistency and lack of predictability of the
FDA inspection process. Can you clarify if and how this can impact
innovation?
Answer 1. As indicated above, regulatory uncertainty is perhaps the
single biggest impediment to moving innovation to the public. To give
some numbers from Dr. Robinson: suppose an investor successfully
commercializes one out of every five investments, and suppose they need
to earn a 15 percent return on average, including the failed
investments, in order to continue to raise new funds. If they expect to
invest 5 years before exiting, they need to earn 10x their initial
investment in the successful investment in order to generate a 15
percent return on average. If the holding period of the investment goes
from 5 years to 8 years, then they have to earn 15 times their
investment instead of 10 times their investment in order to earn 15
percent on average. Thus, uncertainty over the time it will take to
take products to market completely undermines the economics of
investing in biomedical innovation.

Edwards Lifesciences LLC,
Irvine, CA 92614,
April 29, 2015.
Hon. Lamar Alexander, Chairman,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
428 Dirksen Senate Office Building,
Washington, DC 20510.

Dear Chairman Alexander: Thank you for the opportunity to testify
before the Senate Committee on Health, Education, Labor, and Pensions
on March 24, 2015 at the hearing entitled ``Continuing America's
Leadership: Advancing Research and Development for Patients.''
Attached are my responses to the committee's additional questions
for the record. Please contact me if there is any further followup.
Thank you, again, for the opportunity to participate in this important
initiative focused on addressing the challenges in getting cutting edge
innovations to patients.
Sincerely,
Michael A. Mussallem,
Chairman and Chief Executive Officer.
______

Response to Questions of Senator Alexander, Senator Isakson,
Senator Collns and Senator Whitehouse by Michael A. Mussallem
senator alexander
Question 1. There are more than 6,500 medical device companies in
the United States, of which 80 percent of the companies have 50 or
fewer employees. Has FDA improved the quality and frequency of its
communications in the past 2 years that supports the range of
innovative medical device companies?
Answer 1. Yes. Our experience over the past 2 years has improved,
as FDA has worked with industry to improve the quality and frequency of
its communications to support all innovative medical device companies--
including those considered ``small.''
The ability to have frequent, quality discussions with FDA
leadership and reviewers--followed by actionable results by both FDA
and industry--will continue to improve the regulatory environment for
all stakeholders and allow innovative technologies to quickly reach the
patients that need them most. Below are examples of programs and
organizational efforts that are helping the agency continue to improve
its communication with companies.

Dr. Shuren and his team at FDA have outlined strategic
priorities to strengthen the clinical trial enterprise, FDA included as
part of its 2014-15 Strategic Priorities a focus on providing excellent
customer service, which leverages the use of a standardized survey tool
in emails and on the Center's website.
Thanks to the Food and Drug Administration Safety and
Innovation Act (FDASIA), FDA has the resources to improve review and
approval performance metrics--including the number, quality and timing
of interactions with companies. These metrics are tied to dramatic
increases in manufacturer user fees, and we are just beginning to see
positive trends in performance.
A program was established focusing on improving quality
and performance, which included corrective and preventive action (CAPA)
processes. The industry has reported that reviewers have reached out
directly to companies requesting honest and constructive feedback with
regard to FDA performance.
CDRH has supported the U.S. Submission Advancement
Program, an initiative established through the small company division
of our trade association, the Advanced Medical Technology Association
(AdvaMed) used to gauge industry and FDA performance as it relates
specifically to small companies.
Through several meetings between small company executives
and CDRH leadership in 2014, FDA provided useful feedback on common
mistakes observed in sponsor submissions, which is facilitating the
development of a best practices document that includes an outline of
the most frequent mistakes observed by the agency.
CDRH holds an annual Regulatory Education for Industry
(REdI) collaborative conference for small businesses with CDER,
allowing such companies the ability to network, engage with FDA
experts, and learn more about FDA's regulatory requirements for drugs
and medical devices, free of charge.
CDRH has also established the Experiential Learning
Program (ELP), which provides a formal training mechanism for premarket
review staff to visit research, clinical, manufacturing, and health
care facilities to observe firsthand how medical devices are designed,
developed, and utilized.
CDRH's Office of Communication and Education reorganized
in 2014. This reorganization allowed for the Division to focus more
heavily on educating all CDRH stakeholders by providing understandable,
accessible, science-based regulatory information.
CDRH has also provided reviewers and leadership the
opportunity to engage directly with companies in informal industry
settings upon request. Roundtables including participants from industry
and CDRH have been organized as ``assimilation exercises'' to encourage
productive conversations around what the agency and industry are doing
well--and also areas for improvement.

Question 2. Your company has experience using postmarket registries
to help get your innovative product to market. Could you talk about
that experience, what worked, what has not worked, and what role you
think better data after approval can have in helping new, innovative
technologies get to patients faster?
Answer 2. Edwards Lifesciences supports appropriate data collection
for TAVR patients. We generated a substantial amount of clinical
evidence to support the safety, efficacy, necessity and reasonableness
of the Edwards SAPIEN transcatheter aortic heart valve, including a
large, complex, randomized and controlled clinical trial in the United
States. Extensive study of this valve--including an unprecedented four
New England Journal of Medicine papers--has demonstrated the ``triple
win'': a substantial and sustainable clinical benefit, extraordinary
quality-of-life improvement, and cost effectiveness in inoperable
patients. In fact, the SAPIEN valves are the most studied heart valve
in history, with more than 300 peer-reviewed, published articles on
clinical outcomes associated with the valves. There are also more than
120 cost-effectiveness and quality of life articles related to
transcatheter aortic valve replacement (TAVR). Subsequent indications
and different access routes (used when a direct percutaneous approach
is not possible) for SAPIEN were studied in registries, and we
conducted a second large trial in the United States--PARTNER II--for
SAPIEN XT, a much improved and lower profile device that was approved
by FDA in June 2014. Accompanying these large randomized trials have
been cost effectiveness and quality of life studies supporting the
value of the SAPIEN family.
Edwards provides significant support for the TVT Registry.
Following FDA approval and the Medicare National Coverage Decision
(NCD) that provided reimbursement for TAVR through Coverage with
Evidence Development (CED), the Society of Thoracic Surgeons (STS) and
the American College of Cardiology (ACC) created the TVT Registry,
which is designed to monitor and benchmark patient safety and real-
world outcomes related to the TAVR procedure.
The TVT Registry has proven to be useful. Our experience with the
TVT registry underscores that well-executed registries are a useful
postmarket tool. The data from the TVT Registry for transcatheter
aortic valve replacement procedures was used by FDA in 2013 to help
expand the indications for use of our SAPIEN technology, allowing
access to a broader patient population. Through close collaboration
between FDA and CMS, when new patient populations are approved, they
are immediately covered by Medicare. This collaboration takes vision
and commitment by both FDA and CMS, and they should be commended for
their work. We think that these novel approaches reflect agency views
that take promotion of public health as seriously as they take patient
protection, which as consumers of the system, we should all welcome.
The burden and cost of complying with registry requirements is not
insignificant. For example, the patient data registry form for the TVT
Registry for TAVR procedures is 8 pages long and consists of more than
300 separate fields, requiring special staffing, and dedicated
personnel, and hours of work to complete this exhaustive form. Many
physicians have told us that it takes longer to fill out the TVT
Registry form than it does to perform the TAVR procedure. In addition
to the significant financial commitment manufacturers must make to
support the development and ongoing operations of registries, hospitals
are charged ongoing fees to participate.

Question 3. In 2014, FDA proposed a new voluntary expedited access
program intended to speed development and approval of devices that
treat or diagnose a life-threatening or debilitating disease and
fulfill an unmet medical need. How will this program help you? What
additional tools does FDA need to help keep up with the range of new
science?
Answer 3. FDA's proposed Expedited Access Program is very
promising. While we are still evaluating how FDA's recently released
final guidance on its Expedited Access Program (EAP) could be
implemented for products in development, we are encouraged and commend
the agency for its efforts to explore supplementary review pathways to
provide more timely patient access to new technologies for life-
threatening or irreversibly debilitating diseases that address an unmet
medical need.
We look forward to working with Congress, FDA, CMS and other
stakeholders on ways to implement this proposal and others designed to
expedite patient access to safe and effective medical technologies. As
part of its Innovation Agenda, AdvaMed has proposed a new breakthrough
pathway, which builds upon FDA's EAP and would provide for transitional
Medicare and Medicaid coverage for products designated and approved by
FDA as ``breakthrough.''

Question 4. We do not want to waste time this year, and want to
focus on the areas that have the greatest impact on improving our
biomedical research enterprise? What are the two or three things that,
if done right, would help you accomplish your goals?
Answer 4. FDA's vision to improve the regulatory process is
commendable, and we believe it must be accelerated. There are a number
of regulatory reforms, included in the AdvaMed Innovation Agenda, which
would lead to greater efficiency and consistency in the FDA medical
device review process.
To encourage innovation, we need to address issues throughout the
entire ecosystem. A true innovation agenda must address both FDA and
CMS, and we urge this committee and the Senate Finance Committee to
consult with each other as you move forward to find ways to promote
innovation.
The breakthrough pathway is one of the most important proposals in
the innovation agenda; it spans the jurisdiction of both committees and
can only be enacted effectively through a cooperative effort.

Question 5. In our last hearing, Dr. Hamburg said that the FDA had
a record number of new drug approvals last year, touted the success of
the Breakthrough therapies program, and told us that FDA's review times
for drugs is fastest in the world.
From her statement:

Could each of you briefly discuss your thoughts on what she said,
FDA's performance, and where Congress could be helpful?
Answer 5. While I cannot speak to the drug review process and
performance, on the device side, FDA is pursuing initiatives to improve
the regulatory processes to help patients access innovative therapies.
Thanks to the Food and Drug Administration Safety and Innovation Act
(FDASIA), FDA has agreed to improved review and approval performance
metrics tied to dramatic increases in manufacturer user fees, and we
are just beginning to see positive trends in performance. However, it
remains the case that companies' experiences with the FDA device review
process are largely reviewer-dependent.

Question 6. Could you each talk about how the role of the patient
has changed with new technology, and what policy changes need to be
made to use this new excitement and involvement of patients to move
technologies from discovery through development more quickly?
Answer 6. FDA has pursued a number of relatively new initiatives
which we hope will improve patient involvement as they get put into
practice. Edwards Lifesciences and our trade association, AdvaMed,
support efforts to improve patient involvement in the product
development and review process. We believe patients have an important
role in making benefit-risk determinations when it comes to their care.
Both FDA and industry need to work to ensure that these initiatives are
implemented in a way that maximizes patient access to safe and
effective technologies.
FDA has engaged in a commendable effort to involve patients and
incorporate their perspectives into the regulatory process.
Specifically, FDA has issued two guidance documents intended to address
patient perspective of benefit and risk.\1\ These documents address how
patient-centered outcomes can and should be included in clinical trials
of certain devices and how FDA should incorporate these endpoints in
their review of the supporting evidence for a device. Further, FDA and
the Medical Device Innovation Consortium are also working on models to
quantify the patient perspective, and when during the product lifecycle
such input should be sought/provided.
---------------------------------------------------------------------------
\1\ ``Benefit-Risk Factors to Consider When Determining Substantial
Equivalence in Premarket Notifications [510(k)] with Different
Technological Characteristics Draft, July 2014]'' and ``Guidance for
Industry and Food and Drug Administration Staff--Factors to Consider
When Making Benefit-Risk Determinations in Medical Device Premarket
Approvals and De Novo Classifications'' [Final, March 2012].
---------------------------------------------------------------------------
In addition, pursuant to the Food and Drug Administration Safety
and Innovation Act (FDASIA), FDA seeks to solicit patients' as well as
other stakeholders' (e.g., surgeons, other health care professionals,
and caregivers) perspectives and participation throughout the total
product life cycle (TPLC) of medical devices, including regulatory
decisionmaking. It is important to recognize that each patient has a
unique benefit-risk perspective based on their own particular
situation, and that patients are heterogeneous even within a single
disorder (i.e., there is no ``representative patient'').
There exists some concern that adding an additional regulatory
requirement to an already cumbersome process could negatively impact
patient access to new technologies. In some cases, there are devices/
therapies that do not lend themselves to patient input at all phases of
the TPLC (e.g., devices with no patient interface). Surgical devices,
for example, are designed to aid the surgeon in the safe use and/or
application of the device for the benefit of the patient. Therefore,
patient input on device design and clinical trials should not be an
absolute requirement for medical device manufacturers. We believe that
it is appropriate and necessary in some cases for patient
``surrogates,'' such as physicians, surgeons, or other health care
providers, to provide input, especially at the early stages of device
design/development.
senator isakson
Question 1. I understand that some medical device companies have
had challenges with the inconsistency and lack of predictability of the
FDA inspection process. Can you clarify if and how this can impact
innovation?
Answer 1. Inconsistency and lack of transparency and predictability
of the FDA inspection process can have a substantial impact on
innovation and the timing of device development and approval. This is
an important issue to our industry and we encourage the committee to
examine the process and what improvements could be made to the
inspection process.
Specifically, there is inconsistency in investigators' knowledge
and interpretation of the Quality System Regulation (including the
interpretation of risk) and inspection protocols, both domestic and
abroad, and also among field offices domestically. These problems
hamper the ability to assure ongoing and mutual understanding between
FDA and industry of what is required by regulation, which is essential
to achieving high rates of compliance, ultimately leading to the
quicker approval of safer and higher quality medical devices.
FDA's efforts to improve its regulatory management processes and
structure through the recommendations coming from its Program Alignment
Group are an important step in the right direction. It would be
worthwhile for Congress to spend time assessing how to best move this
process forward.
As noted above, these challenges with the inspection process are of
great interest to the industry and in an effort to help identify and
address the issues, AdvaMed has established a working group focused on
the issue of inspections and create opportunities to collaborate with
FDA and Congress to improve the consistency, predictability, and
transparency of the inspection process.

Question 2. A number of stakeholders, including public health
groups, infectious disease doctors, venture capital, and antibiotic
developers to support the PATH Act, legislation sponsored by Senator
Hatch and Senator Bennet. This bill would require FDA to create a new,
limited population approval pathway for antibiotics to treat serious
and life-threatening infections for which there are few or no other
treatments. The bill would allow FDA to approve these drugs on the
basis of smaller amounts of data than it uses to approve other
antibiotics. Can you explain how FDA can use this pathway to get drugs
to patients who really need them without lowering the approval
standards?
Answer 2. As a medical device company, we do not have a perspective
on the drug approval pathway.
senator collins
Question. Mr. Borisy and Mr. Mussallem, you both mentioned in your
written testimonies the need to strengthen and integrate patient
perspectives. The patient perspective in the drug development and
review process is something I am hearing more about from individuals
and families who are suffering from devastating diseases.
Particularly in areas of serious unmet medical need, how does the
patient voice and understanding the benefits and risks to a patient
help ensure that medical innovations are helping to meet patients'
needs?
Answer. FDA has pursued a number of relatively new initiatives
which we hope will improve patient involvement as they get put into
practice. Edwards Lifesciences and our trade association, AdvaMed,
support efforts to improve patient involvement in the product
development and review process. We believe patients have an important
role in making benefit-risk determinations when it comes to their care.
Both FDA and industry need to work to ensure that these initiatives are
implemented in a way that maximizes patient access to safe and
effective technologies.
FDA has engaged in a commendable effort to involve patients and
incorporate their perspectives into the regulatory process.
Specifically, FDA has issued two guidance documents intended to address
patient perspective of benefit and risk.\2\ These documents address how
patient-centered outcomes can and should be included in clinical trials
of certain devices and how FDA should incorporate these endpoints in
their review of the supporting evidence for a device. Further, FDA and
the Medical Device Innovation Consortium are also working on models to
quantify the patient perspective, and when during the product lifecycle
such input should be sought/provided.
---------------------------------------------------------------------------
\2\ Ibid.
---------------------------------------------------------------------------
In addition, pursuant to the Food and Drug Administration Safety
and Innovation Act (FDASIA), FDA seeks to solicit patients' as well as
other stakeholders' (e.g., surgeons, other health care professionals,
and caregivers) perspectives and participation throughout the total
product life cycle (TPLC) of medical devices, including regulatory
decisionmaking. It is important to recognize that each patient has a
unique benefit-risk perspective based on their own particular
situation, and that patients are heterogeneous even within a single
disorder (i.e., there is no ``representative patient'').
There exists some concern that adding an additional regulatory
requirement to an already cumbersome process could negatively impact
patient access to new technologies. In some cases, there are devices/
therapies that do not lend themselves to patient input at all phases of
the TPLC (e.g., devices with no patient interface). Surgical devices,
for example, are designed to aid the surgeon in the safe use and/or
application of the device for the benefit of the patient. Therefore,
patient input on device design and clinical trials should not be an
absolute requirement for medical device manufacturers. We believe that
it is appropriate and necessary in some cases for patient
``surrogates,'' such as physicians, surgeons, or other health care
providers, to provide input, especially at the early stages of device
design/development.
senator whitehouse
Question. We've heard several stakeholders express support for
integrating patient perspectives in the drug development and review
process. As you know, FDA held 20 public meetings to consider different
disease areas as part of its Patient-Focused Drug Development program.
What next steps would you like to see FDA take in its Patient-Focused
Drug Development program? Do you have specific recommendations on how
FDA could better integrate patient perspectives in the development and
review processes?
Answer. While the Patient-Focused Drug Development program is
limited to drugs, there are a number of activities that FDA's device
center is undertaking, with support of the medical device industry, to
incorporate the patient perspective.
FDA has pursued a number of relatively new initiatives which we
hope will improve patient involvement as they get put into practice.
Edwards Lifesciences and our trade association, AdvaMed, support
efforts to improve patient involvement in the product development and
review process. We believe patients have an important role in making
benefit-risk determinations when it comes to their care. Both FDA and
industry need to work to ensure that these initiatives are implemented
in a way that maximizes patient access to safe and effective
technologies.
FDA has engaged in a commendable effort to involve patients and
incorporate their perspectives into the regulatory process.
Specifically, FDA has issued two guidance documents intended to address
patient perspective of benefit and risk.\3\ These documents address how
patient-centered outcomes can and should be included in clinical trials
of certain devices and how FDA should incorporate these endpoints in
their review of the supporting evidence for a device. Further, FDA and
the Medical Device Innovation Consortium are also working on models to
quantify the patient perspective, and when during the product lifecycle
such input should be sought/provided.
---------------------------------------------------------------------------
\3\ Ibid.
---------------------------------------------------------------------------
Response to Questions of Senator Alexander, Senator Isakson,
and Senator Whitehouse by Allan Coukell
senator alexander
Question 1. You mention in your testimony that the cost of doing
clinical trials in the United States is greater than that in other
countries in a few specific cases. Could you expand on what we could do
to make trials here more efficient?
Answer 1. The rising cost of medical product innovation is a
serious concern with multiple underlying causes, including expenses
associated with clinical trials. The data researchers collect through
robust trials are critical for regulators, payors, clinicians, and
patients to make decisions about which products are right for which
patient. A 2013 survey found that phase III clinical trial costs rose
by 86 to 88 percent over 3 years--from $25,000 to $40,000 per patient.
While Pew has not conducted a comprehensive analysis on the cost of
clinical trials, we have identified some strategies--including those
used abroad--to reduce the costs of clinical trials.
Clinical trial experts have proposed other approaches that can
reduce study costs and facilitate innovation. For example, the
Institute of Medicine convened experts who proposed several solutions
to reduce trial costs, including the development of ``large, simple
trials,'' where study investigators would enroll many patients but only
examine a small number of variables.
One source of cost in any trial is the number of data elements that
are collected. Another approach to reducing trial costs involves
``large, simple trials.'' \1\ Such trials have the potential to reduce
costs by simplifying eligibility criteria and reducing the number of
outcomes tracked. No statutory or regulatory barrier precludes adoption
of such trial designs. Rather, a participant in an IOM workshop
described the barrier as ``risk aversion . . . ''

``Researchers may believe that it is better to collect 100
unnecessary variables than to miss one important one.
Additionally, Granger explained, regulatory departments and
contract research organizations have a substantial financial
stake in maintaining the status quo, as their business models
and margins are created by the complexity inherent to current
trial designs. Last, the lack of international harmonization
among trial designs can force the use of the most complicated
common denominator.'' \1\

One approach to large simple trials is the registry-based trial.
Registries are large data bases that contain detailed clinical
information on patients with similar medical conditions. Researchers in
Sweden used a registry to conduct a large cardiovascular trial at a
fraction of the per-patient costs. The TASTE trial enrolled more than
7,000 patients, and allowed investigators to keep track of every
patient throughout the course of the research at a total cost of $50
per patient, or only $300,000 for the entire trial. Conducting a
traditional study of this size in the United States would cost tens of
millions of dollars, if not more.
Pew, together with the Blue Cross Blue Shield Association and the
Medical Device Epidemiology Network, convened experts from the medical
device industry, the registry community and government to consider how
to achieve the full potential of registries in a financially
sustainable way. Several barriers exist to fully achieving the promise
of registries. Despite the dramatic uptake of electronic health
information sources, these systems cannot easily transmit data among
one another. This lack of interoperability, for example, hinders the
ability of registries to extract clinical and outcomes data from EHRs.
Instead, registries must build customized solutions to extract
information from the EHR systems at each facility, or require providers
to manually enter the information. Additionally, many registries have
sought clarity on when their studies are considered research, rather
than quality improvement efforts. This confusion has slowed their use
by hospitals and their ability to make a meaningful contribution.
While the use of registries can supplement existing efforts to
reduce costs, they are not appropriate for all products or studies.
Other strategies to help address trial costs include facilitating
faster trial initiation through, for example, greater use of central
institutional review boards (IRBs) instead of multiple local reviews.
For medical devices in particular, trials are currently required by
statute to obtain IRB review at each facility participating in a
study.\2\ Removing this requirement could help streamline the approval
of these trials.
The growth in trial size is driven in part by the effect size of
the drug. When a drug's effect can only be discerned by studying it in
thousands of patients, the clinical trials required for approval will
necessarily be large. A treatment that worked in 100 percent of
patients, by contrast, would require an extremely small clinical trial.
As Scannell et al. note,

``everything else being equal, clinical trial size should be
inversely proportional to the square of the effect size. If the
effect size halves, the trial has to recruit four times as many
patients to have the same statistical power.'' \3\

Personalized, or precision, medicine has the potential to identify
sub-populations of patients with specific genetic profiles who are more
likely to respond to a particular therapy. This has the potential to
reduce trial size if the response rate is high (as with any drug).
However, it is important to note that if the response rate is low and
seen only in a specific sub-population, the usual challenges of
clinical trial design and recruitment will be further exacerbated.
Innovative trial designs and novel partnerships have the potential
to more efficiently recruit and stratify patients by genetic profile.
The FDA has encouraged the development of such trials. For example, the
recently developed Lung-MAP trial has the potential to improve
efficiency by allowing simultaneous and sequential comparisons of
multiple drugs (from multiple companies) and stratification of patients
by genotype.\4\ Such a trial still involves a 1:1 randomization of
patients that does not change in response to data analysis, and is
therefore not of Bayesian or adaptive design.
While adaptive trials may under some circumstances improve trial
efficiency, it is important to note that--contrary to widely held
perceptions--such trials do not reduce the number of participants
required to achieve adequate power (and can, under certain
circumstances, increase it).

Question 2. Pew conducted surveys on how to define and improve
predictability with the regulatory process. What did those surveys find
would be most helpful in reducing the uncertainty of medical product
development?
Answer 2. Through a series of activities, Pew sought to better
define what is perceived as unpredictability in FDA's regulatory review
process and to identify concrete steps that the FDA and sponsors could
take to improve predictability. Pew staff reviewed relevant peer-
reviewed journal articles and other publicly available documents,
interviewed more than two dozen individuals, including representatives
from small and large drug and device companies, former FDA officials,
consultants, venture capitalists, and patient advocacy groups and held
a 1-day public workshop attended by leaders from the FDA, the drug and
medical device industry, the venture capital community and other
stakeholders. We also fielded a survey of senior drug, biotechnology
and device company executives (randomly selected from a master list
that was compiled to be as comprehensive as possible), assessing their
perceptions and experiences concerning the predictability of FDA's
regulatory review.
Of the 210 drug and device industry professionals polled, about 70
percent said the FDA makes the appropriate decision on new medical
products ``most or all of the time'' and 66 percent said FDA staff's
qualifications are ``excellent or good.'' About 62 percent of the
respondents said FDA's data requirements are necessary in ``all or more
cases,'' with only 2 percent saying the requirements were necessary in
``very few cases.''
Almost all of the survey respondents--98 percent--agreed on the
importance of predictability in the FDA review process. Eighty-one
percent said it was ``extremely important'' and another 17 percent said
it was ``fairly important'' for the FDA review process for new medical
products to be predicable.
When probed further, most respondents to the survey as well as
workshop participants expressed concerns regarding the agency's
predictability. Thirty-eight percent of industry respondents said,
based on their personal experiences, that the FDA's regulatory review
process is ``completely or fairly'' predictable (48 percent among
biotechnology and pharmaceutical professionals). Only 26 percent of
medical device professionals said the same, which reflected an
overarching pattern of greater dissatisfaction within that industry.
(Pew did not explore this discrepancy in its quantitative research, but
some participants in the January 2013 conference attributed the
difference to the greater diversity of medical devices compared to
pharmaceutical products and the subsequent breadth of approaches to
testing their safety and efficacy, as well as staffing issues within
CDRH, which the division acknowledged.)
Sixty-eight percent said that such unpredictability discouraged the
development of new products. Again, a higher proportion of medical
device professionals--84 percent--believed that the FDA's review
process discouraged innovation.
Industry professionals were divided on the degree to which they
believed the system needs to be fixed. Nearly half (49 percent) believe
the agency's product review systems need a ``complete or major
overhaul.'' The same number said the systems worked ``fine as-is'' or
needed only ``minor modifications.''
One clear theme emerged from the Pew conference and related
activities: Regulatory predictability is a broad and subjective term
used to describe a variety of issues. Therefore, attempts to solve
``regulatory predictability'' are less likely to succeed because the
problem itself is not defined precisely enough. Rather than relying on
this broad diagnosis, stakeholders would be better served to articulate
specific issues regarding, for example, communications, staff
experience, or data accessibility. Those identified during the course
of our research include:

Establishing clear data requirements;
Inconsistency among FDA reviewers and review divisions;
Issues related to the publication of guidances;
Data integration and accessibility; and
Sponsor inexperience with regulatory review.
Establishing Clear Data Requirements
Sponsors assert that there is often a lack of clarity or explicit
rationale regarding the type and quantity of additional safety and
efficacy data that FDA staff requests. Specifically, several sponsors
asserted that such requests are manifestations of an inherent and
unwarranted ``risk-aversion'' on the part of FDA staff. As they submit
documents to the agency, FDA staff will request additional information
to address possible concerns with a product or learn more about how a
drug will affect patients. Sponsors contend that many of these data
requests would negligibly affect FDA's decisions but are burdensome and
expensive. Similarly, they assert that some data requests are too
academic and not germane to the safety and efficacy of a product.
Current and former FDA officials contend that the FDA must maintain
some measure of flexibility when evaluating sponsors' applications.
Over the course of a product's lifecycle new information may become
available--from the scientific literature, from its regulatory
counterparts in other jurisdictions, among other places--that compels
the FDA to look at a sponsor's application in a new light. Moreover, in
the course of reviewing applications from other sponsors on a similar
product, and through post-marketing surveillance monitoring, FDA
reviewers identify potential safety and efficacy issues with a product
class and uses that information to make additional data requests of
sponsors. Because specific reference to other sponsor's applications is
prohibited by commercial confidentiality laws, FDA staff cannot always
be specific about the reasons underlying a particular data request,
leading to sponsor perceptions of FDA capriciousness or arbitrariness.
To achieve greater predictability, our conference found
substantial--though not universal--support for the suggestion that the
FDA should release all documents--such as Complete Response Letters--
that would provide information on why the agency requested additional
information. That information will help all companies understand the
data sought for certain diseases and about classes of medical products.
We also found strong support for investments in regulatory science
so that the agency can develop tools, standards, and approaches to
product reviews that can provide some consistent guidance for sponsors
even as science itself advances.
Some sponsors expressed concerns that the FDA did not order Risk
Evaluation Mitigation Strategies (REMS)--which implement controls to
help prevent the harmful effects of new medicines--until very late in
product review. Discussing REMS late in product reviews delays drug
approvals as the sponsor and FDA reach an agreement on the post-market
safety program. Earlier REMS planning would streamline approvals,
though it must be noted that at least some of the time, REMS
development will be in response to risk information obtained in phase
III trials--data the FDA does not have an opportunity to review until
the full application is submitted.
As part of the new review model for new molecular entities and
original biologics license application, the FDA will begin discussing
REMS and other risk-related issues much earlier in product reviews and
even during meetings before the formal submission of an application.
The FDA has also formalized several mid-cycle communications--including
both in-person meetings and letters from the agency--to provide more
interactions between reviewers and drug sponsors for the agency to
provide feedback.
CDRH has created a new Innovation Pathway, where device sponsors
and reviewers interact throughout product development to address any
potential FDA concerns before manufacturers formally submit a product
for review.
Inconsistency Among Reviewers and Between Review Divisions
Ensuring the safety, effectiveness, and quality of human drugs for
these products is a complicated regulatory task, requiring FDA's
consideration of a multitude of complex factors. FDA's regulatory
decisionmaking process takes into consideration not only the data
submitted for a particular marketing application, but also a broad set
of additional factors, including similar products in a class, clinical
context for the proposed product (such as the nature and severity of
the disease or condition that the proposed product is intended to treat
or prevent and the benefits and risks of other available therapies for
that disease or condition) and any risk management tools that might be
necessary to ensure that the benefits of the proposed product outweigh
its risks.
The complexity described above is sufficient to drive some degree
of inconsistency in regulatory decisionmaking among reviewers and
review divisions. A drug with apparent cardiotoxicity might require
investigations that a pharmacologically similar product without that
safety signal did not. The risk tolerance for uncertainty for an
antibiotic to treat a multidrug resistant infection might be different
than for a drug intended as a first-line treatment. However, there are
a host of other internal and external variables that also drive this
inconsistency, including: the number of regulatory filings (workload);
division staff levels; frequency of Advisory Committee meetings;
requests for REMS or other post-marketing commitments; and the variable
quality of the sponsors' applications.
In addition to these differences between review divisions,
differences among reviewers may feed sponsor perceptions of
inconsistency. Judgments about balancing risks and benefits are
inherently value judgments, and such differences among reviewers are,
to a certain degree, inevitable. The FDA should not necessarily
eliminate such differences, but instead should put in place processes
and tools that make these differences transparent and subject to
discussion--at higher levels within the agency, with sponsors, and,
where appropriate, with the public.
Most of the survey respondents attributed these challenges
primarily to staffing shortages. Sixty percent said FDA did not have
sufficient scientists and reviewers to conduct timely product reviews.
In fact, respondents who were satisfied with FDA processes were more
likely to say that FDA was insufficiently staffed.
More tractable may be inconsistencies among reviewers that are
attributable--at least in part--to a lack of training. Not all
reviewers are well-versed on agency policies and guidances. Therefore,
one participant suggested, reviewers occasionally provide inconsistent
advice to sponsors--such as whether an adaptive trial design is
viable--that may not reflect guidance or direction from FDA leadership.
Most respondents (54 percent) suggested that investing in human
resources, such as training staff, would be a ``very effective''
strategy for improving FDA's review process. An additional 26 percent
said it would be ``fairly effective,'' making it the most popular
proposal offered in the survey.
As required by Congress, the FDA has sought to make the rationales
for reviewer judgments more transparent through the implementation of a
structured risk-benefit framework for NDAs and BLAs. Through this
framework, reviewers will explain product risks along with whether the
drug treats an unmet need or provides major advancements to patient
care. Including this framework earlier in product development could
improve FDA decisionmaking. Stakeholders expect this new framework to
serve as a communications tool to explain FDA decisions as well as to
provide a quick summation of a review to help cross-agency consistency
on what review decisions were made. FDA's device center has also issued
a guidance document outlining its benefit-risk framework. To evaluate
benefits, FDA examines the clinical improvements, magnitude of
benefits, probability of the patient experiencing the benefit and the
duration of the effect. For safety, FDA evaluates the serious and non-
serious adverse effects and procedure-related complications (such as
the probability and duration of harmful events or the risk of false
results from diagnostics).
The FDA has contracted independent third parties to examine its
review processes and communications with sponsors. The reviews should
identify areas where the FDA is inconsistent and not following good
review practices.
When meeting with the FDA about adaptive trial designs or other
issues that are not typical for a standard drug application, sponsors
should request the attendance and input of senior FDA leadership. Such
input could provide needed reassurance to reviewers and assuage their
concerns with a product review.
The FDA should provide additional and ongoing training for product
reviewers, with a focus on developing and implementing guidances.
Issues Related to the Publication of Guidances
Guidance documents are nonbinding recommendations that represent
the FDA's current thinking on a particular subject. They are written
for multiple audiences, including sponsors, investigators,
Institutional Review Boards (IRBs) and FDA staff. Guidances fall into
three broad categories: (1) those related to topics that inform product
development, such as study design, use of novel technologies,
statistical considerations, and labeling and promotion, (2) those
related to procedures and processes such as meetings, timelines,
submission requirements, and (3) those related to inspections and
enforcement. In our research, concern focused largely on the first type
of guidance documents. FDA staff, sponsors and other stakeholders all
share the view that the timely publication of relevant guidances--in
either draft or final form--are important for making the regulatory
review process more predictable and transparent. According to the
survey, 90 percent of respondents said written guidances related to
FDA's procedures and processes were extremely or fairly helpful.
Similarly, 73 percent said FDA's written guidances related to
scientific topics that inform product development were extremely or
fairly helpful. But others were skeptical about the value of additional
guidances, noting that the most challenging questions are often product
specific.
We identified several key challenges related to guidances. Among
them, the FDA lacks the staffing capacity necessary to both write
guidances and also keep pace with product reviews. Because these
reviews must meet legislatively mandated deadlines, the FDA prioritizes
them, occasionally at the expense of guidance development. A senior FDA
official noted that the FDA staff viewed as the most capable of writing
guidance documents (regulatory experience, scientific expertise,
writing skill) are frequently the highly skilled reviewers. As a
result, there is reluctance to explicitly curtail their product review
duties in order to devote time to guidance writing.
Data Integration and Accessibility
Drug development--from earliest discovery through post-marketing--
is a complex enterprise that generates reams of preclinical and
clinical data. For data to be marshaled as evidence requires approaches
and tools that systematically facilitate: (1) data integration and (2)
data accessibility. With regard to integration, there is a need for
standardized data submissions to be the norm, not the exception. Such
standards allow for data--clinical and nonclinical--from numerous
applications to be pulled into datasets for comparative or meta-
analyses. These analyses would likely improve predictability by
enabling meaningful comparisons of similar products.
FDA has also heretofore lacked the capacity to make historical
application data readily and routinely available to its reviewers.
Rather, some--but by no means all--reviewers try to track down
applications of similar products in the archives, or they rely ad hoc
on the reviewers of those products (assuming these individuals are
available). Moreover, time pressure created by user fee agreements
disincentivizes efforts to access this historical data.
The lack of data integration and inaccessibility, combined with the
time pressures of review work, means that reviewers may spend the bulk
of their time reorganizing the data attached to a particular new
application and simply rerunning the analyses submitted by sponsors.
While this is a critical first-order task, it forces reviewers to focus
almost exclusively on the application in front of them, without regard
for the agency's regulatory experience with like products. By treating
each new application in a vacuum, there are lost opportunities to
foster the organizational learning needed to improve consistency and
predictability.
CDER has recently increased its support for standardized study data
submissions using CDISC standards, and will continue to do so in the
future. CDER's Office of Translational Sciences has recently launched a
Computational Sciences Center (CSC), whose mission is to improve the
effectiveness of reviewers' evaluation and analysis of nonclinical and
clinical study data. CSC views data integration and accessibility as
core values, and is currently looking for approaches and tools that can
help put these values into the day-to-day practice of drug development
and regulatory review, both at the FDA and in industry.
Sponsor Inexperience With the FDA
Inexperience submitting products for FDA review leads to sponsors
maintaining inaccurate expectations about data requirements and agency
processes, ultimately resulting in perceptions of unpredictability when
those expectations are not met. Small companies are especially
susceptible to this problem. A study by Booz Allen Hamilton found that
large companies obtain approval on their original submission 58 percent
of the time, whereas that is true for only 41 percent of small company
submissions.\5\ More recently, a PriceWaterhouseCoopers survey found
that large companies were more likely to avail themselves of
interactions with the FDA; smaller companies were more likely to rely
on guidance.\6\
Sponsors that have not previously submitted products to the FDA for
review may lack an accurate understanding of the data requirements and
agency processes. Moreover, many small companies fail to hire
experienced consultants and regulatory experts to assist with product
submissions. Without this help, companies may submit inadequate or
noncompliant submissions to the FDA.

Question 3. We do not want to waste time this year, and want to
focus on the areas that have the greatest impact on improving our
biomedical research enterprise? What are the two or three things that,
if done right, would help you accomplish your goals?
Answer 3. We urge the committee to consider S. 185, the Promise for
Antibiotics and Therapeutics for Health (PATH) Act, introduced by
Senator Hatch and Senator Bennet. This legislation, which has the
support of industry stakeholders, key professional societies, public
health groups, and military and veterans' groups, would direct FDA to
establish a new regulatory pathway for antibiotics to treat serious and
life-threatening infections for which there are few or no other
treatment options. This legislation is ripe for consideration given the
growing public health crisis posed by antibiotic resistance and the
consensus that this pathway could make a difference by encouraging the
development of antibiotics to meet serious unmet medical needs. An op
ed has been written by Drs. Patty Wright and William Schaffner, both
infectious diseases specialists at Vanderbilt University, in support of
this legislation.

Question 4. In our last hearing, Dr. Hamburg said that the FDA had
a record number of new drug approvals last year, touted the success of
the Breakthrough therapies program, and told us that FDA's review times
for drugs is fastest in the world.
From her statement:

Could each of you briefly discuss your thoughts on what she said,
FDA's performance, and where Congress could be helpful?
Answer 4. Perhaps the most commonly cited measure of FDA
performance is drug approval time. Recent studies have demonstrated
that FDA approves drugs more quickly than regulators in Europe and
Canada.\7\ \8\ Moreover, median time to approval today is substantially
lower than prior to the implementation of PDUFA goals.\9\ Over recent
decades, the overall success rate for New Drug Applications (NDAs) has
been relatively consistent (averaging 79 percent from 1993-2012), but
the share of drugs approved at the first action date has increased
markedly (45 percent over 20 years, but 77 percent in 2011-12).\10\ To
a large extent that is a function of the quality of the
applications.\5\ FDA has some capacity to influence submission quality
through its communication with industry, either during individual
meetings or through guidance documents. According to a recent
PriceWaterHouseCoopers survey of industry executives, 78 percent
responded that FDA has improved the quality and frequency of its
communications with industry over the last 2 years, and 76 percent
responded that the agency provided ``actionable feedback.'' \6\
Other measures provide insights on additional aspects of agency
operations, such as presentations to societies, consortia, industry and
government organizations (around 100 per month for the center for
drugs).\11\ Of particular interest may be issuance of FDA guidance
documents, which serve to communicate the agency's current thinking on
specific topics. The center for drugs, for example, issued 51 draft
guidances in 2014, but only 13 final guidances.\12\ Earlier years
follow a similar pattern. The reasons for this discrepancy are unclear.
It may be that the agency seeks a wide range of input during
development of a draft guidance, which then serves as an effective tool
for communicating with stakeholders. Alternatively, it may be that the
process for administrative clearance deters the agency from finalizing
guidances. Congress could evaluate the balance between finalizing
guidances and the potential opportunity cost of fewer new draft
guidances on other topics, and potentially identify administrative
simplifications that would facilitate finalization. A similar
investigation of the time required to develop and finalize a formal FDA
rule (often several years) might lead to solutions that would support
greater overall efficiency.
The FDA exhibits substantial flexibility in requirements for
evidence to support drug or device approval. For example, an analysis
by the National Organization for Rare Disorders found that of 135 drug
approvals for non-cancer rare disease, 45 met traditional data
requirements, 32 reflected ``administrative flexibility'' based on a
previously documented FDA system, and 58 reflected flexibility applied
on a case-by-case basis.\13\ Another recent analysis of all drug
approvals (funded by Pew) found that while FDA generally relied on
randomized clinical trials to approve therapeutics, over one-third of
approvals were based on a single efficacy trial.\8\ This same analysis
also showed that FDA used flexibility with regards to which outcomes
these trials had to measure.
Several existing mechanisms provide flexibility for the data
collected. The accelerated approval pathway for drugs, which Congress
codified into law in 2012, allows FDA approval based on surrogate--
rather than clinical--endpoints, with the goal of enabling more
efficient premarket studies. In 2014, FDA approved 20 percent of novel
new drugs through this pathway.\14\
Similarly, for devices that treat or diagnose conditions affecting
fewer than 4,000 patients per year, FDA can also grant a humanitarian
device exemption, which allows the marketing of a product that is
considered safe and is expected to provide benefits, even if less
evidence on effectiveness is available. The FDA's proposed expedited
access pre-market approval (EAP) process would also support the
marketing of new medical devices based on surrogate endpoints, shorter
clinical trials or other adaptive designs. The success of this policy,
though, relies on the efficient collection of data--both pre- and post-
market. Congress should explore codifying this program in statute, and
should address some gaps in FDA's authority to accelerate patient
access to new medical devices while still collecting sufficient
information throughout a product's entire life cycle. In particular,
Congress should assess the agency's ability to promptly remove the
approval of devices that ultimately were not found to be safe and
effective.
These programs provide FDA with significant latitude to tailor the
data collected by sponsors and the agency's review process to reflect
the severity of the disease and availability of alternative treatments,
not to mention each product's risks and benefits. Not all products are
appropriate for inclusion in one of these mechanisms, and FDA should
only apply some of the pathways--particularly those that result in less
than definitive proof of clinical efficacy--to products that are
expected to significantly advance care for patients with serious, unmet
medical needs.

Question 5. Could you each talk about how the role of the patient
has changed with new technology, and what policy changes need to be
made to use this new excitement and involvement of patients to move
technologies from discovery through development more quickly?
Answer 5. This is not an area in which Pew has comments.
senator isakson
Question 1. I understand that some medical device companies have
had challenges with the inconsistency and lack of predictability of the
FDA inspection process. Can you clarify if and how this can impact
innovation?
Answer 1. We refer the Senator to our response to Chairman
Alexander, above.

Question 2. A number of stakeholders, including public health
groups, infectious disease doctors, venture capital, and antibiotic
developers to support the PATH Act, legislation sponsored by Senator
Hatch and Senator Bennet. This bill would require FDA to create a new,
limited population approval pathway for antibiotics to treat serious
and life-threatening infections for which there are few or no other
treatments. The bill would allow FDA to approve these drugs on the
basis of smaller amounts of data than it uses to approve other
antibiotics. Can you explain how FDA can use this pathway to get drugs
to patients who really need them without lowering the approval
standards?
Answer 2. Antibiotic resistance remains a serious patient safety,
public health, and national security concern. As a 2014 report by the
President's Council of Advisors on Science and Technology (PCAST)
noted, the development of antibiotic resistance is occurring at an
alarming rate and far outpacing the development of new antibiotics. As
a result, increasing numbers of patients are contracting serious and
even deadly infections that are difficult and sometimes impossible to
treat, resulting in longer hospital stays, complications of other
medical treatments such as surgery or chemotherapy, and even deaths.
Patients with weakened immune systems, such as those with HIV/AIDS,
preterm infants, cancer patients, transplant patients, the elderly, or
patients treated in intensive care units are at heightened risk, but
even healthy young people are contracting and dying from serious,
antibiotic resistant infections.
Antibiotic development has dwindled, with many pharmaceutical
companies leaving this market. One key reason has been the lack of a
clear, feasible regulatory pathway for Food and Drug Administration
(FDA) approval of a new antibiotic for some of the most serious
infections caused by multidrug-resistant (MDR) pathogens. It is often
not feasible to develop antibiotics for some of the most serious
infections using traditional, large clinical trials due to the limited
numbers of patients in whom these infections currently occur. PCAST
explicitly recommended the creation of a new limited population pathway
for antibiotics to treat a serious or life-threatening infection in
order to meet an unmet medical need. This is exactly what the PATH Act
would do.
Importantly, any drug approved under this new pathway must still
meet the Food and Drug Administration's (FDA) standards of evidence for
safety and effectiveness for the indicated limited population. Further,
the PATH Act contains several important provisions to help guide the
appropriate use of antibiotics approved under this new pathway.
Appropriate use is critical to deliver optimal patient care while
limiting the likelihood of antibiotic resistance developing to these
new antibiotics.
senator whitehouse
Question. We've heard several stakeholders express support for
integrating patient perspectives in the drug development and review
process. As you know, FDA held 20 public meetings to consider different
disease areas as part of its Patient-Focused Drug Development program.
What next steps would you like to see FDA take in its Patient-Focused
Drug Development program? Do you have specific recommendations on how
FDA could better integrate patient perspectives in the development and
review processes?
Answer. We do not have a specific recommendation.
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[Whereupon, at 11:26 a.m., the hearing was adjourned.]

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