[Senate Hearing 115-255]
[From the U.S. Government Publishing Office]
S. Hrg. 115-255
FDA USER FEE AGREEMENTS: IMPROVING MEDICAL PRODUCT REGULATION AND
INNOVATION FOR PATIENTS, PART I
=======================================================================
HEARING
OF THE
COMMITTEE ON HEALTH, EDUCATION,
LABOR, AND PENSIONS
UNITED STATES SENATE
ONE HUNDRED FIFTEENTH CONGRESS
FIRST SESSION
ON
EXAMINING FDA USER FEE AGREEMENTS, FOCUSING ON IMPROVING MEDICAL
PRODUCT REGULATION AND INNOVATION FOR PATIENTS, PART I
__________
MARCH 21, 2017
__________
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COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS
LAMAR ALEXANDER, Tennessee, Chairman
MICHAEL B. ENZI, Wyoming PATTY MURRAY, Washington
RICHARD BURR, North Carolina BERNARD SANDERS (I), Vermont
JOHNNY ISAKSON, Georgia ROBERT P. CASEY, JR., Pennsylvania
RAND PAUL, Kentucky AL FRANKEN, Minnesota
SUSAN M. COLLINS, Maine MICHAEL F. BENNET, Colorado
BILL CASSIDY, M.D., Louisiana SHELDON WHITEHOUSE, Rhode Island
TODD YOUNG, Indiana TAMMY BALDWIN, Wisconsin
ORRIN G. HATCH, Utah CHRISTOPHER S. MURPHY, Connecticut
PAT ROBERTS, Kansas ELIZABETH WARREN, Massachusetts
LISA MURKOWSKI, Alaska TIM KAINE, Virginia
TIM SCOTT, South Carolina MAGGIE HASSAN, New Hampshire
David P. Cleary, Republican Staff Director
Lindsey Ward Seidman, Republican Deputy Staff Director
Evan Schatz, Minority Staff Director
John Righter, Minority Deputy Staff Director
(ii)
C O N T E N T S
__________
STATEMENTS
TUESDAY, MARCH 21, 2017
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.............................................. 4
Burr, Hon. Richard, a U.S. Senator from the State of North
Carolina....................................................... 45
Collins, Hon. Susan M., a U.S. Senator from the State of Maine... 49
Bennet, Hon. Michael F., a U.S. Senator from the State of
Colorado....................................................... 51
Young, Hon. Todd, a U.S. Senator from the State of Indiana....... 53
Murphy, Hon. Christopher, a U.S. Senator from the State of
Connecticut.................................................... 54
Roberts, Hon. Pat, a U.S. Senator from the State of Kansas....... 56
Warren, Hon. Elizabeth, a U.S. Senator from the State of
Massachusetts.................................................. 57
Hassan, Hon. Maggie, a U.S. Senator from the State of New
Hampshire...................................................... 61
Cassidy, Hon. Bill, a U.S. Senator from the State of Louisiana... 63
Whitehouse, Hon. Sheldon, a U.S. Senator from the State of Rhode
Island......................................................... 64
Scott, Hon. Tim, a U.S. Senator from the State of South Carolina. 66
Kaine, Hon. Tim, a U.S. Senator from the State of Virginia....... 68
Franken, Hon. Al, a U.S. Senator from the State of Minnsota...... 71
Witnesses
Woodcock, Janet, M.D., Director, Center for Drug Evaluation and
Research, Food and Drug Administration, Silver Spring, MD...... 6
Prepared statement........................................... 8
Marks, Peter, M.D., Ph.D., Director, Center for Biologics
Evaluation and Research, Food and Drug Administration, Silver
Spring, MD..................................................... 42
Shuren, Jeffrey E., M.D., J.D., Director, Center for Devices and
Radiological Health, Food and Drug Administration, Silver
Spring, MD..................................................... 44
(iii)
FDA USER FEE AGREEMENTS: IMPROVING MEDICAL PRODUCT REGULATION AND
INNOVATION FOR PATIENTS, PART I
----------
TUESDAY, MARCH 21, 2017
U.S. Senate,
Committee on Health, Education, Labor, and Pensions,
Washington, DC.
The committee met, pursuant to notice, at 10:05 a.m. in
room SD-430, Dirksen Senate Office Building, Hon. Lamar
Alexander, chairman of the committee, presiding.
Present: Senators Alexander, Burr, Collins, Cassidy, Young,
Roberts, Scott, Murray, Franken, Bennet, Whitehouse, Murphy,
Warren, Kaine, and Hassan.
Opening Statement of Senator Alexander
The Chairman. Good morning. The Senate committee on Health,
Education, Labor, and Pensions will please come to order.
We are holding a hearing today on Food and Drug
Administration User Fee Agreements: Improving Medical Product
Regulation and Innovation for Patients, Part I.
Senator Murray and I will each have an opening statement
and then we will introduce our panel of witnesses. After our
witness testimony, Senators will have 5 minutes of questions.
The subject today is the Food and Drug Administration's
Medical Device and Drug User Fees. It seems like a long time
ago--but it really was not very long ago--that Congress passed
the 21st Century Cures Act. Ninety-four Senators voted for it.
President Obama and Vice President Biden were strongly in
support of it, so was Speaker Ryan. Mitch McConnell called it
the most important piece of legislation in the last Congress.
That came through this committee, and I thank the members
of the committee, especially, for resolving our differences of
opinions and making it possible for us to reach consensus.
That bill was about moving medical products, drugs, and
devices more rapidly in a safe way through the investment and
the regulatory process, and into the hands of patients and
doctors' offices.
Today, we are talking about really implementing that great
goal, one that shows so much promise for virtually every
American. We are here to talk about how we continue to fund the
Food and Drug Administration, which is the agency responsible
for making sure the promising research supported by the 21st
Century Cures Act actually reaches patients.
We will hear from witnesses from the agency itself to tell
us how the User Fee Agreements will improve the agency's
abilities to regulate medical products and promote innovation.
We will hear from patients, device manufacturers, and brand
and generic drug manufacturers in a second hearing, which is
tentatively scheduled for April 4.
I want to thank the witnesses for taking the time to
testify today. We respect the great amount of expertise and
service that you have given to our country. I want to thank
you, also, for moving so quickly to implement the 21st Century
Act. I noticed especially that the provision involving
regenerative medicine was published within about a month after
President Obama signed the law.
The first medical product User Fee Agreement was enacted in
1992. The FDA worked with the drug manufacturers to hammer out
an agreement that the agency would collect user fees from drug
manufacturers in exchange for more timely, predictable reviews.
The agreement was a success. It decreased review times and
increased patient access to medicines.
Before September 30 of this year, four different User Fee
Agreements need to be reauthorized. The Prescription Drug User
Fee is the first one. It is common around here to call it
PDUFA. I am not going to do that. I just cannot stand PDUFA,
and MDUFA, and GDUFA, and the other UFA.
[Laughter.]
I am going to call them, if you do not mind, the
Prescription Drug User Fee, which accounted for over 70 percent
of the brand drug review in 2015.
The second one is the Medical Device User Fee, which
accounted for 35 percent of the medical device review budget in
2015.
The Generic Drug User Fee accounted for 70 percent of
generic drug review budget.
The Biosimilar User Fee accounted for 7 percent of the
biosimilar review budget.
A lot of the money for the FDA comes from these agreements
with manufacturers of prescription drugs and devices.
The authority for the FDA to collect user fees for medical
product review will expire on September 30 of this year, 6
months from now.
This is probably the most important part of what I have to
say this morning.
If we do not move quickly to authorize these Agreements,
the FDA will be forced to begin sending layoff notices to more
than 5,000 employees to notify them they may lose their jobs in
60 days. That is what they have to do by law.
A delay in reauthorizing these Agreements would delay the
review of drugs and devices submitted after April 1, only a few
days away.
For example, if we do not pass these reauthorizations into
law before the current Agreements expire, an FDA reviewer, who
gets started reviewing a cancer drug submitted to the agency in
April, would be laid off on October 1 before the reviewer is
able to finish his or her work.
The sooner we reauthorize the Agreements, the better, to
give patients, reviewers, and companies certainty.
In addition to harming patients and families that rely on
medical innovation, a delay in reauthorizing the User Fees
would threaten biomedical industry jobs and America's global
leadership in biomedical innovation.
I am hopeful that this committee, and this Congress, can
work in a bipartisan manner to reauthorize the User Fees before
the August recess. Congress must pass legislation reauthorizing
and updating the fees to support the recommendations contained
in what are called ``commitment letters'' sent to Congress in
January.
These commitment letters are part of the Agreements between
the FDA and the industry to establish the agency's commitments,
such as timelines for application review or to put out
guidances in exchange for the fees that Congress authorizes.
The letters were transmitted to Congress in January of this
year. Today's hearing is not the first time Members of
Congress, or the public, is hearing about the recommendations
for reauthorization.
In Congress, while we were working on the 21st Century
Cures, after it was signed into law, the HELP committee had 15
bipartisan hearings throughout that time--before it was signed
into law and after it was signed into law, the 21st Century
Cures some of which were in conjunction with the Energy and
Commerce Committee in the House of Representatives--so that we
could hear from the FDA and industry about the reauthorization.
The first of those briefings was back in late 2015.
Outside of Congress, the FDA posted meeting minutes after
every negotiation and held public meetings to hear feedback.
The content of the commitment letters and the changes to the
fee authorizations should not be new or a surprise for any
member of this committee.
After the April 4 hearing, I hope to move to markup the
legislation in committee as soon as possible. This is the first
time the User Fees have sunset in the first year of a new
administration, so we are starting hearings a little later this
year than we did in 2012.
In order to get this done on time, any additional policies
that Senators may want to attach need to be broadly bipartisan,
related to human medical products, and noncontroversial in
order to avoid slowing the package down.
There are many improvements in the commitment letters and
fee structures in these reauthorizations to be excited about.
The Prescription Drug and Medical Device reauthorizations
included many provisions that build on the work of 21st Century
Cures such as involving patients in the drug and medical device
development. A dedicated staff to assist in the development and
review of rare disease drugs, improved timelines, increased
guidance for drug and device combination products, and
modernizing the clinical trial process.
There are structural reforms. Each Agreement contains
reporting measures built both by the FDA and by independent
third parties so we can see how the changes are working.
The FDA is going to work to implement full-time reporting
by 2022, so Congress, patients, and medical product
manufacturers will have a better picture about how resources
are being used at the FDA and understand what is needed to do
what we ask.
The Biosimilar and Generic Drug User Fees Agreement
includes additional staff and resources to approve more
biosimilars and more generic drugs, which provide more
competition and lower drug costs.
These are just a few of the highlights of the
reauthorization and commitment letters. It is a good Agreement
for patients, and I look forward to working with Senator Murray
and all the members of the committee to get it done
expeditiously.
Senator Murray.
Opening Statement of Senator Murray
Senator Murray. Thank you very much, Chairman Alexander.
Thank you to all of our colleagues and our witnesses for
joining us today.
Mr. Chairman, before I start, I want to talk about the
letter that every Democrat on this committee signed and sent to
you this past Friday requesting that our hearing on User Fees
be delayed in order to make time for an urgently needed
discussion of Trump Care.
To be frank, the hearing that we are having today seems
inappropriate for the moment that we are in. House Republicans'
Trump Care bill could be on the House floor in a matter of
several days.
This is legislation that will take tens of millions of
people off of coverage, cause premiums to spike, target seniors
with higher healthcare costs just because of their age, end
Medicaid as we know it, and make coverage too expensive for
millions of rural and older Americans, and cutoff access to
critical health services at Planned Parenthood. And I could go
on.
Trump Care will cause all this harm and more, while giving
the wealthiest one-tenth of 1 percent of Americans a nearly
$200,000 tax cut, and give insurance company executives a
massive tax break as well.
Senator McConnell has indicated that Trump Care could
change significantly in the Senate if it passes the House. But
instead of giving Senators time to review and evaluate a
possibly very different bill, he has indicated it will go
straight to the floor for a vote.
We are talking about legislation that will have a profound
and profoundly negative impact on the lives, well-being, and
financial security of people across the country. People who, I
might add, are truly terrified about the uncertain path
forward.
The idea that our committee, the Health Committee, would
not have a single hearing to discuss and debate it is
completely appalling, and leaves me very concerned that our
bipartisan tradition on the HELP Committee is continuing to
give way to extraordinary partisanship from Republican leaders
in the Trump administration.
I really hope that we see a reversal of this pattern, and I
hope it begins with a HELP Committee hearing on the impact of
this legislation, especially given that I know Democrats are
not the only ones with grave concerns about the many ways that
Trump Care could hurt women, and families, and seniors
nationwide.
I hope the Republicans do the right thing, step back from
the precipice, and work with us to strengthen our healthcare
system, not destroy it. It would be truly unfortunate if this
intense partisanship from Republicans in the healthcare arena
were to impact Congress' ability to work together on shared
priorities, like reauthorizing the User Fee Agreements this
year.
The already finalized User Fee Agreements for drugs,
generics, biosimilars, and medical devices reflect thorough
negotiations. They will help support the growth and maturation
of the FDA to an agency ready for 21st century technology and
the movements toward precision medicine, and build on the
bipartisan policies passed in the 21st Century Cures Act last
year.
Especially in light of a very tight fiscal reality, these
Agreements are an important tool to help make sure that the FDA
can uphold its gold standard of approval while evaluating new
drugs and devices efficiently.
I oppose efforts by the Trump administration to take
unprecedented actions to alter these Agreements or to undermine
the important public health work of the agency. I am also
concerned that the Administration is hampering the FDA by
depriving it of key staff, blocking it of key staff, and
blocking its ability to issue the guidance and regulations
needed to foster innovation.
Moving forward with the Agreements as already finalized is
absolutely necessary if Congress wants to advance safe,
effective, and innovative medical products for patients and
families across the country. Without these Agreements, the
agency will be crippled.
Another key concern for me--and one that I know is a huge
burden for families in my State and nationwide--is the
astronomically high price of prescription drugs. To be clear,
the FDA's approval processes and standards are not direct
causes of high drug prices. But everyone in this room knows we
are facing a dire situation when it comes to the rising costs
of drugs.
Our broken system results in patients and families across
the country being unable to afford the drugs and treatments
they need. And this is a situation that does demand action from
this committee.
I know our Members on both sides of the aisle have ideas
about ways to reduce the burden of drug costs and I am
committed to working with all colleagues on both sides of the
aisle on this issue.
Chairman Alexander, I do want to reiterate my sincere
disappointment and really shock that there is so much at stake
for patients and families in the bill working its way through
the House now and here, apparently, to the Senate very quickly.
That that kind of bill could be jammed through the Senate in a
matter of days and this committee having no formal opportunity
to discuss it is really concerning.
We all should know, Trump Care is causing millions of
people fear and worry, and while there is every reason for
Republicans to want to avoid talking about its disastrous
consequences, that is no excuse for trying to make it an
elephant in the room.
Thank you, Mr. Chairman.
The Chairman. Thank you, Senator Murray.
We have this opportunity to talk about the Food and Drug
Administration User Fees. We have the experts from the agency
here to do that today and April 4, tentatively scheduled, we
will have patient safety groups and manufacturers here to talk.
So I hope we can take full advantage of the time.
We have a vote scheduled for noon. I will be glad to come
back if Senators have more questions of the FDA representatives
or something they would like to say.
Each witness will have up to 5 minutes to give his or her
testimony. I am pleased to welcome our three witnesses to
today's hearing.
First, thank you for taking time to be here.
The first witness is Dr. Janet Woodcock. We know her well.
She is Director of the Center for Drug Evaluation and Research
at the FDA, which performs the critical task of ensuring safe
and effective drugs are available to improve the health of
people in the United States.
She has been at the FDA for 30 years, and been the Center
Director since Congress reauthorized the Prescription Drug User
Fee Agreements and first authorized the Biosimilar and Generic
Drug Agreements in 2012.
We will then hear from Dr. Peter Marks, Director of the
Center for Biologics Evaluation and Research at the FDA. He
joined the Center as Deputy Center Director in 2012 and became
Center Director in 2016. The Center for Biologics Evaluation
and Research is responsible for ensuring the safety and
effectiveness of biological products including vaccines, and
cellular and gene therapies.
I look forward to hearing how the User Fee funds will help
the Center keep up with rapidly advancing science and promote
certainty for sponsors.
Third to testify will be Dr. Jeffrey Shuren. He is Director
of the Center for Devices and Radiological Health, which is
responsible for ensuring the safety, effectiveness, and quality
of medical devices and fostering device innovation. He has been
Director since January 2010.
Welcome, again, to this panel of experts.
Dr. Woodcock, we will start with you.
STATEMENT OF JANET WOODCOCK, M.D., DIRECTOR, CENTER FOR DRUG
EVALUATION AND RESEARCH, FOOD AND DRUG ADMINISTRATION, SILVER
SPRING, MD
Dr. Woodcock. Thank you, Mr. Chairman, members of the
committee.
I am glad to be here to discuss three Drug User Fee
programs that are due for reauthorization in fiscal year 2018.
The first one, the Prescription Drug User Fee Act program
supports innovation. That is basically what that one is about.
PDUFA has resulted in fast and predictable review of innovative
therapies for Americans.
U.S. patients are first in the world to get innovative
therapies in over two-thirds of the cases. Compared to the
entire rest of the world, they are first.
New therapies often are for rare, fatal, untreatable
diseases, orphan conditions, cancers, degenerative neurologic
diseases. These are important therapies that the PDUFA program
helps get to the market in many cases.
In some cases recently, with the advance of science, we
have actually been able to get cures onto the market. For
example, the hepatitis C drugs are curing that infection, that
chronic infection that was resulting in so many transplants in
chronically ill people.
Programmatic improvements that are envisioned in the next
PDUFA program include more support for a breakthrough therapy
program. This was enacted by Congress around 5 years ago, and
has been extremely successful in getting those breakthrough
game-changing drugs to patients in as quick a manner as
possible. This Agreement would provide more support for that
program.
Advancing the use of surrogate endpoints; surrogate
endpoints are used to speed market access when the actual
clinical outcomes might take a very long time.
Accelerating drug development tools; this is something that
this committee paid a great deal of attention to in the 21st
Century Cures, the biomarkers, and so forth. The new PDUFA
agreement would provide additional support for that as well as
complex trial designs.
Also, there is additional support in renovation for our
review of combination products. These are becoming more and
more common. We have auto-injectors. We have drugs and devices
that are used together in different ways, and we need to make
sure those reviews are predictable, that they are streamlined,
and we can get those innovative products to patients as soon as
possible.
And finally, there are provisions for supporting our
evaluation of real world evidence; another type of evidence
that was discussed in the Cures legislation.
The second User Fee program is the Generic Drug User Fee
program. This would be the second version of this program.
GDUFA, instead of supporting innovation, it supports
affordability of drugs by introducing generic competition.
Almost 90 percent of prescriptions that are dispensed in the
United States today are generic drugs. This program over the
years has been extremely successful.
It is estimated that over a decade, it has saved U.S.
consumers about $1.5 trillion by being able to purchase
affordable generics instead of expensive brand drugs.
The first Generic Drug User Fee program had quite a few
problems because there was a huge backlog. The success of the
program had really overwhelmed our ability to review all these
generic drugs. But we also had a non-automated paper-based
review process, and thousands and thousands of generic drugs to
review.
GDUFA I, met or exceeded all its submission review goals.
All those thousands of drugs have been taken up into the review
process and are in process or on the market. In fact, about
one-quarter of all currently approved generic drugs have been
approved in the last 4 years.
We approved in 2016 alone, the highest number of generic
drugs ever approved in a year; 835 generics approved or
tentatively approved. Of all of those generics we approved, 405
of those during the program were first generics, so the first
competitor to come onto the market for a brand drug; a very
important landmark.
GDUFA II, the second program, builds on the first. It
provides for a faster review of priority applications. Those
would be applications that lack that competition and they would
be reviewed within 8 months.
There is also for the complex generics--those that are not
simple tablets, but may have an auto-injector or a device
associated with them, or they may be a very complicated
molecule or dosage form--it provides for a preprogram where
they can come in and talk to us. We can help them with their
development. This is what we do for innovator drugs. There is
also going to be more communication and improved facility
assessments.
The third program is the Biosimilars User Fee Act, and this
is again different. The Biosimilars Act, with the help of
Congress and your legislation, is establishing a new industry,
the biosimilars industry. It will provide competition for those
biological drugs, most of which are very expensive.
We have already approved four biosimilar products, which
provide competition to very widely used biologic drugs and
there are numerous applications that we are reviewing in-house.
There are actually 64 biosimilar products in development
programs. So we hope to grow this program in the next User Fee
program.
These have all benefited patients, the medical community,
and the public.
I would really be happy to answer any questions you might
have.
[The combined prepared statement of Dr. Woodcock, Dr. Marks
and Dr. Shuren follows:]
Prepared Statement of Janet Woodcock, M.D., Peter Marks, M.D.,
and Jeffrey Shuren, M.D., J.D.
introduction
Mr. Chairman and members of the committee: We are the directors of
the Center for Drug Evaluation and Research (CDER), Center for
Biologics Evaluation and Research (CBER), and Center for Devices and
Radiological Health (CDRH) at the U.S. Food and Drug Administration
(FDA or the Agency), which is part of the Department of Health and
Human Services (HHS). Thank you for the opportunity to be here today to
discuss the reauthorization of the Prescription Drug User Fee Act
(PDUFA VI), the reauthorization of the Medical Device User Fee Act
(MDUFA IV), the first reauthorization of the Generic Drug User Fee
Amendments (GDUFA II), and the first reauthorization of the Biosimilar
User Fee Act (BsUFA II). The User Fee programs help FDA to fulfill its
mission of protecting the public health, while improving the
predictability of review processes and accelerating innovation in the
industry. Since the inception of these programs, FDA has dramatically
reduced the review time for new products, without compromising the
Agency's high standards for demonstration of safety, efficacy, and
quality of new drugs or devices prior to approval.
The reauthorization proposals for PDUFA, MDUFA, GDUFA, and BSUFA
that are described below were submitted to Congress in January, under
the previous Administration and reflect a different approach to the
Federal Budget. The Blueprint Budget supports many of the goals of the
reauthorization proposals but proposes a different way of financing
these goals. The Administration looks forward to working with Congress,
with industry input, to develop reauthorization proposals that speed
the development and approval of vital medical products that are safe
and effective.
pdufa
The timely review of the safety and effectiveness of new drug
applications (NDAs) and biologics license applications (BLAs) is
central to FDA's mission to protect and promote the public health--and
PDUFA is essential to these efforts.
Before PDUFA's enactment in 1992, Americans' access to innovative,
new medicines lagged behind other countries. FDA's pre-market review
process was understaffed, unpredictable, and slow. The Agency lacked
sufficient staff to perform timely reviews or develop procedures and
standards to assure a more rigorous, consistent, and predictable
process.
To tackle these challenges, Congress passed PDUFA, which authorized
FDA to collect industry user fees to hire additional staff and upgrade
its information technology systems. In return, it committed the Agency
to speed the application review process for new drugs without
compromising its high standards for new drug safety, efficacy, and
quality.
Speeding Americans' Access to Safe and Effective New Therapies
PDUFA has revolutionized the United States' drug approval process.
It reversed the lag in drug approvals that prompted its creation,
providing Americans with more rapid access to safe and effective new
drugs and biologics.
As shown in Figure 1, today, almost two-thirds of new active
substances approved in the world market are launched first in the
United States. To put this figure in perspective, that is more than
triple the rate approved first in the United States in the first year
of PDUFA.
[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]
The 5-year reauthorization cycles for PDUFA have supported
continuous program innovation, evaluation, and improvement. The
enhancements to the process of human drug review originally focused on
the FDA pre-market review of NDAs and BLAs. Through successive PDUFA
reauthorizations, program enhancements have evolved and expanded to
include extensive communication and consultation between drug sponsors
and FDA throughout drug development. This has enabled better
incorporation of advances in regulatory science applied to drug
development and regulatory oversight. The continued modernization of
drug review under PDUFA has also strengthened and enabled innovation in
approaches to post-market safety. Most recently, the program has been
enhanced by increasing patient focus and modernizing supporting
informatics.
These enhancements have contributed to the United States becoming a
global leader in drug innovation and Americans are typically the first
to benefit from safe and effective new medicines. PDUFA, with its
reauthorization cycles, has resulted in a scientifically and
financially strong program with transparent stakeholder engagement as a
routine way of doing business.
Throughout this program evolution, FDA has continued to review
large volumes of sponsor submissions and deliver predictably high
levels of performance against PDUFA goal commitments for timely
regulatory review and development phase consultation, as shown in
Figure 2.
---------------------------------------------------------------------------
\1\ NME = New Molecular Entity: NDA = New Drug Application; BLA =
Biologic Licensing Application; CBE = Changes-Being-Effected.
[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]
Increasing the Timeliness and Efficiency of Premarket Review
A key element of the success of the PDUFA program is ongoing
development-phase consultation provided to drug sponsors by FDA,
helping to minimize unnecessary or suboptimal development steps, and
getting important new drugs to patients more rapidly and efficiently.
FDA's capacity to provide sponsors, including small first-time
innovators, with timely advice enabled by PDUFA funding, has
contributed to the strong drug development pipeline in the United
States today. This is reflected in the increased numbers of drug
development programs underway in companies, and the corresponding
growth in company requests for development phase meetings with FDA, as
shown in Figure 3.
[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]
The volume of formal meetings requested by drug sponsors has
steadily grown over the course of PDUFA. Early and frequent
communication between sponsors and FDA serves to improve the efficiency
of drug development. Indeed, it is one of the cornerstones of the
Breakthrough Therapy program. FDA-sponsor meetings help sponsors
navigate key milestones during drug development, support the assembly
and submission of sponsors' marketing applications, and enable sponsors
to clarify requirements for complete application submissions and
potentially avoid the need for an additional review cycle.
The improvement in the quality of drug development programs and the
submitted applications, supported by these PDUFA-enabled consultations
between FDA and drug sponsors, is but one explanation for the observed
trend toward higher first cycle approvals of applications for novel
drugs (referred to as new molecular entity (NME) NDAs and BLAs), as
shown in Figure 4.
[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]
Development-phase consultations can be particularly helpful in
support of the most innovative drug programs. Of the NME NDAs and BLAs
that FDA approved in calendar year (CY) 2016, over one-third were
indicated for rare diseases. In addition, over one-third (36 percent)
of the drugs approved by the Center for Drug Evaluation and Research
were first in their drug class and over 80 percent (86 percent) were
approved first in the United States.
While a standard review is typically completed in 10 months, FDA
expedites review for priority drugs to be completed within 6 months.
Priority drugs are generally targeted at severe illnesses with few or
no available therapeutic options. They typically receive greater
assistance from FDA reviewers throughout the development process,
including providing advice in the design and implementation of the
clinical trials necessary to demonstrate product safety and
effectiveness.
In 2016, over 60 percent of NME NDAs and new BLAs approved by FDA
benefited from one or more of FDA's expedited programs.
Expanded Access to Investigational Products
While the best means of providing access to useful medical
treatments for all Americans is to approve drugs demonstrated to be
safe and effective as quickly as possible, FDA also recognizes
circumstances in which there may be value to patients and physicians in
having access to products prior to marketing approval. In some cases
where an individual has a serious or life-threatening disease and lacks
a satisfactory therapy, that individual may believe that a promising
but not yet fully evaluated treatment is his or her best choice.
FDA allows for access to investigational products through clinical
trials and the Agency's Expanded Access program. Clinical trials
collect the necessary clinical information needed for FDA review and,
if appropriate, approval, of investigational drugs, thereby making the
drug widely available to patients. However, there are times when an
individual cannot enroll in a clinical trial. In these cases, the
patient may be able to gain access to an investigational therapy
through the Expanded Access program.
In order for an individual patient to qualify for the Expanded
Access program, several criteria must be met, including that the
patient must have a serious or life-threatening disease or condition
and no comparable or satisfactory alternative therapy. The patient's
physician then approaches the pharmaceutical company to ask for its
agreement that it will provide the drug being sought. The company has
the right to approve or disapprove the physician's request. If the
company agrees to the physician's request, the physician can then apply
to FDA for authorization to proceed. Should they do so, they are highly
likely to be allowed to proceed with the expanded access use. FDA has
authorized more than 99 percent of the requests received in fiscal
years 2010-15. Emergency requests are usually granted immediately over
the phone and non-emergencies are processed in a median of 4 days.
Access to investigational products requires the active cooperation
of the treating physician, industry and FDA in order to be successful.
In particular, the company developing the investigational product must
be willing to provide it--FDA cannot force a company to manufacture a
product or to make a product available. Companies might have their own
reasons to turn down requests for their investigational products,
including their desire to maintain their clinical development program
or simply because they have not produced enough of the product.
For over 20 years, FDA has been committed to ensuring that this
program works well for patients and has recently made significant
improvements to its functioning and efficiency.
Breakthrough Therapy Designation
The Breakthrough Therapy (BT) program, authorized by the FDA Safety
and Innovation Act (FDASIA), has further enhanced the engagement of FDA
and sponsors during drug development. This program, which is for new
drugs to treat serious and life-threatening diseases with unmet medical
need, calls for intensive FDA-sponsor consultation during development,
when preliminary clinical evidence indicates that the drug may
demonstrate substantial improvement over available therapies on one or
more clinically significant endpoints.
Given the known benefits of development-phase consultation with
FDA, the BT designation has been much sought after by sponsors. As of
November 30, 2016, FDA had received 492 requests for BT designation and
had granted 165 requests. Figure 5 shows the trend of increasing
numbers of development programs.
[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]
Although oncology, hematology and antiviral products account for
the largest share of BT designation requests in CDER, it should be
noted that BT requests and the granted designations and ongoing
programs span the entire spectrum of disease areas as shown in Figure
6a, reflecting granted designations as of November 30, 2016. In CBER,
most of the BT designation requests and granted designations are for
gene therapies, vaccines and immunotherapies as shown in Figure 6b.
[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]
PDUFA V
We are currently in the final year of the PDUFA V program. Over the
years since the start of PDUFA I in 1992, the complexity of scientific
and clinical issues in the study of new drugs has grown, including use
of genetic targeting, biomarkers, novel trial designs, plans and
programs to ensure effective post-market risk management. These
approaches and issues were less common or nonexistent at the start of
PDUFA. In addition, predictability and increased communication with FDA
during drug development and application review emerged as a top
priority for drug sponsors.
PDUFA V sought to achieve a better balance between the desire for
increased communication with sponsors and the need to ensure adequate
review time for the most complex and innovative products reviewed by
FDA. This resulted in a cornerstone of the PDUFA V agreement, a new
program for NME NDAs and BLA reviews that is designed to promote
greater transparency and improve communication between the FDA review
team and the applicant. We anticipated that the increased
communications before application submissions and at key points within
the first review cycle would ensure that FDA had access to all of the
information that might inform and enable a first-cycle approval for
those applications that could be approved, avoiding unnecessary
additional cycles of review. This would enable faster access to new
drugs for the patients who need them and would help reduce avoidable
costs for drug sponsors.
A key measure of program success is the percentage of applications
approved in a single, first review cycle. Figure 7 illustrates the
success of the PDUFA V NME Program in achieving its first cycle review
goals for both standard and priority reviews. The figure presents the
share of first-cycle approvals for priority and standard NDAs and BLAs
filed. First cycle approvals for NME NDAs and new BLAs have been
significantly higher under the new PDUFA V review program.
[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]
Other PDUFA V enhancements include improved communications during
drug development, strengthening the rare disease program, exploring new
methods for regulatory science, and implementation of structured
benefit-risk assessment. PDUFA V also provided for additional drug
safety enhancements focused on standardizing the design of Risk
Evaluation and Management Systems (REMS) and using the Sentinel
Initiative, FDA's active surveillance systems for post-market safety
(see PDUFA IV), to evaluate drug safety issues. This has prepared the
way for expanded reliance on the data from Sentinel.
Patient-Focused Drug Development
As part of the PDUFA V benefit-risk assessment initiative, FDA and
industry recognized that patients are uniquely positioned to inform
aspects of FDA's benefit-risk assessment, particularly the
understanding of the disease and its severity and the adequacy of
existing treatment options. Therefore, FDA committed to hold at least
20 public meetings over the 5-year period, with each meeting focused on
obtaining direct patient input in a specific disease area. This
initiative, referred to as ``patient-focused drug development,'' has
since been described as potentially transformational in advancing the
role of the patient in drug development and decisionmaking. Although
initially committing to conduct 20 meetings, FDA is on track to conduct
24 meetings each in different disease areas. The goal of the meeting is
to hear from patients and their caregivers about the impact of their
disease on their lives, and for FDA to hear more about what treatment
benefits would be most meaningful to patients, and what treatment
burdens are most important to consider. Following each meeting FDA
develops a Voice of the Patient report to capture what was heard in the
meetings (and comments from patients received in the docket); these
documents serve as a valuable reference for FDA reviewers in subsequent
drug reviews and related decisionmaking.
Patient-focused drug development has provided key learnings for FDA
that are being carried forward and integrated into our methods and
approaches to development and decisionmaking. We recognize that
patients with chronic serious disease are experts on what it is like to
live with their condition, and we have learned that they want to be as
active as possible in the work to develop and evaluate new treatments.
In the past, patients' ``chief complaints'' were often not factored
explicitly into drug development plans (as endpoints and measures of
drug benefit planned in trials), and this is an area of needed
attention going forward. Although the PDUFA V patient-focused drug
development initiative was intended as a pilot to elicit broader
patient input, a key question for the agency was how to best buildupon
this pilot to advance the science and processes for effective
incorporation of the patient's voice in drug development and
decisionmaking.
In preparing for PDUFA VI reauthorization discussions, FDA has
worked to build on the successes and learnings of PDUFA V and pursue
new areas of opportunity for innovation in the enhancement of
regulatory decision tools and new potential sources of evidence to
inform drug development and review.
PDUFA VI Reauthorization Process
Congress directed the Agency to reach out to all stakeholders to
solicit thoughts and insights on PDUFA reauthorization and changes to
PDUFA performance goals. FDA held an initial public meeting on July 15,
2015, which included presentations by FDA and representatives of
different stakeholder groups, including patient advocates, consumer
groups, regulated industry, health professionals, and academic
researchers. A transcript and webcast recording are available on FDA's
website at https://www.fda.gov/ForIndustry/UserFees/
PrescriptionDrugUserFee/ucm446608.htm.
Based on comments to a public docket, and the Agency's own internal
analyses of program challenge areas, FDA developed a set of potential
proposed enhancements for PDUFA VI and began negotiations with
industry. Parallel discussions with public stakeholders were held
monthly from September 2015--February 2016 to update participants on
ongoing negotiations and solicit thoughts. Meeting minutes were posted
on FDA's website and are available at https://www.fda.gov/ForIndustry/
UserFees/PrescriptionDrugUserFee/ucm446608.htm.
A final public meeting was held on August 15, 2016, to discuss the
PDUFA VI agreement and engage with interested parties on proposed
recommendations. A summary of the agreement and a draft of the
Commitment Letter were provided a month in advance of this discussion.
Final PDUFA VI recommendations were transmitted to Congress in December
2016.
PDUFA VI Overview
Building on the success of previous agreements, PDUFA VI continues
to support early and meaningful communication between FDA and drug
sponsors to deliver safe and effective medications to Americans more
quickly, and, expands on such communications by providing resources for
the popular, highly successful, and resource-intensive Breakthrough
Therapy program and streamlining review of products combining a drug or
biologic with a device. It enhances drug development tools including
biomarker qualification and provides resources to increase our
understanding of how ``real-world evidence'' can be generated and used
appropriately in regulatory decisionmaking. The agreement also enables
us to leverage the use of real-world health data by enhancing the
capabilities of FDA's Sentinel System.
Many of these core provisions are explained in greater detail
below.
Capturing the Patient Voice in Drug Development
Central to PDUFA VI, and its largest single investment component,
are plans to elevate patient voices in developing new drugs to treat
their diseases. The agreement shares the committee's goals reflected in
the 21st Century Cures Act (``Cures'')--and the highest priority of our
stakeholders--to leverage essential patient input and insights to fight
disease.
We are building on the success of PDUFA V which established the
Patient-Focused Drug Development (PFDD) program to obtain valuable
patient perspectives. Areas of focus were carefully chosen based on a
public process soliciting patient and stakeholder input. Under PDUFA
VI, we look forward to engaging in a transparent, multi-stakeholder
approach that will lead to development of the methods and approaches to
ensure patients not only become active participants but informants to
industry drug development and agency review. The performance
commitments and matching resources to sufficiently staff this critical
new work are intended to bridge from patient-focused drug development
meetings to fit-for-purpose tools to collect meaningful patient input,
including capturing information on the natural progression of disease.
To help identify sound and rigorous methods to capture science-
based, disease-specific patient input, FDA has committed to enhance its
staff capacity, hold a series of four public workshops, and develop
four key guidance documents on needed methods and approaches. The
Agency will also publish on its website a repository of publicly
available tools as a resource for stakeholders and ongoing efforts.
We are gratified by the enthusiastic response within the patient
community to PFDD, and look forward to working with the broader
community to advance the science of patient input--and deliver new and
better treatment options.
Building a Solid Foundation for Breakthrough Therapies
The Breakthrough Therapy program, authorized by FDASIA, has become
one of the most popular components of the human drug review program
with requests and designations far exceeding expectations.
The increase in promising new drugs to treat serious and life-
threatening diseases with unmet medical need is, of course, a very good
thing for both patients and public health. But the growth of the BT
program has strained limited available review staff resources. A
hallmark of the BT program is intensive Agency interaction with
sponsors during the development process on complex products with
transformative potential. This ``all hands on deck'' approach provides
a sponsor of a designated breakthrough product with guidance from the
Agency on efficient drug development beginning as early as the Phase I
period, an organizational commitment to involve senior managers, and
eligibility for rolling review. Many of the BT designations granted so
far have been for rare disease indications.
The PDUFA VI agreement provides dedicated funding to ensure the
sustained success of the BT program. Additional resources will enable
FDA to increase review staff and to supplement resources for clinical
pharmacology, statistics, and product quality. This renewed commitment
will enable the Agency to continue to work closely with sponsors to
ensure expedited development and review of breakthrough therapies for
serious or life-threatening diseases.
Advancing Biomarker Development
FDA and industry share the goals of Cures to accelerate development
of reliable biomarkers to advance important new therapies. Biomarkers
are currently used throughout the drug development process, including
as surrogate endpoints to support earlier evidence for regulatory
decisionmaking when evidence from a clinical endpoint could take much
longer or require many more patients to be studied.
FDA commonly uses surrogate endpoints in accelerated approvals
where confirmatory evidence is required to verify the expected clinical
benefit after marketing begins. Surrogate endpoints have been the basis
for 60 percent of rare-disease approvals. Once a surrogate endpoint is
well-established to predict clinical benefit, surrogate endpoints can
be used to support traditional approvals as well. For example, FDA
regularly relies on a surrogate endpoint for approval of new therapies
for diabetes (the HbA1C test, a measurement of hemoglobin with attached
sugar in the blood that reflects the extent and persistence of elevated
blood sugar) greatly expanding patient treatment options.
The PDUFA VI proposed enhancements include some of the same
activities specified in Cures. PDUFA VI addressed the opportunity for
application of biomarkers in two different areas, one involving
proprietary use of a biomarker as a surrogate endpoint in a specific
drug development program, and the other involving the more public
process of biomarker qualification as a drug development tool.
FDA recognizes that early consultation can be important to an
efficient development program when a sponsor intends to use a biomarker
as a new surrogate endpoint that has never been used as the primary
basis for product approval in the proposed context of use. The PDUFA VI
commitments therefore provide for early consultation with the sponsor
to enable the FDA review team to consult with senior management to
evaluate the sponsor's proposal before providing advice to the sponsor
on a critical aspect of their development program. This will enable FDA
to discuss the feasibility of the surrogate as a primary endpoint, any
knowledge gaps, and how these gaps should be addressed before the
surrogate endpoint could be used as the primary basis for approval.
PDUFA VI also provides enhancements for the more public drug
development tool qualification pathway for biomarkers. The biomarker
qualification program was established to support FDA's work with
external partners to develop biomarkers that aid in the drug
development process. To facilitate the enhancement of the drug
development tools qualification pathway for biomarkers in PDUFA VI, FDA
proposes to convene a public meeting to discuss taxonomy and a
framework with standards for biomarkers used in drug development, to
develop guidance on biomarker taxonomy, contexts of uses, and general
evidentiary standards for biomarker qualification, and to maintain a
public website to communicate a list of biomarker qualification
submissions in the qualification process.
Meaningful progress in developing additional biomarkers for public
qualification requires collaboration among a wide range of
stakeholders. FDA will continue to work with the National Institutes of
Health, the Biomarkers Consortium, the Critical Path Institute and
others to advance biomarker development.
Streamlining Combination Product Review
More streamlined oversight of combination products is another FDA
and industry priority reflected in PDUFA VI. Under the proposed
enhancements FDA will pursue improvements in inter-center and intra-
center combination product review coordination and transparency for
PDUFA products that are combination products regulated by CDER and CBER
(PDUFA combination products). FDA proposes to enhance staff capacity
and capability across the relevant medical product centers and the
Office of Combination Products to more efficiently, effectively, and
consistently review combination products. FDA also proposes to
streamline the process for combination product review and to improve
the Agency's ability to track combination product review workload,
including a third party assessment of current practices for combination
drug product review.
Our goal, consistent with Cures, is to enhance the overall
efficiency, consistency, and predictability of combination product
review without imposing new administrative burdens.
Under PDUFA VI enhancements FDA will also establish new performance
goals and submission procedures for the review of human factors
protocols for PDUFA combination products. These goals will be to
provide the sponsor with written comments on these protocols within 60
days of receipt. The goals to provide written comments within 60 days
will begin at the 50 percent level in fiscal year 2019, and increase to
90 percent by fiscal year 2021.
Advancing the Use of Complex Innovative Trial Designs and Model
Informed Drug Development
FDA routinely works closely with industry to facilitate innovative
approaches to drug development that maintain our high standards for
drug safety and efficacy. PDUFA VI promises to encourage future efforts
by advancing Model-Informed Drug Development (MIDD) and the use of
complex innovative and adaptive clinical trial designs.
The development and application of exposure-based, biological, and
statistical models derived from preclinical and clinical data sources
can be used to inform regulatory decisionmaking, for example, in
determining patient selection in clinical trials, individualized dosing
for specific populations, or the need for post-marketing studies. To
facilitate the development and application of these approaches during
PDUFA VI, FDA proposes to convene a series of workshops to identify
best practices for MIDD, to conduct a pilot program, to develop
guidance on MIDD, and to update policies and procedures, as
appropriate, to incorporate guidelines for the evaluation of MIDD
approaches.
To facilitate the advancement and use of complex adaptive,
Bayesian, and other novel clinical trial designs during PDUFA VI, FDA
proposes to convene a public workshop on complex innovative trial
designs, publish guidance on complex innovative trial designs, to
conduct a pilot program, and to update policies and procedures as
appropriate to incorporate guidelines on evaluating complex innovative
trial designs.
Utilizing Real-World Observational Data
It has been said that medical care and biomedical research are in
the midst of a data revolution, and networked systems, electronic
health records, electronic insurance claims databases, social media,
patient registries, and other new sources may comprise an immense new
set of sources for data about health and healthcare. In addition, these
``real-world'' sources can provide data about patients in the setting
of their environments--whether at home or at work--and in the social
context of their lives. There is little doubt that the new sources of
data now becoming increasingly available to researchers, clinicians,
and patients hold enormous potential for improving the quality, safety,
and efficiency of medical care. More work is needed to understand both
the promise and pitfalls of far-reaching technological changes,
including the multiple dimensions of quality and fitness for purpose
for appropriate use of such data in regulatory decisionmaking.
FDA recognizes the potential value of utilizing ``real-world''
evidence in evaluating not only the safety of medications but also
their effectiveness. To better understand how real-world evidence can
be generated and used appropriately in product evaluation, FDA proposes
to conduct one or more public workshops, as well as other appropriate
activities (e.g., pilot studies or methodology development projects).
Considering the available input, FDA will then publish draft guidance
on how real-world evidence can contribute to the assessment of safety
and effectiveness in regulatory submissions.
Under PDUFA VI, FDA also proposes to pursue a more well-established
use of real-world evidence to support post market drug safety
surveillance utilizing Sentinel. FDA's Sentinel Initiative is a long-
term program designed to build and implement a national electronic
system for monitoring the safety of FDA-approved medical products. FDA
recently transitioned from the Mini-Sentinel pilot to the Sentinel
System, but full utilization of the Sentinel System remains a work in
progress. Continued development and integration of the Sentinel System
is needed to realize the system's full value to the postmarketing
safety review process.
To help realize the full value of the Sentinel System during PDUFA
VI, FDA proposes to continue to expand the systems' data sources and
core capabilities, to systematically integrate Sentinel into
postmarketing review activities, to enhance communication practices
with sponsors and the public regarding general methodologies for
Sentinel queries, and to conduct an analysis of the impact of Sentinel
expansion and integration for regulatory purposes.
Hiring and Retaining Highly Qualified Experts
To speed and improve development of safe and effective new
therapies for patients requires that FDA hire and retain sufficient
numbers and types of technical and scientific experts to efficiently
conduct reviews of human drug applications. In order to strengthen this
core function during PDUFA VI, FDA proposes to commit to completing
implementation of: a modernized position management system; corporate
recruiting practices; augmenting capacity with contractor support;
establishing a dedicated scientific recruiting function; setting metric
goals for human drug review staff hiring; and conducting a
comprehensive independent assessment of hiring and retention system
performance. We want to thank you again for providing vital new hiring
authority in Cures. Cures will greatly improve FDA's ability to hire
and retain scientific experts in more complex and specialized areas and
meet our growing responsibilities.
The hiring commitments proposed in PDUFA VI will complement Cures
by supplementing the expertise and resources the Agency needs to
perform its vital prescription drug mission.
Enhancing Management of User Fee Resources
FDA is committed to enhancing management of PDUFA resources and
ensuring PDUFA user fee resources are administered, allocated, and
reported in an efficient and transparent manner. In PDUFA VI, the
Agency proposes to establish a resource capacity planning function to
improve its ability to analyze current resource needs and project
future resource needs, modernize its time reporting approach, conduct
an evaluation of PDUFA program resource management, and publish a 5-
year PDUFA financial plan with annual updates.
In addition, under PDUFA VI, FDA proposes to enhance the program
fee structure and related mechanisms, to achieve increased
predictability, stability, and efficiency. The current overall PDUFA
fee structure and the fee setting process were established in 1992.
Both FDA and industry recognize that updating some elements of the fee
structure and the fee setting process will enhance administrative
efficiency and the predictability and stability of fee amounts and
revenues and improve FDA's ability to engage in long-term financial
planning. FDA proposes to shift a greater proportion of the target
revenue allocation to more predictable fee-paying types (20 percent to
applications; 80 percent to Program fees), and make other modifications
to improve efficiency and stability including discontinuation of the
establishment and supplement fees, modifying the annual fee billing
date to minimize the need for multiple billing cycles, and other
technical changes.
We are incredibly proud of the progress FDA has made to speed
medical products to patients through the PDUFA program, and look
forward to working with Congress and industry to significantly further
progress.
mdufa
Enacted by Congress in 2002, MDUFA is a user fee program through
which medical device companies pay fees to FDA when they submit a
request for marketing authorization or register their establishments
with FDA. The program includes commitments between the U.S.-medical
device industry and FDA to improve the predictability, transparency,
and consistency of regulatory processes, which are intended to reduce
the time for FDA to make a decision about whether to authorize
marketing of a device.
MDUFA has been reauthorized every 5 years since Congress created
the program. As the program has evolved, FDA and industry have
successfully negotiated agreements to improve patient access to medical
devices and streamline regulatory processes.
During the 2012 MDUFA III testimony, many of you may recall that
the program was in a much different place:\2\
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\2\ See Appendix A: ``U.S. Food and Drug Administration, Center for
Devices and Radiological Health: Progress in Achieving Our Vision of
Patients First.''
In fiscal year 2009, it took an average of 427 days to
reach a decision on a pre-market approval application (PMA), the
submission type required for the highest risk devices.
In fiscal year 2010, it took an average of 150 days to
reach a decision on a pre-market notification submission (also known as
a 510(k)), the submission type required for low- to moderate-risk
devices.
Thanks to the investment provided by industry, and direction
provided by Congress, we have made substantial progress toward reducing
decision times. As of 2015:
It took an average of just 276 days to reach a decision on
a PMA, a 35 percent decrease in 6 years; and
It took an average of just 133 days to reach a decision on
a 510(k), an 11 percent decrease in 5 years.
Further, we went beyond our MDUFA III commitments to reduce the
median time to approve an Investigational Device Exemption (IDE) study
to just 30 days in fiscal year 2015, down from 442 days in fiscal year
2011--a 93 percent decrease in 4 years. This improvement has allowed
companies to begin their clinical trials earlier so they can begin
collecting data to support a decision on their submission requesting
marketing authorization. In addition, we reduced the average time to
reach a decision on a De Novo classification request, the submission
type typically used by novel low- or moderate-risk devices, to 259 days
in fiscal year 2014, down from 770 days in fiscal year 2009--a 66
percent decrease in 5 years.
Changes we have made at CDRH to our culture, policies, and
processes--in addition to user fee funding and changes to Federal law--
have resulted in an improved medical device pipeline and innovative
technologies being introduced in the United States earlier than in the
past. For example, since 2009, the number of innovative devices we have
approved has almost quadrupled. In 2016, we approved 91 innovative
devices--the highest of any year since the user fee program began in
2003. In 2015, we approved the second highest number of innovative
devices.
An example of an innovative technology that FDA approved first in
the world is the ``artificial pancreas,'' something many members of
this committee supported. Working interactively with the device
manufacturer from the earliest stages of development to assist in
making this technology available as quickly as possible, FDA approved
the first device in the world that is intended to automatically monitor
glucose levels around the clock and automatically provide appropriate
insulin doses.
While we have made progress in many areas, we also recognize that
more work remains and there are additional opportunities for
improvements. We look forward to working with industry and Congress to
ensure there are sufficient user fees resources as we strive to make
these improvements. MDUFA IV agreement includes a new quality
management program that will enhance consistency and predictability in
pre-market review processes.
MDUFA IV agreement would also allow FDA to move forward in some
critical and strategic areas such as strengthening our partnerships
with patients.\3\ Strengthening patient input will allow us to promote
more patient-centric clinical trials, advance benefit-risk assessments
that are informed by patient perspectives, and foster earlier access to
new devices.
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\3\ See Appendix B: ``Center for Devices and Radiological Health
(CDRH): 2016-2017 Strategic Priorities--2016 Accomplishments.''
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Another critical area supported by the MDUFA IV agreement is the
development of the National Evaluation System for health Technology, or
NEST.\4\ The NEST is system-owned and -operated by multiple
stakeholders that will use real-world data collected as part of routine
clinical care. A robust NEST will enable manufacturers to harness real-
world evidence that could enable them to drive down the time and cost
of bringing a new device to market, expand the indications for already
approved devices, and meet postmarket reporting requirements. The NEST
will also enable faster identification of safety issues, reducing harm
to patients and liability for companies.
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\4\ See Appendix B: ``Center for Devices and Radiological Health
(CDRH): 2016-2017 Strategic Priorities--2016 Accomplishments.''
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The MDUFA IV agreement, which was supported by a broad array of
stakeholders during the public review of the draft agreement, will
expedite the availability of innovative new products, and its
enhancements will continue to increase the efficiency of FDA's
programs. Improvements in total time to decision, transparency,
consistency, and predictability will benefit industry, healthcare
providers, and, most importantly, patients.
gdufa
The remarkable success of the GDUFA program demonstrates how FDA,
industry and other stakeholders can work together to achieve tremendous
results. GDUFA has expanded access to affordable generic medicines.
About 25 percent of all generic drugs that FDA has ever approved were
approved in the past 4 years. At the same time, GDUFA helps assure the
quality of generic drugs. Patient confidence that generic drugs will
work the same as brand products, and can be freely substituted, is the
foundation for trillions of dollars in savings that generics produce
for the healthcare system.
Historically, the generic drug program has been a great success.
The generic drug industry has grown from modest beginnings into a major
force in healthcare. According to the QuintilesIMS Institute, generic
drugs now account for 89 percent of prescriptions dispensed in the
United States, and saved the U.S. healthcare system $1.46 trillion from
2005 to 2015.
This success brought new challenges. Over the last several decades,
the generic industry, the number of generic drug applications, and the
number of foreign facilities making generic drugs grew substantially.
As a result, FDA's generic drug program became increasingly under-
resourced. Its staffing did not keep pace with the growth of the
industry.
Solution: GDUFA. After much negotiation, FDA and the generic drug
industry, in consultation with other stakeholders, developed a proposal
for a generic drug user fee program and submitted it to Congress.
Congress enacted it (GDUFA I) as part of the Food and Drug
Administration Safety and Innovation Act of 2012 (FDASIA).
Under GDUFA I, industry agreed to pay approximately $300 million in
fees each year of the 5-year program. In exchange, FDA committed to
performance goals, including a commitment to complete reviews in a
predictable timeframe.
GDUFA Achievements
Met or Exceeded All Submission Review Goals to Date. FDA met or
exceeded all GDUFA review goals to date, including goals for original
Abbreviated New Drug Applications (ANDAs), ANDA amendments, Prior
Approval Supplements (PAS), and controlled correspondence.
Record Increase in Approvals. In fiscal year 2016, FDA approved or
tentatively approved 835 ANDAs. This was the most approvals ever in 1
year. Our previous high was 619.
[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]
Expanded Consumer Access to Quality, Affordable Generic Medicines.
As noted previously, approximately 25 percent of all currently approved
generic drugs were approved over the past 4 years.
Prioritization and Approval of ``First Generics.'' FDA expedites
the review of potential ``first generic'' ANDAs because they can open
the market to generic competition for the first time. Most ``first
generic'' ANDAs cannot lawfully be filed until a specific date, either
4 or 5 years after the innovator drug was approved. On this date, FDA
often receives a bolus of ANDAs, from many different applicants.
Beginning October 2014, in accordance with GDUFA I, these ANDAs
received goal dates. We worked hard to review ANDAs for first generics
even faster, expediting their review like an express line at the
supermarket. For example, last year we had timely approvals of nine
generic versions of Crestor, a cholesterol drug with approximately $5
billion in annual sales. Significant first generic approvals for 2016,
and the indications (abbreviated) for which these products were
approved, are listed in the following text box.
[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]
Increase in First Cycle Approvals. Prior to GDUFA, ANDAs were
approved in one review cycle less than 1 percent of the time. Now,
approximately 9 percent of ANDAs are approved in the first review
cycle.
Expanded Communications. To facilitate generic drug approval, in CY
2016 the Agency sent product developers approximately 1,800
communications and ANDA applicants approximately 6,600 communications.
The Agency also issued 158 product-specific guidances, identifying
methodologies for developing drugs and generating evidence needed to
support generic approval. These guidances help companies develop ANDAs
that will meet FDA's regulatory expectations. Over 1,500 product-
specific guidances are currently available as resources for prospective
applicants.
Risk-Based Inspection Parity. Before 2012, the law required us to
inspect domestic facilities at a 2-year interval, but was silent on
frequency for foreign facilities, regardless of their relative risk.
Since 2012, FDASIA directed us to target inspections globally on the
basis of risk. Many ANDAs rely on third-party facilities to manufacture
active pharmaceutical ingredients or perform other roles in product
development, and many of these facilities are located outside of the
United States. Thanks to GDUFA, we have achieved the goal of risk-based
inspection parity for foreign and domestic facilities.
How did FDA achieve these results?
Deep, foundational restructuring. We achieved these results by
building a modern generic drug program to comply with our commitments
in GDUFA I. This involved major reorganizations. We reorganized the
Office of Generic Drugs and elevated it to ``Super-Office'' status, on
par with the Office of New Drugs. We established a new Office of
Pharmaceutical Quality to integrate the quality components of ANDA
review. FDA's Office of Regulatory Affairs also made significant
inspection program enhancements. In addition, we re-engineered our
business processes, developed an integrated informatics platform to
support the review process, and hired and trained over 1,000 new
employees.
Current Challenges
We do have some ongoing challenges. The first challenge relates to
submission completeness. Historically, it has taken on average about
four review cycles to approve an ANDA as a result of deficiencies by
generic drug sponsors in submitting complete applications.
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This has resulted in the submission of numerous amendments to
applications by the companies to correct deficiencies in the original
ANDAs, and comprises a huge amount of re-work for FDA and industry
alike. Currently, about 1,800 applications are back with industry
awaiting resubmission to correct deficiencies in the original
application. More work by both FDA and industry will be necessary to
have the filings be ``right the first time.''
Improvement may take some time. In the first few years of the
Prescription Drug User Fee Act (PDUFA) program, the first cycle
approval rate for new drugs was as low as 23 percent. Now it is about
80 percent on average. Achieving this was the result of many years of
cooperative work by the Agency and industry in establishing standards
and meeting these expectations.
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The second challenge relates to the volume of applications. We
received many more applications than expected. As the GDUFA I
Commitment Letter stated, GDUFA I review goals and planning were based
on the assumption that FDA would receive approximately 750 ANDAs per
year. We budgeted and planned with this projection in mind. However, in
fiscal years 2012, 2013 and 2014, we received over 1,000 ANDAs--nearly
1,000--and nearly 1,500 applications, respectively. As discussed below,
GDUFA II would have a program size commensurate with the Agency's
overall ANDA workload.
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Third, several factors can delay timely consumer access to less
expensive generic medicines. These factors include:
inappropriate use of statutory requirements regarding
single-shared system Risk Evaluation and Mitigation Strategies (REMS)
to delay generics entry to the market;
delaying or denying generic companies' access to
reference-listed drug products, thereby preventing the companies from
conducting studies required for approval; and
misuse of FDA's citizen petition process as a means to
block generic approvals.
Reauthorization
Faster review of priority ANDAs. GDUFA II would establish faster
review of priority submissions. Priority review would be available for
submissions that FDA considers to be public health priorities pursuant
to CDER's Manual of Policies and Procedures (MAPP) 5240.3 Rev. 2,
Prioritization of the Review of Original ANDAs, Amendments and
Supplements, as revised (the CDER Prioritization MAPP). In the final
year of GDUFA I, all ANDAs receive a review goal of 10 months. In GDUFA
II, standard ANDAs would continue to be reviewed within 10 months of
submission, but priority ANDAs would be reviewed within 8 months of
submission. To help ensure the more aggressive 8-month timeline can be
met, for each priority review, the applicant would have to submit a
pre-submission facility correspondence (PFC) listing all of the
facilities that will require FDA inspection at least 2 months prior to
the date of ANDA submission.
FDA and the generic drug industry agreed to an 8-month priority
review goal for two main reasons. First, it is the shortest time
feasible given the global nature of generic drug manufacturing. In most
cases, before the ANDA can be approved, FDA needs to inspect one or
more manufacturing facilities to confirm that the drug will meet
quality standards. Many ANDA applicants rely on multiple overseas
manufacturing facilities, and conducting inspections of facilities in
foreign countries requires additional time for FDA inspectors to obtain
State Department approval and country-specific visas, and to meet other
travel-related requirements. By providing FDA with information about
the manufacturing facilities in advance of the ANDA submission, the PFC
would give the Agency critical lead time to determine whether facility
inspections will be needed, and when they are, to initiate travel
planning.
Second, 8 months is enough time for FDA to communicate--and
applicants to correct--application deficiencies, so a priority ANDA can
be approved in the current review cycle, not a later review cycle. A
goal date set at fewer than 8 months would wind down work just when it
is gaining momentum. Applicants would not have time to make corrections
and thus get their ANDAs approved. To resolve outstanding issues, an
additional cycle of review would be necessary. Approval would be
delayed for at least 6 to 10 more months, depending on how quickly the
applicant could develop an amendment and the GDUFA II review goal for
the specific type of amendment submitted.
Pre-ANDA Program Enhancements. To reduce the number of cycles to
approval, particularly for complex products, GDUFA II would establish a
pre-ANDA program. It would clarify regulatory expectations for
prospective applicants early in product development and help applicants
develop more complete submissions, thus promoting a more efficient and
effective review process.
The GDUFA II pre-ANDA program would establish three types of
meetings for complex products. In a product development meeting, FDA
would provide targeted advice concerning an ongoing ANDA development
program. Pre-submission meetings would give applicants an opportunity
to discuss and explain the content and format of an ANDA before it is
submitted. Mid-review-cycle meetings would occur post-submission, after
the last key review discipline has communicated deficiencies, and would
enable applicants to discuss current concerns and next steps. FDA
intends to issue a guidance concerning the pre-ANDA program, setting
forth meeting policies and procedures. In addition, the Agency intends
to establish metric goals for product development and pre-submission
meetings.
For products that are not complex, GDUFA II would direct the Agency
to establish metric goals for FDA to issue product-specific guidance.
Product-specific guidance identifies the methodology for developing
generic drugs and generating evidence needed to support generic
approval. They help companies develop ANDAs that will meet FDA's
regulatory expectations. In addition, the pre-ANDA program would
enhance controlled correspondence, regulatory science, the Inactive
Ingredient Data base, and Safety Determination Letters.
ANDA Review Program Enhancements. GDUFA II would further refine and
modernize the ANDA review process from start to finish.
The GDUFA II ANDA review program would start with submission of an
ANDA. When an ANDA is submitted, FDA first determines whether an ANDA
is sufficiently complete to permit a substantive review. If it is
sufficiently complete, then FDA ``receives'' it within the meaning of
the statute. FDA would aspire to make these receipt determinations
within consistent deadlines. The Agency also would increase receipt-
related communications in an attempt to fix applications and resolve
certain receipt disputes within consistent timelines.
When the ANDA has been received and is under review, pursuant to
GDUFA II, FDA would communicate review deficiencies beginning at about
the mid-point of the review. Then, communications would continue on a
rolling basis. In GDUFA I, many deficiencies were communicated at the
very end of the review, in the form of a Complete Response Letter, too
late for the applicant to fix them. This produced additional cycles of
review, and delayed approval. By contrast, GDUFA II would use ``real
time'' communications to give applicants more opportunities to correct
deficiencies in the current review cycle.
To support product launches and business planning that can improve
access to generics, Regulatory Project Managers (RPMs) would provide
review status updates and certain other types of notifications. The
Agency would also establish new technical procedures to facilitate
approval of tentatively approved ANDAs on the earliest lawful approval
date.
When deficiencies in an ANDA prevent FDA from approving it, FDA
issues a Complete Response Letter (CRL) itemizing deficiencies that
must be corrected for the ANDA to be approved. GDUFA II would establish
post-CRL teleconferences to allow applicants to seek clarification
concerning deficiencies identified in CRLs. This would help applicants
meet FDA's expectations when an ANDA is re-submitted for additional
review. There would be metric goals for such teleconferences, and for
formal dispute resolutions.
Finally, in GDUFA I, different cohorts and tiers of submissions
received very different goals. The scheme was challenging for FDA to
operationalize and administer. In addition, there was a significant gap
between the negotiated commitments and stakeholder expectations. We
appreciate that this has been an understandable area of concern for all
of us. In GDUFA II, all ANDAs and ANDA amendments would fall within a
single, consolidated review goals scheme. This would simplify and
streamline GDUFA operations, and better align commitments with
expectations.
Drug Master File (DMF) Review Program Enhancements. DMFs are
submissions that provide FDA with confidential information about
facilities, processes, or articles used to manufacture, process,
package, or store drugs. They support approval of ANDAs and are often
submitted by API manufacturers that sell to ANDA sponsors. The
commitment letter that accompanies GDUFA II contains five significant
DMF review program enhancements.
Facility Assessment Enhancements. As previously mentioned, FDASIA
eliminated longstanding minimum inspection frequency requirements and,
instead, directed FDA to inspect drug facilities globally on the basis
of risk. The transition to this new paradigm has been commercially
disruptive for industry, which over time had developed expectations and
business processes based on the old model. To mitigate export-related
challenges identified by U.S.-based active pharmaceutical ingredient
(API) manufacturers, GDUFA II would require FDA to issue guidance and
conduct outreach to foreign regulators on the risk-based selection
model and take steps to support exports. To mitigate ANDA sponsor
concerns, FDA would enhance the speed and transparency of
communications concerning facility assessment, and generally update and
seek feedback from industry. In addition, to enhance transparency
concerning GDUFA facilities and sites, FDA would update its existing,
publicly available facility compliance status database.
Accountability and Reporting Enhancements. In GDUFA II, enhanced
infrastructure and analytics would increase transparency and
accountability and strengthen program management and resource use. FDA
would develop internal capacity to enable improved productivity and
performance through regular assessment of progress toward GDUFA II
goals and transparent, efficient administration, allocation and
reporting of user fee resources. In addition, an independent third
party would evaluate the program.
FDA would expand GDUFA program reporting on a monthly, quarterly
and annual basis. Robust performance reporting would enable Congress,
industry and other stakeholders to gauge the generic drug program's
performance.
Program Size Commensurate with Overall ANDA Workload. ANDAs are the
primary workload driver of the generic drug program. In GDUFA I, the
number of submissions received substantially exceeded projections. In
order to maintain productivity and implement proposed GDUFA II
improvements, FDA and the generic drug industry agreed that user fees
should total $493.6 million annually, adjusted for inflation.
Modification of User Fee Structure. For program stability, user fee
collections must be predictable. Application volume can fluctuate from
year to year, but there is a relatively stable universe of generic drug
facilities and ANDA sponsors. To maintain a predictable fee base and
better align responsibility with program costs and fee-paying ability,
FDA and industry propose to shift the burden more toward annual program
fees. Firms that sponsor one or more approved ANDAs would pay an annual
fee. In addition, Finished Dosage Form (FDF) and API facilities would
continue to pay annual fees as they did in GDUFA I.
In GDUFA I, ANDA sponsors making changes to an already approved
ANDA through a Prior Approval Supplement (PAS) were required to pay a
PAS application fee. The volume of PASs is unpredictable. Collecting
the fees was resource intensive. The new ANDA program fee is meant to
be an investment in the program, and includes the cost of reviewing PAS
submissions. For these reasons, FDA and industry propose to eliminate
the PAS fee.
Small Business Considerations. GDUFA II takes small business
considerations into account. First, no facility or ANDA sponsor would
be charged an annual fee until an ANDA in which it is listed is
approved. This eliminates a situation that occurred in GDUFA I, where a
company could be charged an annual fee, sometimes for several years in
a row, even though no ANDA linked to the facility had been approved
yet. Second, the annual program fee would have three tiers--small,
medium and large--based on the number of approved ANDAs owned by the
firm and its affiliates. Third, Contract Manufacturing Organizations
(CMOs are hired by ANDA sponsors to manufacture their generic drugs)
would pay one-third the annual facility fee paid by ANDA holders.
In summary, FDA and the regulated industry, in consultation with
other stakeholders, spent nearly a year developing the proposed GDUFA
II agreement. It contains numerous, major reforms to address the main
challenge facing the generic drug review program--namely, multiple
review cycles. It is very inefficient for FDA and applicants alike to
cycle through an ANDA over and over again. GDUFA II's pre-ANDA program,
ANDA review program enhancements, and priority review program will
increase the odds of first cycle approval, reduce the number of cycles
to approval, and expand consumer access to quality, less expensive
generic medicines. While we have made significant progress in our
generic drug review, GDUFA II will support the agency in improving
consumers' timely access to generic medicines.
bsufa
FDA is supportive of and fully engaged with the development and
approval of biosimilar and interchangeable products. Many of our most
important drugs are biological products. Biological products are used
to treat patients who have serious and life-threatening medical
conditions including rheumatoid arthritis, diabetes, and cancer. It is
important for the public health of the U.S. population to have access
to safe, effective, and affordable biological products. Biosimilars can
provide more treatment options for patients, and possibly lower
treatment costs, enabling greater access for more patients.
To earn and sustain both physicians' and patients' confidence in
biosimilar and interchangeable products, FDA is applying a
scientifically rigorous review process and approval standard.
Healthcare providers and patients have consistently emphasized that
FDA's approval of biosimilars should provide assurance that biosimilars
will have the same clinical performance as the originator, or reference
product. FDA is committed to providing this assurance, and recognizes
its importance to the uptake and acceptance of these products, and the
future success of the biosimilars program.
Biologics Price Competition and Innovation Act (BPCI Act) and
Biosimilar User Fee Act (BsUFA): Important Additions to FDA
Statutory Authority
BPCI Act. The Biologics Price Competition and Innovation (BPCI) Act
established a new abbreviated approval pathway for biological products
shown to be ``biosimilar to'' or ``interchangeable with'' an FDA-
licensed biological product. With this abbreviated approval pathway, an
applicant can get a biosimilar approved by demonstrating, among other
things, that it is highly similar to a reference biological product
already licensed by FDA. Biological products are made from living
organisms and usually consist of large, complex molecules that cannot
be easily copied, in contrast to ``small molecule'' drugs that
generally are produced through chemical processes and can be replicated
as ``generic'' drugs. Unlike generic drugs, biosimilars must be highly
similar to, not the same as, the reference product to which they are
compared. While biosimilars may have certain allowable differences from
the reference product, the applicant must demonstrate that there are no
clinically meaningful differences between the biosimilar and its
reference product in terms of safety, purity and potency.
The abbreviated approval pathway permits a biosimilar application
to rely, in part, on FDA's previous determination that the reference
product is safe and effective, saving the applicant time and resources
and thereby encouraging price competition and lowering healthcare
costs. The ongoing and future impact of this relatively new law is
significant. FDA's biosimilars program has sparked the development of a
new segment of the biotechnology industry in the United States. The
growth of this new market segment should expand opportunities for
technical innovation, job growth, and patient access to treatment.
BsUFA I. The Biosimilar User Fee Act (BsUFA) was enacted as part of
the FDA Safety and Innovation Act (FDASIA) (Public Law No. 112-144,
enacted on July 9, 2012). The first Biosimilar User Fee Agreement
(BsUFA I) between the Agency and industry allowed FDA to begin
development of the infrastructure needed to support this new program
and devote additional resources to support the abbreviated development
process leading to the approval of safe and effective biosimilar
products for patients.
One of the first steps in the development and review process for a
biosimilar is for an applicant to join FDA's Biosimilar Product
Development (BPD) Program. The BPD Program was created as a part of
BsUFA I to provide a mechanism and structure for applicants to engage
with FDA during the development of a biosimilar. As of February 2017,
64 programs were enrolled in the BPD Program and CDER has received
meeting requests to discuss the development of biosimilars for 23
different reference products.
In engaging with sponsors regarding biosimilar development, CDER
holds development-phase meetings and provides written advice for
ongoing development programs. These meetings include a Biosimilar
Initial Advisory meeting where there is an initial discussion on
whether licensure would be feasible for a particular product; and BPD
meeting Types 1-4 where applicants can receive advice at different
stages of product development. The meeting that is in highest demand
and often requires significant review effort on behalf of FDA is the
BPD Type 2 meeting where FDA conducts a substantive review of summary
data and an applicant receives advice on specific issues. For
additional details on the BsUFA BPD meeting types, please see Appendix
C.
As shown in Figure 12, the total number of meetings scheduled has
increased each year since the beginning of BsUFA I. Additionally, in
order to provide ongoing support for BPD programs, FDA has provided
written advice to sponsors in instances where meeting requests were
denied or canceled due to incomplete or premature requests.
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The BPD meetings have provided valuable advice to biosimilar
sponsors in the development of their products and associated biosimilar
marketing applications. Since program inception and as of February
2017, nine companies have publicly announced submission of 13
applications for proposed biosimilar products to FDA.
FDA approved the first biosimilar in the United States, Zarxio
(filgrastim-sndz), a biosimilar to Neupogen, on March 6, 2015. In 2016,
FDA approved three additional biosimilars: Inflectra (infliximab-dyyb),
a biosimilar to Remicade; Erelzi (etanercept-szzs), a biosimilar to
Enbrel; and Amjevita (adalimumab-atto), a biosimilar to Humira.
Challenges
While we have made significant progress in creating and
implementing this fairly new program, there is more work to do and, as
with any new initiative, there are challenges that we need to address.
These challenges in BSUFA I provide context for the discussions we had
with industry during the BSUFA II negotiations. The ability to hire the
right staff is critical to ensure the timely review of new biosimilars.
While it's true that FDA has been somewhat limited in its capacity to
recruit and retain the critical scientific, technical, and professional
talent needed to address the complex and often novel scientific and
legal issues involved in biosimilar review, we are committed to making
meaningful and measureable progress.
The lack of additional staffing to handle the increased workload
for biosimilar review also has impacted review performance. For
example, in fiscal year 2015, FDA was able to schedule only 50 percent
of Initial Advisory meetings within the 90-day meeting goal, only 67
percent of Type 1 meetings within the 30-day meeting goal, only 49
percent of Type 2 meetings within the 75-day meeting goal, and zero
Type 4 meetings within the 60-day meeting goal. FDA's performance
during fiscal year 2016 was an improvement from fiscal year 2015;
however, FDA still faced challenges and was unable to meet some of the
applicable performance goals. Despite the BsUFA I performance
challenges, industry indicated that in BsUFA II, they would like to see
more meetings and faster turnaround of Agency advice.
BsUFA II
FDASIA directed FDA to develop recommendations for BsUFA II for
fiscal years 2018 through 2022. To develop these recommendations, FDA
consulted with industry and public stakeholders, including scientific
and academic experts, health care professionals, and patient and
consumer advocates, as directed by Congress. In addition to meetings
with industry organizations, FDA held two public meetings on December
18, 2015, and October 20, 2016, to obtain input from public
stakeholders.
As discussed below, BsUFA II incorporates lessons learned from
implementation of BsUFA I and provides a roadmap to successfully
overcome some of the unexpected challenges encountered with BsUFA I.
Proposed Fees. At the time BsUFA I was authorized, the size and
costs of the program were uncertain. As such, it was agreed that user
fees for BsUFA I should be based off the fees established under the
PDUFA program. As part of the recommendations for BsUFA II, FDA and
industry agreed to establish an independent fee structure based on
BsUFA program costs to generate a total of $45 million in revenue for
fiscal year 2018. FDA and industry representatives also propose that
FDA can adjust this amount to reflect updated workload and cost
estimates for fiscal year 2018 when FDA publishes the Federal Register
(FR) notice establishing fee revenue and fees for fiscal year 2018. The
adjustment cannot increase the target revenue more than $9 million, and
FDA must describe the methodology used to calculate the adjustment in
the FR.
FDA's recommendations for the BsUFA II user fee structure include
additional changes to enhance the predictability of BsUFA funding
levels and sponsor invoices, minimize inefficiency by simplifying the
administration of the program, and improve FDA's ability to manage
program resources and engage in effective long-term planning. These
changes include the removal of the supplement fee and establishment
fee, while retaining the initial, annual, and reactivation biosimilar
biological product development (BPD) fees. Under the recommendations,
the product fee is renamed the BsUFA Program fee and includes a new
provision that sponsors shall not be assessed more than five BsUFA
Program fees for a fiscal year per application. These changes are
consistent with changes proposed for the fee structure under PDUFA VI.
Under BsUFA II, FDA also would establish a capacity planning
adjustment as well as an operating reserve adjustment. The capacity
planning adjustment, once operational (expected in fiscal year 2021),
would establish a mechanism to adjust the annual fee revenue target
based on analytically demonstrated sustained changes in BsUFA workload.
The operating reserve adjustment would provide the ability to further
adjust up or down the annual fee revenue to ensure the program is
adequately resourced to sustain operations, while also preventing the
accrual of unnecessarily large carryover balances. Under BsUFA II, the
$20 million (adjusted for inflation) spending trigger would be
considered to be met in any fiscal year if the costs funded by budget
authority are not more than 15 percent below the inflation adjusted
amount for that year. This flexibility, similar to the spending trigger
provisions in PDUFA and GDUFA, will enhance FDA's level of certainty
that it can allocate and spend the required amount of non-user fee
funds for a given fiscal year and thereby spend user fee funds in that
fiscal year.
Proposed Performance Goals. The BsUFA II commitment letter
establishes an application review model similar to ``the Program''
established under PDUFA V for new molecular entity new drug
applications and original biological licensing applications. This new
model is intended to promote the efficiency and effectiveness of the
first cycle review process and minimize the number of review cycles
necessary for approval. The parameters of the Program will include the
following: (1) pre-submission meeting, (2) original application
submission, (3) Day 74 Letter, (4) review performance goals (10-month
user fee clock starts at 60-day filing date), (5) mid-cycle
communication, (6) late-cycle and advisory committee meetings, (7)
inspections, and (8) assessment of the Program.
The additional 2-month review clock time (10 month plus 60 days,
noted above) is intended to provide FDA more time to complete
additional late cycle activities added as part of the new review model
(e.g., late-cycle meeting) and address other late cycle review work,
such as application deficiencies, Advisory Committee advice, and
inspection issues to improve the efficiency of the first review cycle.
Under the BsUFA II commitment letter, Biosimilar Initial Advisory
meetings will occur within 75 calendar days, instead of 90 days agreed
to in BsUFA I, from receipt of the meeting request and meeting package.
This type of meeting will be limited to a general discussion on whether
a proposed product could be developed as a biosimilar and to provide
high-level overarching advice on the expected content of the
development program. To provide necessary time for FDA discussions and
to develop comprehensive responses, BPD Type 2 Meetings will occur
within 90 calendar days, instead of 75 days as in BsUFA I, from receipt
of the meeting request and meeting package. There will be phased-in
performance goals for meeting these deadlines of 80 percent in fiscal
years 2018 and 2019 and 90 percent in fiscal years 2020 through 2022.
In addition, the Agency will send preliminary responses to the
sponsor's questions contained in the background package no later than 5
calendar days before the face-to-face, video conference or
teleconference meeting date for BPD Type 2 and Type 3 meetings.
Proposed Guidance Development. While the BPCI Act states that there
is no requirement for FDA to issue guidance before reviewing or taking
an action on a biosimilar application, industry has indicated to FDA
that guidances are an important product development tool. As part of
its work to implement the BPCI Act, FDA has finalized six guidances and
issued four draft guidances. The six guidances that are final are:
1. Scientific Considerations in Demonstrating Biosimilarity to a
Reference Product (finalized on April 28, 2015).
2. Quality Considerations in Demonstrating Biosimilarity of a
Therapeutic Protein Product to a Reference Product (finalized on April
28, 2015).
3. Biosimilars: Questions and Answers Regarding Implementation of
the Biologics Price Competition and Innovation Act of 2009 (finalized
on April 28, 2015).
4. Formal Meetings Between the FDA and Biosimilar Biological
Product Sponsors or Applicants (finalized on November 17, 2015).
5. Clinical Pharmacology Data to Support a Demonstration of
Biosimilarity to a Reference Product (finalized on December 28, 2016).
6. Nonproprietary Naming of Biological Products (finalized on
January 12, 2017).
Under the BsUFA II commitment letter, FDA has committed to
publishing a revised draft guidance on Formal Meetings Between the FDA
and Biosimilar Biological Product Sponsors or Applicants no later than
September 30, 2018, and updating the draft guidance on Best Practices
for Communication Between IND Sponsors and FDA During Drug Development
by December 31, 2018.
Additionally, under the BsUFA II commitment letter FDA has
committed to publishing draft or final guidance describing the
following:
Considerations in Demonstrating Interchangeability with a
Reference Product (draft on or before December 31, 2017, and revised or
final guidance 24 months after close of the public comment period)
Statistical Approaches to Evaluate Analytical Similarity
(draft on or before December 31, 2017, and revised or final guidance 18
months after close of the public comment period)
Processes and Further Considerations Related to Post-
Approval Manufacturing Changes for Biosimilar Biological Products
(draft on or before March 31, 2019, and revised or final guidance 18
months after the close of the public comment period)
Clinical Pharmacology Data to Support a Demonstration of
Biosimilarity to a Reference Product (draft guidance published in May
2014, revised or final guidance will be published on or before May 31,
2019)
Nonproprietary Naming of Biological Products (draft
guidance published in August 2015, revised or final guidance will be
published on or before May 31, 2019)
Labeling for Biosimilar Biological Products (draft
guidance published March 2016, and revised or final guidance on or
before May 31, 2019).
FDA has already published or finalized three of these guidances
ahead of schedule: the draft Considerations in Demonstrating
Interchangeability with a Reference Product and final guidance on
Clinical Pharmacology Data to Support a Demonstration of Biosimilarity
to a Reference Product and Nonproprietary Naming of Biological
Products.
As with all review programs within FDA, the ability to hire and
retain qualified staff is critical to ensure the availability of new
safe and effective drugs and biologics. Congress included much-needed
new hiring authorities in the recently enacted Cures bill. FDA looks
forward to applying these new authorities to further improve our
biosimilars program. Several FDA goals in the BsUFA II commitment
letter support this process: FDA will strengthen staff capacity;
modernize the hiring system and infrastructure; augment human resources
capacity through the use of dedicated expert contractors; establish a
dedicated function for the recruitment and retention of scientific
staffing; set clear goals for hiring; and conduct a comprehensive and
continuous assessment of hiring and retention practices. These
enhancements will allow us to meet our performance goals which in turn
will help us save the applicant time and resources and ultimately
encourage price competition.
The Path Forward
BsUFA I provided critically needed funding for FDA to implement the
beginning of a successful biosimilars program. We look forward to
working with Congress and industry as we continue to strengthen this
program and make improvements where needed. This relatively new pathway
for biosimilar and interchangeable products has the potential to offer
a significant contribution to the public health of many Americans by
increasing access to more affordable biologics. At FDA, we are working
hard to ensure this positive impact can be realized. We are optimistic
and energized about the future of biosimilars.
Human drug user fees have revolutionized the drug review process in
the United States since they were adopted 20 years ago for prescription
drug products, allowing FDA to speed the application review process
without compromising the Agency's high standards. User fees offer a
strong example of what can be achieved when FDA, industry and other
stakeholders work together on the same goal. User fees provide a
critical way to ensure that FDA has the resources needed to conduct
reviews in a timely fashion.
conclusion
The FDA user fee agreements have revolutionized the drug and device
review process in the United States since they were adopted, allowing
FDA to speed the application review process without compromising the
Agency's high standards. User fees offer a strong example of what can
be achieved when FDA, industry, and other stakeholders work together
toward the same goal. User fees provide a critical way to ensure that
FDA has the resources needed to conduct reviews in a timely fashion.
While we have made demonstrable progress in partnering to bring medical
products to market in as timely a manner as possible, we know that more
work remains to be done to further enhance and optimize our processes.
The reauthorization of PDUFA, MDUFA, GDUFA, and BsUFA will allow FDA to
buildupon the demonstrated success of these programs, and in so doing,
further benefit patients and affirm our Nation's standing as a global
leader in biomedical innovation.
Appendix A
U.S. Food and Drug Administration Center for Devices and Radiological
Health: Progress in Achieving Our Vision of Patients First
In the early part of this decade, industry argued that FDA
regulation hindered innovation and contributed to the growing number of
device companies seeking marketing authorization for their devices
abroad before introducing them in the United States, and the increasing
gap between when a device is approved in another country and when it is
approved in the United States. This reality, its adverse impact on
patients, plus CDRH's own awareness of our declining performance over
almost a decade, led CDRH to implement new programmatic changes. These
changes, along with increased user fee funding and changes in Federal
law have helped us strengthen our performance and better address the
rapidly evolving field of medical device innovation. To guide us in our
mission to improve the health and quality of life of patients, in 2012
we adopted a new vision\5\ to reflect this change in mindset, that:
Patients in the United States have access to high-quality, safe and
effective medical devices of public health importance first in the
world.
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\5\ CDRH Mission, Vision and Shared Values.
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doing business better
Since late 2009, CDRH has continuously improved the way we do
business through a series of culture, policy and process changes. This
can be seen through our commitment to providing excellent customer
service, new patient-centered paradigms, and our strong performance
across a range of objective measures, including the time it takes to
review several types of medical device submissions. These improvements
are reflected by the nearly four-fold increase in the annual number of
novel medical device approvals.
[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]
Fast Facts: CDRH oversees approximately 175,000 medical devices on
the U.S. market, more than 18,000 medical device manufacturers, and
more than 25,000 medical device facilities worldwide. Each year we
receive some 22,000 pre-market submissions (includes supplements and
amendments) and more than 1.4 million reports on medical device adverse
events and malfunctions.
Time. Time, with its cost implications, plays a critical role in an
innovator's decision as to whether and when to bring a new technology
to the United States. What good is a new technology if patients do not
have timely access to it? How helpful is a new technology that doesn't
benefit patients or poses unacceptable risks? By reducing the time of
every regulatory stage of the total product life cycle, including the
review of medical device submissions, while still assuring robust but
appropriate (least burdensome) evidence generation and high-quality
decisionmaking, we help patients get access to safe and effective
medical technologies and foster innovation. After steadily worsening
performance from 2002 to 2010 on a variety of measures, including pre-
market review times, CDRH has reduced the decision time on all key pre-
market submission types.
PMA. While pre-market approval applications (PMAs) only account for
approximately 1 percent of all pre-market medical device submissions,
they represent medical devices with the highest risk to patients (Class
III devices) and, therefore, require more data and a more rigorous
review by CDRH. In 2009, it took an average of 427 total days to reach
a decision on a PMA. By 2015, we had reduced the total decision time by
35 percent.
510(k). Named after its section number in Federal law, this
category represents the bulk of pre-market submissions for medical
devices. Manufacturers submit 510(k)'s to CDRH for devices with low to
moderate risk to patients (Class II), and our review standard is based
on substantial equivalence (whether a device is at least as safe and
effective as a device already on the market). In 2010, it took an
average of 150 total days to reach a decision on a 510(k). By 2015, we
had reduced the total decision time by 11 percent.
De Novo. De novo classification is a pathway that enables
manufacturers of certain low- to moderate-risk novel devices for which
there are no similar marketed devices to come to market, instead of
having to submit a PMA. In 2009, it took an average of 770 total days
to reach a de novo decision. By 2014, we had reduced the total decision
time by 66 percent.
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IDE. Manufacturers submit Investigational Device Exemptions (IDEs)
for certain devices they want to study via a clinical trial. CDRH
reviews an IDE submission before a manufacturer can begin to collect
clinical data that may be necessary for future approval. CDRH slashed
median review times for IDE full approvals by more than a year between
2011 and 2015.
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doing business different
Since 2009, CDRH has been evaluating all of our programs to address
concerns from patients, industry, health care providers, our own staff,
and other customers about issues including review times, backlogs, and
our expertise in increasingly complex technology. We have sought to
address these concerns by changing our culture to put patients first
and recognizing that advancing innovation and assuring patient safety
are not mutually exclusive, revising or eliminating old policies, and
developing new policies and approaches with an eye on meeting
measurable objectives. Increased medical device user fees have
supported these efforts so that we are better positioned to respond to
the needs of patients.
Clinical Trials. In addition to dramatically improved
performance\6\ in reviewing IDEs, CDRH has encouraged the use of
innovative methodologies and study designs in clinical trials. We
recognize that manufacturers need CDRH input early and often so that
the ultimate device review process moves as quickly and smoothly as
possible. In 2013, CDRH issued final guidance for manufacturers on
early feasibility studies to encourage conducting these studies in the
United States. Innovators tend to market their technologies sooner in
countries where they elect to conduct their early clinical studies.
Since 2013, the number of early feasibility studies approved has more
than doubled--from 17 in fiscal year 2013 to 40 in fiscal year 2016.
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\6\ CDRH Clinical Trial Enterprise Targets and Performance.
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CDRH encourages the use of innovative clinical trial designs and
statistical methods such as adaptive clinical trials\7\ and Bayesian
statistics\8\ because, where appropriate to use, they can reduce the
time and cost of a clinical study. In recent years, many devices have
come to market based on the results of clinical trials using adaptive
trial designs. For the period from 2007 to May 2013, CDRH received 201
submissions that were adaptive.
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\7\ Guidance Document: Adaptive Designs for Medical Device Clinical
Studies Issued July 27, 2016.
\8\ Guidance for the Use of Bayesian Statistics in Medical Device
Clinical Trials.
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CDRH continues to develop computational models that can, in some
instances, supplement or replace data from clinical investigations,
such as the Virtual Family (VF)\9\--a set of highly detailed,
anatomically correct, computational whole-body models, designed to
mimic humans of both sexes at various stages of growth. Since 2007,
more than 160 submissions have included Virtual Family research.
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\9\ Virtual Family.
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Flexible, Risk-Based Regulatory Approaches. CDRH continues
to adapt our oversight policies to emerging new technologies. In a
manner consistent with our statutory mission, we now approach a medical
technology by first asking whether active CDRH oversight will be value-
added. If not, we take a less active regulatory approach. If it would,
we focus on assuring timely patient access to technologies that will
benefit patients by considering the device's innovation cycles and
evidence generation needs.
For example, widespread adoption and use of digital health
technologies is creating new and innovative ways to improve health and
health care delivery. In one of the biggest de-regulatory actions for
CDRH in decades, to foster greater innovation in the digital health
space while promoting public health, we have exercised our enforcement
discretion to cease subjecting certain lower risk medical devices (such
as apps for patient care management and medication reminders) to
medical device requirements.
Additionally, balancing data needs between what's collected before
the device comes on the market (premarket) and what's collected after
it is on the market (postmarket) reflects our approach to best assure
timely patient access to safe and effective devices.
In 2015, CDRH completed a retrospective review\10\ of the benefit-
risk profile of all types of high-risk devices to determine if we could
reduce pre-market data collection requirements for at least some
devices. As a result, for 30 percent of high-risk medical devices, CDRH
determined, based on the current body of evidence and experience, we
could consider some devices candidates for down-classification,
eliminate some data requirements or shift some pre-market data
requirements to the postmarket setting. In 2016, CDRH reached out to
stakeholders for input on the results of the retrospective reviews, in
order to determine next steps.
\10\ CDRH Strategic Priorities and Updates.
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Patient-Centered Benefit-Risk. For the past 5 years, CDRH
has encouraged the use of a more flexible, patient-centric, and
transparent benefit-risk framework to evaluate medical devices,
starting with a 2012 guidance on the factors to consider when making
benefit-risk determinations in support of device pre-market approval
decisions, which includes patient perspectives on potential benefits
and risks. We are focusing more on what matters to patients.
In 2016 and 2017, CDRH expanded this approach by revising the 2012
guidance to include additional patient-centric factors,\11\ and issuing
two additional benefit-risk guidance documents: one which outlines the
principal factors CDRH considers when making benefit-risk
determinations during the pre-market review process for IDEs\12\, and
one which outlines factors to consider when determining whether and
what postmarket actions\13\ we may take to address a problem, such as a
recall, based on the benefits and risks of that action to patients.
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\11\ Guidance Document: Factors to Consider When Making Benefit-
Risk Determinations in Medical Device Premarket Approval and DeNova
Classification (August. 24, 2016).
\12\ Guidance Document: Factors to Consider When Making Benefit-
Risk Determinations in Medical Device Investigational Device
Exemptions.
\13\ Guidance Document: Factors to Consider When Making Benefit-
Risk Determinations in Medical Device Product Availability, Compliance,
and Enforcement Decisions.
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Patients as Partners. CDRH had traditionally determined
whether the benefits of a device outweighed its risks based on the
tradeoffs we thought were acceptable. However, patients who live with a
disease or condition often have their own perspectives on what benefits
and risks related to medical devices they are willing to accept. CDRH
collaborates with patient scientists and other experts outside the FDA
to help us advance the scientific field of assessing patient
preferences and incorporate the patient perspective into our benefit-
risk assessments and decisionmaking.
For example, in 2014, CDRH funded a collaborative study on patient
preferences that led to changes in our review paradigm for obesity
devices, and used the results to inform our decision to approve the
first medical device for treating obesity since 2007. Better
understanding of patient preferences can also help rejuvenate
development pipelines; since then, CDRH has approved or granted
marketing applications for five more medical devices that address
obesity or weight loss.
In 2016, CDRH issued a final guidance that outlined patient
preference information (PPI)\14\ that CDRH may use in decisionmaking.
Since then manufacturers have begun to submit--and we have approved--
IDEs with patient preference studies.
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\14\ Guidance Document: Patient Preference Information--Voluntary
Submission, Review in Premarket Approval Applications, Humanitarian
Device Exemption Applications, and De Novo Requests, and Inclusion in
Decision Summaries and Device Labeling.
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CDRH's efforts to incorporate the voice of patients in our
decisionmaking also are reflected in medical device clinical studies,
which have been increasingly assessing what matters most to patients.
Between 2009 and 2014, the number of premarket submissions that
included clinical studies with patient reported outcomes (PROs)
increased by more than 500 percent and half of IDE pivotal clinical
studies now include PROs.
In 2015, CDRH established the first FDA advisory committee focused
on the interests and needs of patients, and recruited potential new
members in 2016. The Patient Engagement Advisory Committee\15\ will
hold its first meeting in 2017.
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\15\ The Patient Engagement Advisory Committee.
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National Evaluation System for Health Technology (NEST).
Despite rigorous premarket evaluation, we cannot fully understand how
well a medical device works until it is used day-to-day by patients,
caregivers, and clinicians. Premarket clinical trials provide
critically important information but we don't understand the long-term
benefit-risk profile until it is used in routine clinical practice.
Currently our Nation is limited in its ability to make widespread use
of real-world evidence (RWE) to best inform all members of the medical
device ecosystem.
CDRH intends for NEST to increase the quality and use of real-world
data (RWD) collected as part of routine clinical care, which should
also help reduce the time and cost of evidence generation. Ongoing
implementation of the Unique Device Identification (UDI) system also
will enable NEST to perform enhanced analyses of devices on the market,
providing a clear and standard way to identify devices in electronic
medical records.
CDRH is already relying on RWE to approve new devices, expand the
indications for already marketed devices, and reduce the time and cost
for device makers to meet their postmarket study requirements. In 2016,
CDRH documented access to more than 28 million electronic patient
records (from national and international clinical registries, claims
data, and electronic health records) that included device
identification and awarded $3 million to the Medical Device Innovation
Consortium to establish the NEST Coordinating Center.
Streamlining the Pathway from FDA Approval to Payer
Coverage. Timely access to innovative medical technologies has been
identified as a significant issue in the delivery of high quality
health care. Manufacturers of innovative medical products have said
that after undergoing the FDA approval process the availability of
their products to consumers is often slow because, in order to obtain
coverage and payment from third-party payers, the manufacturers must go
through a second review process by such payers. Therefore, CDRH
established the Payer Communication Task Force (PCTF) to facilitate
communication between device manufacturers and payers to shorten the
time between FDA approval or clearance and coverage decisions. By
communicating earlier, manufacturers may design their pivotal clinical
trials to produce both the data required for regulatory approval or
clearance, and positive coverage determinations.
To support these efforts, CDRH and the Centers for Medicare &
Medicaid Services (CMS) began to pilot an approach in 2011 called
Parallel Review that would give eligible device makers the voluntary
option for CMS to start their national coverage determination process
while the device is under review by CDRH. This process serves the
public interest by reducing the time between FDA marketing approval or
clearance decisions and CMS national coverage determinations. In 2016,
CDRH and CMS established Parallel Review as a permanent program. Last
year, CDRH also established an additional opportunity for device
manufacturers to invite CMS, private payers, or health technology
assessment groups (HTAs) to join FDA pre-submission meetings to provide
early feedback on clinical trial design.
evidence of impact
Our investments are starting to pay off. For example, in 2016, CDRH
approved 91 novel medical devices--the highest number since the advent
of the user fee program in 2003. This followed the second highest
number from 2015, and continued a 7-year trend that has resulted in a
marked increase in the annual number of novel device approvals since
2009. These novel technologies, which can help improve the quality of
life of patients, especially those that require day-to-day maintenance
and ongoing attention, are yielding promising results. In addition,
several of these devices are reaching U.S. patients much earlier than
they would have in previous years.
``Artificial Pancreas'' Approximately 5 percent of
diabetics have Type 1 diabetes, also known as juvenile-onset diabetes.
People with type 1 diabetes have to constantly monitor their glucose
levels throughout the day and have insulin therapy through injection
with a syringe, an insulin pen, or an insulin pump, to avoid becoming
hyperglycemic (high glucose levels). Working interactively with the
sponsor from the earliest stages of development to assist in making
this technology available as quickly as possible while assuring it is
safe and effective, CDRH, in 2016, approved the first automated insulin
delivery (AID) device in the world that is intended to automatically
monitor glucose (sugar) and provide appropriate basal insulin doses--
what some have called a first-generation ``artificial pancreas.''\16\
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\16\ The Artificial Pancreas Device System.
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Transcatheter Aortic Valve Replacement (TAVR) Therapy.
About 80,000 surgical aortic valve replacements (SAVR) are performed in
the United States annually. One-third of these patients are at
intermediate surgical risk for death or complications. An aortic valve
replacement that can be inserted through the blood vessels or, in some
cases, through the tip of the heart by a catheter, rather than through
open surgery, could avoid the risks of surgery and provide an
alternative effective treatment to patients who are in the
``intermediate surgical risk'' category.
In 2011, CDRH approved the first TAVR device in the United States
for patients who are not surgical candidates for SAVR, more than 4
years after the device entered the European Union (EU) market. When, in
2016, CDRH approved the expanded indication\17\ for use for a TAVR
device in patients at intermediate surgical risk for death or
complications, the positive impact of CDRH initiatives was evident. The
gap between EU and U.S. approval for the expanded indication for use
was reduced from over 4 years to only 18 days. U.S. Medicare coverage
is also a factor in patients' access to devices. For TAVR devices,
access to real-world evidence--what NEST hopes to expand--proved to be
a valuable asset. The U.S. Medicare program immediately covered TAVR
devices due to the ongoing collection of real-world evidence on these
devices in a national registry--there was no delay between U.S.
approval and access to this technology. As a result, more than 25,000
additional patients each year are now eligible for this life-saving
procedure.
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\17\ Press Release: FDA approves expanded indication for two
transcatheter heart valves for patients at intermediate risk for death
or complications associated with open-heart surgery--Aug. 2016.
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Diagnostics for National Emergencies. Accurate detection
and diagnostics are critical to addressing national public health
threats. For example, in 2016, CDRH authorized the use of 14 diagnostic
tests for Zika\18\ virus under our Emergency Use Authorization (EUA)
authority--12 tests to diagnose active infection and 2 tests to assess
whether individuals who may have recently been exposed to Zika were
actually infected. This rapid action provided timely patient access to
Zika tests before the summer of 2016, when officials detected the virus
in the United States. Since 2009, CDRH has granted 50 EUAs,
reauthorized 19 EUAs, and granted 30 amendments for tests to help meet
the country's needs during a national public health emergency, such as
outbreaks from Zika, Ebola, and H1N1.
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\18\ Zika Virus Response Updates from FDA.
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Appendix B. Center for Devices and Radiological Health (CDRH)--2016-17
Strategic Priorities--2016 Accomplishments
establish a national evaluation system for medical devices
To successfully harness real-world evidence (``evidence from
clinical experience'') in an efficient manner, the United States must
develop the necessary infrastructure--a National Evaluation System for
health Technology (NEST).
Goal: Increase Access to Real-World Evidence to Support Regulatory
Decisionmaking
------------------------------------------------------------------------
2016 Target Results
------------------------------------------------------------------------
25 Million. by December 31, 2016, gain 28.6 Million. Gained access
access to 25 million electronic patient to more than 28 million
records (from national and international electronic patient records
clinical registries, claims data, and (from national and
EHRs) with device identification. international clinical
registries, claims data,
and EHRs) with device
identification using a
variety of mechanisms, such
as cooperative agreements
and access through
regulatory process.
------------------------------------------------------------------------
Goal: Increase Access the Use of Real-World Evidence to Support
Regulatory Decisionmaking
------------------------------------------------------------------------
2016 Target Results
------------------------------------------------------------------------
40 percent. By December 31, 2016, increase 85 percent. The number of
by 40 percent the number of pre-market pre-market and post-market
and post-market regulatory decisions that regulatory decisions that
leverage real-world evidence. (compared used real-world evidence
to fiscal year 2015 baseline). increased by 85 percent in
2016. (compared to fiscal
year 2015 baseline).
------------------------------------------------------------------------
Supporting Actions
In 2016, CDRH took a number of actions to achieve the goals and
targets established for this priority:
Establish the National Evaluation System for health
Technology (NEST).
In Progress: A multi-stakeholder Planning Board and the Medical
Device Registry Task Force issued a series of reports that outlined an
organizational structure and infrastructure for the NEST Coordinating
Center (February 2015,\19\ April 2016,\20\ September 2016,\21\ August
2015,\22\. In 2016, FDA awarded $3 million to the Medical Device
Innovation Consortium (MDIC) to establish the Coordinating Center, and
$1 million to other organizations to continue projects that generate
real-world evidence on device performance.
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\19\ Recommendations for a National Medical Device Evaluation
System.
\20\ The National Evaluation System for health Technology:
Priorities for Effective Early Implementation; Planning Board Report.
\21\ The National Evaluation System for health Technology:
Priorities for Effective Early Implementation; Planning Board Report.
\22\ Recommendations for a National Medical Device Evaluation
System.
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Develop a framework for the incorporation of real-world
evidence into regulatory decisionmaking.
In Progress: Issued draft guidance\23\ to describe how real-world
evidence may be used to support pre- and post-market regulatory
decisions. Final guidance is planned for 2017.
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\23\ Guidance Document: Use of Real-World Evidence to Support
Regulatory Decisionmaking for Medical Devices.
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partner with patients
We believe that if CDRH is to successfully achieve a mission and
vision in the service of patients, we must interact with patients as
partners and work together to advance the development and evaluation of
innovative devices, and monitor the performance of marketed devices.
Goal: Promote a Culture of Meaningful Patient Engagement by Facilitating
CDRH Interaction Pwith Patients
------------------------------------------------------------------------
2016 Target Results
------------------------------------------------------------------------
10 Organizations. By December 31, 2016, 34 Organizations. CDRH staff
establish one or more new mechanisms for participated in 21 patient
CDRH employees to obtain patient input on interaction opportunities,
key pre- and post-market issues facing involving 34 patient
CDRH and foster participation of 10 organizations.
patient groups.
50 percent. By December 31, 2016, 50 68 percent. More than 68
percent of CDRH employees will interact percent of CDRH interacted
with patients as part of their job duties. with patients in 2016. When
asked, 99 percent of staff
who interacted with
patients described their
interaction as meaningful
and 89 percent as relevant
to their jobs.
------------------------------------------------------------------------
Goal: Increase Use and Transparency of Patient Input as Evidence in Our
Decisionmaking
------------------------------------------------------------------------
2016 Target Results
------------------------------------------------------------------------
50 percent. By September 30, 2016, 50 65 percent. In fiscal year
percent of PMA, de novo and HDE decisions 2016, 65 percent of PMA, de
will include a public summary of novo, and HDE decisions
available and relevant patient included a public summary
perspective data considered. of available patient
perspective data.
By September 30, 2017*, increase the 65 percent. PRO and 4 PPI.
number of patient perspective studies Increased by 65 percent the
(e.g., evaluating patient reported number of approved IDEs
outcomes (PRO) or patient preference (pivotal studies only) with
information (PPI)) used in support of pre- patient reported outcomes
market and post-market regulatory (PRO). Increased to four
decisions. (Compared to fiscal year 2015 (from none) the number of
baseline). patient perspective studies
conducted by sponsors in
support of pre- and post-
market regulatory
decisions.
------------------------------------------------------------------------
* 2017 Target.
Supporting Actions
In 2016, CDRH took a number of actions to achieve the goals and
targets established for this priority:
Patient Engagement Advisory Committee. Convene the Patient
Engagement Advisory Committee to discuss high priority topics regarding
patient input in the total product lifecycle.
In Progress: CDRH chartered and began to recruit members for FDA's
new Patient Engagement Advisory Committee (PEAC). PEAC members will be
selected and announced in 2017.
Education and Training. Develop education and training for
CDRH staff and industry on the development and use of the science of
measuring and communicating patient input throughout the total product
lifecycle.
In Progress: CDRH trained more than 80 staff members on patient-
reported outcomes (PRO) and patient-preference information (PPI), to
advance staff understanding and CDRH review capacity in these areas.
promote a culture of quality and organizational excellence
A manufacturer's ability to design and make high-quality, safe and
effective devices and CDRH's ability to provide the necessary oversight
to assure devices on the market are high-quality, safe and effective
will increase as manufacturers and CDRH embrace a culture of quality
and excellence throughout our respective organizations.
Goal: Strengthen FDA's Culture of Quality within the Center for Devices
and Radiological Health
------------------------------------------------------------------------
2016 Target Results
------------------------------------------------------------------------
10 percent. By September 30, 2016, 300 percent. In fiscal year
increase by 10 percent the number of CDRH 2016, CDRH tripled the
staff with quality and process number of staff with
improvement credentials to improve quality credentials by
organizational excellence. (compared to providing onsite quality
fiscal year 2015 baseline). training and certification
examinations.
------------------------------------------------------------------------
Goal: Strengthen Product and Manufacturing Quality within the Medical
Device Ecosystem
------------------------------------------------------------------------
2016 Target Results
------------------------------------------------------------------------
By September 30, 2016, develop metrics, Partnered with MDIC to
successful industry practices, standards, develop metrics and best
and tools that manufacturers can use to practices to assess quality
evaluate product and manufacturing system performance, and
quality beyond compliance with regulatory analytical tools to assess
requirements. device quality by hospital
value analysis committees.
By December 31, 2016, pilot voluntary use Partnered with MDIC and
of product and manufacturing quality Capability Maturity Model
metrics and evaluation tools. Integration (CMMI)
Institute on a proof-of-
concept and pilot with
three device manufacturers,
to evaluate use of the CMMI
appraisal process as a
foundation for a future
third-party program.
------------------------------------------------------------------------
Supporting Actions
In 2016, CDRH took a number of actions to achieve the goals and
targets established for this priority:
Quality Management Framework. Resources permitting,
continue to implement the CDRH Quality Management Framework.
In Progress: CDRH completed development of its document control
system (DCS). DCS will ensure that current and approved quality program
and key processes documentation--standard operating procedures, work
instructions, forms, templates and process maps--is available to staff.
Education and Training. Develop education and training for
CDRH staff to facilitate adoption of practices characteristic of a
culture of quality and organizational excellence.
In Progress: CDRH became an American Society for Quality (ASQ)
enterprise member--enabling every employee at FDA to take advantage of
ASQ's vast collection of learning resources. CDRH also offered onsite
quality training to 150 staff. More than 90 percent of those who
participated in the training earned ASQ quality certifications
(Certified Quality Auditor and Certified Quality Improvement
Associate).
Case for Quality. As part of the Case for Quality,
collaborate with members of the medical device ecosystem to identify,
develop, and pilot metrics, successful practices, standards, and
evaluation tools that will be specific to the medical device industry
and focus on assuring product and manufacturing quality.
In Progress: In partnership with MDIC, CDRH collected input from
stakeholders through six Case for Quality Forums; developed metrics and
best practices designed to assess quality system performance using pre-
production, production and post-
production data; and led development of a product quality dashboard to
assist
hospital-value analysis committees in identifying high quality devices.
Voluntary Program. Identify external partnerships and
mechanisms to support a sustainable, voluntary third-party program that
will utilize quality metrics, practices, standards, and evaluation
tools to assess and promote medical device product and manufacturing
quality within industry beyond compliance with regulatory requirements.
In Progress: Continuing partnership with MDIC, CMMI Institute and
other stakeholders, to expand application of maturity appraisal
process; with the goal of developing the framework for a voluntary
program in 2017.
Appendix C. BsUFA Meeting Types
The BsUFA program established five meeting types specific to
biosimilar development programs:
A Biosimilar Initial Advisory meeting is an initial
assessment limited to a general discussion regarding whether licensure
under section 351(k) of the Public Health Service (PHS) Act may be
feasible for a particular product.
A BPD Type 1 meeting is a meeting that is necessary for an
otherwise stalled BPD program to proceed. Examples of a BPD Type 1
meeting include discussion of: a clinical hold, a special protocol
assessment, an important safety issue, dispute resolution, and/or a
Complete Response.
A BPD Type 2 meeting is a meeting to discuss a specific
issue (e.g., proposed study design or endpoints) or questions where FDA
will provide targeted advice regarding an ongoing BPD program. This
meeting type includes substantive review of summary data, but does not
include review of full study reports.
A BPD Type 3 meeting is an in-depth data review and advice
meeting regarding an ongoing BPD program. This meeting type includes
substantive review of full study reports, FDA advice regarding the
similarity between the proposed biosimilar biological product and the
reference product, and FDA advice regarding the need for additional
studies, including design and analysis. This meeting has no counterpart
in the Prescription Drug User Fee Act (PDUFA) program and is unique to
BsUFA to support an evaluation of residual uncertainty regarding the
demonstration of biosimilarity and to support the concept of stepwise
evidence development.
A BPD Type 4 meeting is a meeting to discuss the format
and content of a biosimilar biological product application or
supplement to be submitted under section 351(k) of the PHS Act.
The Chairman. Thank you, Dr. Woodcock.
Dr. Marks.
STATEMENT OF PETER MARKS, M.D., Ph.D., DIRECTOR, CENTER FOR
BIOLOGICS EVALUATION AND RESEARCH, FOOD AND DRUG
ADMINISTRATION, SILVER SPRING, MD
Dr. Marks. Mr. Chairman and members of the committee. Thank
you for the opportunity to provide this testimony today on the
reauthorization of FDA's User Fee Acts.
At the Center for Biologics Evaluation and Research, we
have regulatory responsibility for many complex biologics
including vaccines, allergenic products, blood and blood
derivatives, and cellular tissue and gene therapies.
As part of this responsibility, in addition to biologics,
we also regulate medical devices used to prepare blood and
tissue products, and blood and tissue screening tests to
prevent infectious disease transmission.
The unique products that we regulate range from vaccines,
which are administered routinely to almost all Americans to
protect the public health, to gene and cellular therapies that
are on the cutting edge of science and show promise for the
treatment of seriously ill patients including those with rare
disorders.
These User Fees play an important role in supporting our
review of many of these critical products, promoting
innovation, and speeding the availability of medical products
to those who need them.
Though we regulate a wide variety of products, a common
theme that runs through all of our complex biologics is that
their safety and efficacy are intimately intertwined with the
quality of their manufacturing processes. Indeed, some of the
products that we oversee involve the most complicated and
advanced technologies in pharmaceutical manufacturing.
Just one illustration of this is the pneumococcal conjugate
vaccine, which involves 14 different fermentation processes and
39 chemical reactions for production.
Indeed, vaccines represent one of the most important public
health measures widely implemented during the 20th century that
resulted in a significant decrease in morbidity and mortality
in both children and adults. Vaccines are still every bit as
important in the 21st century for maintaining public health.
The correlation of the introduction of infective
vaccination campaigns in the United States with the elimination
of polio virus is incontrovertible and there are similar data
for other infectious diseases.
Our Center plays a key role in ensuring the safety,
effectiveness, and availability of our Nation's vaccines. For
example, in collaboration with other Federal partners, the
Center plays an integral role in national and global
preparedness for seasonal and pandemic influenza.
In addition to licensing vaccines, we are involved across
the vaccine development process from influenza virus strain
selection, to preparation of crucial reagents in our
laboratories for distribution to manufacturers, to monitoring
large databases like the Sentinel System to ensure the post-
marketing safety of the vaccines that we approve.
CBER also regulates some of the most highly innovative
biologic products that have the potential to transform medical
care. These include gene therapies and genetically modified
cellular therapy such as chimeric antigen receptor T cells.
Although there is not yet an approved gene therapy, such
therapies very much appear to be on the horizon. In fact, the
Center currently has 560 active investigation new drug
applications involving gene therapy while having received 82
applications in 2016 alone.
Given the thousands of rare diseases without effective or
optimal therapies available, it is relevant to note that more
than two-thirds of these applications address such rare
diseases, which include both inherited conditions and acquired
diseases such as certain cancers.
Toward the objective of further expediting the development
and approval of important cellular and tissue-based therapies
addressing unmet medical needs and serious and life-threatening
conditions, the Center is very actively working to implement
the Regenerative Medicine provisions of the 21st Century Cures
Act that Congress recently enacted.
We are now receiving requests for Regenerative Medicine
Advanced Therapy, or RMAT, designation and our Center looks
forward to working with sponsors of these products along with
other stakeholders in order to help facilitate the availability
of those new therapies to patients.
Because of the broad scope of the products that we
regulate, which even include a few generic drugs, our Center is
supported in part by all four of the existing Medical Product
User Fees. User Fees fund approximately 44 percent of the full
time equivalents at the Center. The agreements that have been
reached and the resources that they have provided the Center,
along with the rest of the agency, have resulted in reduced
time to regulatory actions.
For example, during the past 5 years, we have met or
exceeded the performance goals regarding product reviews for
both the Prescription Drug and Medical Device User Fee
Agreements of 2012. A number of our performance measures have
improved significantly.
In addition, User Fees have helped make it possible for us
to fully implement recent initiatives that facilitate product
development, such as the Breakthrough Therapy designation that
was enacted by Congress in 2012. In this regard, as of January
31, 2017 our Center has received 93 breakthrough designation
requests and we granted 27 of those requests.
The support from User Fees is a critical factor in
providing us with the resources for the accomplishment of our
Center's mission to protect and promote the public health by
expediting the development and approval of important and
innovative medical products.
We greatly appreciate your efforts toward ensuring the
seamless continuation of the User Fee Agreements that have
helped facilitate the availability of such products for the
benefit of the health of the people of our Nation.
Thank you once again for the opportunity to provide this
testimony.
I look forward to answering any questions that you might
have.
The Chairman. Thank you, Dr. Marks.
Dr. Shuren. Welcome.
STATEMENT OF JEFFREY E. SHUREN, M.D., J.D., DIRECTOR, CENTER
FOR DEVICES AND RADIOLOGICAL HEALTH, FOOD AND DRUG
ADMINISTRATION, SILVER SPRING, MD
Dr. Shuren. Thank you, Chairman Alexander, Ranking Member
Murray, members of the committee.
Thank you for the opportunity to have me here today to
discuss the reauthorization of the Medical Device User Fee
Amendment or MDUFA.
When I was last here testifying about MDUFA, I am sure many
of you may recall that the program was in a much different
place. Since then, much has changed for the better, but we have
more work to do.
Between 2010 and 2016, we reduced the average total time to
reach a decision on the 510(k)--the submission type required
for low to moderate risk devices--by 11 percent.
Between 2009 and last year, we reduced the average total
time to reach a decision on the PMA--the submission type
required for the highest risk devices--by almost 150 days, a 35
percent decrease.
We went beyond our MDUFA III commitments. For example, we
reduced the median time to approve a clinical trial submission
from 442 days in 2011 to just 30 days in 2015 and 2016, a 93
percent decrease.
Changes we have made at the Center for Devices and
Radiological Health, or CDRH, to our culture, policies, and
processes, the investment provided by industry through User Fee
funding, and the direction provided by Congress through changes
to Federal law have resulted in an improved medical device
pipeline and innovative technologies being introduced into the
United States earlier than in the past.
In fact, the number of novel devices we have approved has
almost quadrupled from 24 in 2009 to 91 in 2016, the highest
since the advent of the Medical Device User Fee program in
2003.
In fact last year, we approved the first artificial
pancreas working interactively with the device manufacturer
from the early stages in development.
FDA approved the first device in the world that is intended
to automatically monitor glucose levels around the clock and
automatically provide appropriate insulin doses. Overall,
working with the manufacturer, we helped bring this technology
to market 3 years earlier than the company had originally
planned.
MDUFA IV could continue the trajectory of more timely
patient access to novel technologies, supporting CDRH's vision
that patients in the United States have access to high quality,
safe, and effective medical devices of public health importance
first in the world.
The MDUFA IV proposal submitted to Congress in January
includes programmatic enhancements, such as a new quality
management program that will improve consistency, efficiency,
predictability, and the application of the least burdensome
approach in our premarket review program and decisionmaking.
The proposal would also allow the FDA to move forward in
some critical and strategic areas, such as strengthening our
partnerships with patients, allowing us to promote more
patient-centric clinical trials, advanced benefit risk
assessments that are informed by patient perspectives, and
foster earlier patient access to new devices.
Another critical area is the development of the National
Evaluation System for health, with a small ``h,'' Technology or
NEST. The NEST is a nongovernment system that will be operated
by stakeholders of the medical device ecosystem including
patients, providers, and the medical device industry. That
would facilitate the use of real world data collected as part
of routine clinical care, such as from electronic health
records and registries consistent with the goals of 21st
Century Cures.
A robust NEST will enable manufacturers to harness real
world evidence that could enable them to drive down the time
and cost to bring a new device to market, expanding indications
for already approved devices, meeting post-market reporting
requirements, and obtaining payer coverage and reimbursement.
The NEST will also enable faster identification of safety
issues, reducing harm to patients and liability for companies.
In conclusion, reauthorization of the Medical Device User
Fee program could expedite the availability of innovative new
products, create jobs, protect patients, and provide the
enhancements that will continue to increase the efficiency of
FDA's programs.
Improvements in total time to decision, transparency,
consistency, predictability, efficiency, and assuring the least
burdensome approach will benefit industry, healthcare
providers, and most importantly, patients.
Thank you for the opportunity to testify today and I look
forward to your questions.
The Chairman. Thank you, Dr. Shuren.
We will now have a 5-minute round of questions. I am going
to defer my questions, and we will start with Senator Burr, and
go to Senator Murray.
Statement of Senator Burr
Senator Burr. Thank you, Mr. Chairman. Thank you for
holding this hearing.
I welcome our agency folks from the FDA. Let me ask all of
you, if I can; just a yes or no answer.
Would you be opposed to a modification in the Agreement
that would return a percentage of the User Fee money to any
manufacturer for those portions of the Agreement you did not
live up to? Yes or no.
Dr. Woodcock.
Dr. Woodcock. Yes.
Senator Burr. Yes?
Dr. Woodcock. Yes.
Senator Burr. Dr. Marks.
Dr. Marks. Yes.
Senator Burr. Dr. Shuren.
Dr. Shuren. Yes.
Senator Burr. OK. Listen, as a part of the 2012 PDUFA, the
FDA promised to hire an additional 129 employees to review
applications and to conduct other critical tasks to improve the
performance of the agency.
For the 2013 through 2017 cycle, the agency has only hired
86 percent of the total number of new, full-time paid for by
the industry. So the FDA has not been able to hire all the
employees agreed to under the PDUFA agreement.
Does the agency plan to return those dollars?
Dr. Woodcock. No.
Senator Burr. Do you feel that living up to the agreement
that you made with the industry is important?
Dr. Woodcock. Absolutely.
Senator Burr. Has the FDA ever diverted User Fee money to
construct buildings versus to hiring employees as was part of
the agreement?
Dr. Woodcock. To my knowledge, the agency has only spent
money on the User Fee Agreements for the things that are
allowable under there. Certainly, rent and overhead costs are
one of the allowable costs.
Senator Burr. The White Oaks Facility did not take User Fee
money for construction?
Dr. Woodcock. I do not know the answer to that. We can get
back to you.
Senator Burr. I would love for you to. I think that User
Fees, dollars toward rental payments totaled $59.54 in 2015,
that is GAO. Let me say, 27.1 of that was devoted to staff and
it went toward rent.
Listen, this is really important. I believe all the
statistics as you have told me. I have heard them for 23 years
from the FDA.
Let me ask this, has what you agreed to in the User Fee
Agreements differed greatly from the 1997 statutory
requirements that you had?
Dr. Woodcock. For drugs, there has been significant
difference in the amount of advice we give.
Since the first User Fee program, which set timeframes for
conducting the premarket review, much of the attention has been
paid to providing advice to industry in meetings during drug
development and developing standards. Because the most
important thing for the drug industry, at least, is
predictability; so what is needed to get it onto the market?
What standards have to be met?
Senator Burr. I believe we negotiated that in the last
Agreement.
In 2015, FDA did not meet five of the meeting management
goals established under the User Fee Agreement. A critical
piece of the review process is the communication between the
agency and the sponsor of the drugs, biologics, or devices.
Regular correspondent progress updates, meetings between
the two parties create greater predictability and certainty
throughout the process. The agency promised to schedule 80
percent of certain meetings within 75 days. That is over 2
months allowing for a meeting to be set up.
The agency scheduled only 49 percent of these meetings. You
came up short of what the goal was in PDUFA, yet there is in
this Agreement no penalty that the FDA pays.
If you do not meet the FTE's that you agreed to in the
agreement, there is no penalty that the FDA meets.
If money is diverted over to rent versus to processing
applications, there is no penalty that is met.
Ninety-two percent of priority applications are approved in
the first review cycle at the FDA and now, this is great news.
However, that is not the case for standard applications moving
through the agency. The percentage of standard applications
approved in the first review cycle is 60 percent.
What is the reason?
Dr. Woodcock. The reason, generally, is that more questions
arise. Standard applications do not provide an additional
health benefit to the public. They are usually another option.
The burden on them to be at least as good as what is out there
is somewhat higher than something that is curing something.
Senator Burr. Could that be part of 51 percent that did not
get a regularly scheduled meeting?
Dr. Woodcock. That I cannot comment on.
Senator Burr. Let me just ask you, my time is running out.
Dr. Woodcock. I would like to, if I may, explain that rent
is an allowable part of the User Fee Agreements, as I said
earlier.
Senator Burr. Well, I just want my colleagues to be fully
aware of what User Fees go to. They do not necessarily go to
put reviewers in front of applications to make decisions that
live within the timeframes that you agreed to.
Since we are new to Generic User Fees, how has the backlog
changed on generics in this first User Fee period?
Dr. Woodcock. Prior to enactment of the first Generic User
Fee program, there was a very large number of applications,
thousands, sitting at the FDA that had not been picked up and
looked at.
Typically before that program started, they would go
through a minimum of four cycles of review before they got out
onto the market and done, which meant some of them went through
11 cycles of review.
We have reviewed virtually all of those applications. They
have been reviewed and many of them--there are 1,800 current
applications sitting back with the manufacturers waiting for
them to decide whether to resubmit them or move on.
We have 2,300 applications in process at the FDA, under
review, with goal dates. So they have a predictable path that
they will follow.
I cannot tell you at the end of their review that every one
will get approved. Why? Some of them have manufacturing
facilities that are unacceptable and we cannot approve generics
where the parties have, perhaps, made up data or other things.
So there may be blocks. We will send them a complete response
saying, ``You have to fix this problem.''
However, everything is under goal right now and it is a
predictable process for the industry. Not as fast as they would
like it to be, or we would like it to be, because we had to get
through that huge bolus, which I compared to like a python
trying to, or a snake, trying to swallow a giant donkey or
something like that. It was an amazing amount of work that we
had to get done, but it is in process.
Senator Burr. We need to move on.
The Chairman. Thank you, Senator Burr.
Senator Murray.
Senator Murray. Thank you, Mr. Chairman.
Before I ask my questions, I do have to say again, I am
deeply concerned that we have a major healthcare bill moving
through Congress that has not had a hearing.
As a reminder, during consideration of the Affordable Care
Act, this HELP committee held 47 bipartisan meetings on that
issue including 14 bipartisan roundtables, 13 bipartisan
hearings, and 20 bipartisan walk-throughs.
It is really concerning to me that given all of the harm
and chaos and everything that goes along with Trump Care, there
are no plans in this committee to talk about this legislation
as it moves through. I have a lot of constituents, like I am
sure many of us do, coming up to us with really personal
stories. They are very fearful and I just think it is critical
that this committee have a hearing to talk about the impact of
this legislation.
I hope our colleagues think about why they do not want to
have a hearing and hope they agree to allow us to have some
closer scrutiny of this. I think it is extremely critical and I
am going to stay focused on it.
On this subject, Dr. Woodcock, let me talk with you first.
Polls show that the high price of prescription drugs is one
of America's top health concerns. We know when costs are too
high, patients sometimes forego their necessary treatments.
However, the FDA is not permitted, of course, to set drug
prices. I am hopeful that our Republican colleagues will work
with me and other Democrats on this side of the aisle. CMS is
currently prohibited from negotiating the price of drugs under
Medicare Part D. I would love to work on reviewing that, seeing
if we can change that.
The FDA can help promote a robust, competitive marketplace
that makes treatments more affordable for patients by
continuing to advance generic and biosimilar drugs.
Dr. Woodcock, can you tell us the key ways the generic and
biosimilar agreements will help to get those products to market
for consumers?
Dr. Woodcock. In the generic space, it is very important
that they not only have a predictable process, we also need to
shorten the cycle numbers.
Having four cycles as happened in the past is an
inefficient process for both the industry and the FDA. It
wastes resources. We would like to move to where we have
finally moved in the Prescription Drug User Fee program where
the majority of approvals are after one review cycle. That is
No. 1; a predictable, prompt path to the market.
Other parts of the Agreement include us continuing
research. There are parts of the innovator, the brand drugs,
certain types of products that really have very little generic
competition. That is because you cannot do traditional bio-
equivalents testing on them. For example, topical drugs and
drugs with other routes of administration other than oral.
We have been doing research on these and have begun to
develop methods whereby instead of doing large clinical trials
to get a generic on the market, which is, of course,
counterintuitive that we can use other methods to show they are
just the same as the innovator.
Similarly in the biosimilar world, the advanced methodology
that we have is helping us compare the drugs before they go
into any clinical testing in the biosimilar world, and this is
what is allowing biosimilar development.
These activities are really helping enhance competition.
Senator Murray. According to the FDA's own data, there are
over 2,300 applications for generic drugs in some stage of the
review process at the FDA.
How many of those 2,300 applications are for products that
would offer competition to a brand name drug for the first time
or products that could bring competition to an uncompetitive
market; the kinds of products that could actually bring new
competition to some of the high-priced drugs?
Dr. Woodcock. My understanding is there are six waiting,
but they have to wait, offer experience, and so forth. Six
first generics and there are nine where they are a sole source,
where there is only one other. Is that correct, Keith? Yes,
that is correct.
Senator Murray. That is not very many.
Dr. Woodcock. That does not address the entire problem.
I must stress that the second Generic Drug User Fee program
has many features that is intended to move these along as much
as possible. We have a preprogram, as I said, for complex
generics, which is an area where there is difficulty getting
generics on the market, where we give advice and more
handholding on how to get through the process for these more
complicated products.
We also have, right now, a prioritization program where
first generics and sole source products can be expedited in
their review.
Senator Murray. Well, I appreciate it. It is not very many.
Dr. Woodcock. No.
Senator Murray. I think it is pretty clear that this
agreement will make some important improvements to the generic
drug approval process, which I support. But it alone is not
going to solve the drug crisis. We are going to have to work
outside of this to make that happen.
Thank you.
The Chairman. Thank you, Senator Murray.
Senator Collins.
Statement of Senator Collins
Senator Collins. Thank you, Mr. Chairman.
First, let me thank you for holding this hearing. We are
facing the expiration date of September 30 for four laws that
authorize these extraordinarily important fee programs that
have helped to improve the healthcare, and the availability of
medications and devices for the American people. I am glad that
you are moving ahead and not jeopardizing these programs.
Speaking of which, Dr. Shuren, I was delighted to hear you
talk about the artificial pancreas. I chaired and founded the
Diabetes Caucus in the Senate back in 1998. We have tripled
funding for research, which has helped.
The collaboration that you talked about that has allowed
the artificial pancreas to come to market 3 years earlier, I
believe you said, than otherwise would be the case is going to
make such a tremendous difference in the lives of so many
children who have Type 1 diabetes.
I remember holding a hearing on the promise of an
artificial pancreas 10 years ago, and it was really wonderful
to learn of this development last year, and to see it coming to
market.
I understand, however, that the initial access is going to
be limited to older children and adults with Type 1 diabetes.
Can you update me on what is going on as far as clinical
trials to allow younger children access to this potentially
life altering technology?
Dr. Shuren. I appreciate, by the way, all your support in
the diabetes community for all these many years.
So yes, the device will be available for patients, really,
14 and older, but additional data is being collected in terms
of younger children. The reason is because they are more
active; their lifestyle is different. We just have to make sure
that that technology, that they are able to use it given how
they eat, how they play. But it is our hope that that will move
forward very quickly as well.
Senator Collins. Thank you. That is great news.
Dr. Woodcock, as you are well aware, the Senate Aging
Committee, which I chair, spent a whole year looking at the
explosion in prices of off-patent drugs for which there was no
generic equivalent.
One of the issues that we identified were the restricted
distribution programs that were intended to prevent side
effects, or they were high-risk drugs that patients were going
to be using. So they were intended to be pro-consumer.
What we found is that these systems could be abused to
delay generic entry into the marketplace. And the abuses are
serious. By one estimate in 2014, such abuses resulted in
increased costs to consumers of $5.4 billion per year.
We have talked before about the REMS system that has been
used by some drug companies to prevent potential generic
competitors from getting access to the drugs, so that they can
conduct the bioequivalent studies that you require.
What can be done to ensure that these restricted
distribution programs, which were enacted with the best of
intentions, are not abused and are a source of delay for
generics coming to the marketplace?
Dr. Woodcock. These are a source of delay in two ways.
No. 1, as you said, companies are refusing to give drugs to
the generic companies so they can perform the bioequivalent
studies.
We have done a program to try and counter that. We review
the protocols of the generic company, the clinical bio-
equivalents protocol, and then we send a letter to the
innovator company saying, ``We find this acceptable. There are
no problems.'' But we cannot force brand companies to give a
drug to generic companies.
We do talk to the FTC. We send them information when this
happens, and we have actually sent about 150 different settings
about drugs over to them regarding this.
REMS are also a source when there is a restricted
distribution system and Congress had said in the original FDA
Amendments Act that there had to be a single shared system
unless there were good reasons not to, which means the
innovator would have to have a shared system of distribution
with its competitors.
This has delayed availability of generics a very long time,
in some cases, and that is something we cannot do too much
about. That is a standing law on the books. It says there
should be a single shared system.
In some cases, we have had to go to separate systems that
talk to each other so that the generics actually can come onto
the market.
Senator Collins. So, would you like to see a change in the
law in that area?
Dr. Woodcock. Well, I cannot comment on that, but I would
say that that is a problem that we are seeing.
Senator Collins. Thank you, Mr. Chairman. I hope when we
get to the markup stage, that the bill that Senator Claire
McCaskill and I introduced as a result of the investigation we
did in the Aging Committee will be part of our consideration.
The Chairman. Thank you, Senator Collins.
Senator Bennet.
Statement of Senator Bennet
Senator Bennet. Thank you, Mr. Chairman.
I am grateful for you holding this hearing.
I want to also join Senator Murray and just urge my
colleagues to find a way to have a bipartisan discussion as
this healthcare bill comes forward.
I did 2 days of town meetings last week all over Colorado
in Democratic and Republican areas. There are a lot of people,
as everybody on this panel knows, who are dissatisfied with our
healthcare system right now as it is, and they are worried that
the Congress is about to make it even worse than it is.
Sign me up. We had 13 hearings here. We had a 7-day markup
in the Finance Committee. We had, I think, 25 days on the bill
in the Senate, and I remember some people saying it was being
rushed through even with that kind of approach. I hope we can
work to improve something as it comes through.
Second, I would like to thank Senator Collins for her
leadership on diabetes and also recognize the good work that
Dr. Shuren and his team have done.
I had Commissioner Califf out to Denver to visit the
Barbara Davis Center and to meet a number of young people there
who are just so excited about the potential of this artificial
pancreas to change their lives. And there is more work,
obviously, to be done there.
It is just a reminder that the work you do, and the work we
do, can actually improve people's lives and that people are
watching. And not withstanding the politics around here, they
would like their government to actually be responsive to them.
I want to thank you also for the progress that you have made in
terms of the speeding up of approvals of medical devices.
You mentioned, Dr. Woodcock, the Breakthrough Therapies
legislation that Senators Burr, and Hatch, and I wrote a number
of years later. We now have seen that about 50 drugs have been
approved as a result of that legislation. Treatments such as
Kalydeco for cystic fibrosis have made a dramatic difference in
the lives of Coloradoans who are fighting a life or death
disease.
I would love to hear you talk a little bit more about why
you think that has been a success? What we have learned from
that that we are going to be able to apply in other parts of
the agency, if others would like to be responsive?
A question also is that when we look at the Breakthrough
Therapies, only one has been approved for use in a neurological
disease, specifically Parkinson's and I wonder whether you
could address Coloradoans who are suffering from ALS,
Alzheimer's, and other neurological diseases? How we can better
support efforts to identify and speed up the approval of
promising new therapies for neurological?
Maybe we will start with Dr. Woodcock and then if anybody
else wants to respond.
Dr. Woodcock. Well, the Breakthrough Therapy program has
put focused attention on potentially game-changing drugs. And
we have been lucky that there are more of them now, probably
because of the advance of science.
When we get that preliminary clinical data--as you said in
the statute that shows that promise to be a game changer--we
focus management attention on that development program, make
sure it is as streamlined as possible, and we really help the
sponsors get over the finish line for those drugs. That is
really a very important intervention that has led to this.
As far as neurologic diseases, we did recently approve a
very high-tech product called Nusinersen for spinal muscular
atrophy, a fatal disease of children and a debilitating disease
of young people. That was approved to slow down the disease and
it is actually an antisense oligonucleotide.
Senator Bennet. Hold on. Let me write that down.
Dr. Woodcock. Yes, it probably takes more than 5 minutes to
explain, but it is a very high-tech intervention that actually
turns on a gene and helps produce the protein that is missing
and is needed.
We are starting to see that, but neurologic diseases are
behind cancer and other diseases. We do not know as much about
them.
As I said many years ago to someone on this committee, that
if we had put a war on neurologic diseases at the same time we
declared a war on cancer, we probably would not be having this
conversation. But our scientific understanding of neurologic
diseases has lagged. But the good news is we have a robust
pipeline now.
Senator Bennet. Is there anybody else who would like to?
Dr. Marks.
Dr. Marks. I would just quickly add that I think that for
our products too, we are starting to see products for
neurologic diseases start to come into our Center. The
Breakthrough designation is something that, with the enhanced
communication, hopefully as those products come down the
pipeline, we will help bring those forward more quickly to
patients.
Senator Bennet. Thank you, Mr. Chairman.
The Chairman. Thank you, Senator Bennet.
Senator Young.
Statement of Senator Young
Senator Young. Thank you, Mr. Chairman, for holding this
important hearing.
I want to thank the Ranking Member for her support of this
hearing as well, and thank our panelists.
Regenerative medicine has been invoked a number of times
here. I think it is really exciting the possibilities in that
area and I thank you for your work there. It provides hope to
those whose family members die on account of a lack of
sufficient supply of organs being available in this country.
I just want to publicly announce my interest in this issue.
There is no organized constituency, to my knowledge, of family
members of people awaiting organ donations in this country. We
have, I think to put it mildly, a suboptimal system, and I am
looking for opportunities to make improvements there.
Turning to User Fees, the pharmaceutical and medical device
industries are very important to the State of Indiana, not just
on account of the jobs that they lead to, but we are proud of
the innovations in the area.
The 21st Century Cures Act and the Prescription Drug User
Fee Act VI--the technical agreement--directs the FDA to explore
uses of real world evidence that are now possible. We can pull
a raft of evidence out of clinical trials and analyze that to
assist our regulatory decisionmaking. We directed that that be
done in furtherance of safety and effectiveness.
How will the FDA approach the exploration of this new area
of regulatory science? And does the FDA have some plans to
learn from the experiences of other sectors, say, the health
insurance sector, various hospital systems, and their use of
real world evidence with regards to reliance on real world
evidence?
Dr. Woodcock. Well, certainly we have harnessed the health
insurance industry data. Our Sentinel System has about 193
million patient experiences and different patients from claims
data from health insurance. That links to what happened to
them, what their diagnosis was, what condition they were
hospitalized for.
We have used that many times. That is now part of our
routine safety, surveillance, and assessment of signals that we
get on safety. We can go into those data, and do analyses, and
bolster the evidence, whether there is a real safety problem or
whether it was simply something that was a false signal.
Senator Young. So you are looking at claims data in those
data packages FDA receives.
Any other sort of data sets from registries?
Dr. Woodcock. Absolutely. We are interested in data in any
possible form we can get it. We do work with, say, PCORnet.
They have set up a network that includes the electronic health
record, and we are very interested in integrating that into
Sentinel. We do this work with the Center for Biologics.
That will take some more work, but we are working on that
integration, and getting all the standards together, and so
forth. We want to incorporate registries. I know devices, maybe
Jeff, you ought to talk about that more.
Dr. Shuren. Yes. We are already using device registries,
and we have been involved in helping to set up over two dozen
device registries.
In the past 6 years, we have been engaged in over 50
projects related to real world evidence. We are currently
relying on it to approve new devices. Last year, we approved a
balloon catheter based upon registry data.
We are expanding labeling indications based on it. In fact,
in one case for a heart valve, the company was going to do a
clinical trial. We saw the data was good enough in registry. We
called the company and said, ``Do not do the study. Send us a
request. We are going to approve the indication.''
We are using it for post-market studies. We are finding
nesting clinical trials in a registry is reducing costs by
about 40 to 60 percent.
Senator Young. Fantastic. Moving to MDUFA, or the Medical
Device User Fee Act IV. That Agreement includes new
requirements for User Fee revenue to support the National
Evaluation for health Technology to develop a coordinating
center with expertise in the use of real world evidence to
support premarket activities. A number of pilot projects are to
be created.
Could you very briefly discuss how these are going to work
and how they might allow patients to benefit from new safe and
effective technologies more quickly?
Dr. Shuren. Well, first off, this is not a Government
system, so we have already provided initial seed funding to the
Medical Device Innovation Consortium, a public-private
partnership, to serve as the coordinating center.
They are in the midst of hiring an executive director and
setting up a governing committee that has representatives from
the device ecosystem. So patients will also have a voice in
that entity.
As part of the pilots, they are going to be looking at
return on investment for use of real world evidence in
approving products, expanding labeling indications, and using
it for malfunction summaries.
Also as part of it, they will start laying out the rules of
the road, infrastructure and methodologies, to make greater
use. The whole goal here is drive down the time and cost, and
increase the value of use of real world data.
Today, there are a lot of challenges in using the data. It
may be of poor quality or incomplete. The other is, it is only
available for certain devices. We want to make that available
more systematically across the device industry.
Senator Young. Thank you.
The Chairman. Thanks, Senator Young.
Senator Murphy.
Statement of Senator Murphy
Senator Murphy. Thank you, Mr. Chairman.
I just think it is outrageous that we are holding this
hearing today instead of talking about what is actually
happening in this building right now; an effort to rewrite the
rules that concern one-sixth of this country's economy.
An effort to jam down the throats of the House and the
Senate the repeal of the Affordable Care Act, the most massive
change in American healthcare in our entire lifetime. We are
not talking about it in the Health Committee. We are the Health
Committee. We are charged with overseeing the American
healthcare system. And we are acting as if this is not
happening.
IPDUFA, MDUFA, I understand they are important, but I am
just going to tell you, the people that are sitting in this
audience today, they are not representing uninsured Americans.
They are representing the industry by and large. They are
representing the million and billion dollar companies that have
a lot at stake in this legislation.
We are the Health Committee and I do not know what the
relevance of sitting on this committee is if we have nothing to
do or say about a piece of legislation that is going to
dramatically alter the landscape of American healthcare for our
constituents.
We have heard about what the Health Committee has done in
the past, and so, I will not regurgitate those numbers, but I
watched those hearings. I was proud to watch those hearings.
In the Health Committee, there were 300 amendments that
were considered in developing the ACA. There were 160
Republican amendments that were accepted as part of that
legislation. Republicans did not vote for it in the end, but
this committee had the chance to weigh in. The American people
got to see over the course of a year an actual debate play out.
And though Republicans eviscerated Democrats for ramming
that bill through, let us be honest about why we are not having
a hearing here today. It is because my Republican colleagues
did not learn a lesson of a bill being rammed through the
process. They actually think that process took too long.
The reason that this bill is being jammed through on an
extraordinary timeframe is because the lesson they learned from
the ACA is that there was too much debate, and so they want
less so that nobody can see what is in this bill.
I get that we can make your job easier and speed more
transformational drugs to market, but if you do not have
insurance to afford these drugs, then nothing we do here in the
reform of these User Fee Agreements matters.
Twenty-four million people are about to lose their
healthcare. That is the entire population of Alaska, Delaware,
Hawaii, Idaho, Kansas, Maine, Montana, Nebraska, Nevada, New
Hampshire, New Mexico, North Dakota, Rhode Island, South
Dakota, Vermont, West Virginia, and Wyoming.
This is not a minor adjustment of the number of people who
have access to the drugs that we are talking about here today.
This is a humanitarian catastrophe that is about to happen, and
we are pretending like the debate does not exist.
I asked to be on this committee because I wanted to be at
the center of the most important debates about the future of
the American healthcare system. But it is possible that next
week in the U.S. Senate, we are going to be asked in a handful
of hours to vote up or down on a bill that is going to
dramatically change the reality of healthcare for consumers all
across this country. Driving rates up for millions of people,
especially older Americans, taking healthcare away for millions
of Americans, passing on enormous tax breaks to the drug
industries that we are talking about here today to healthcare
insurance companies. This committee will have nothing to say
about it.
I do not have any questions for the witnesses.
The Chairman. Senator Roberts.
Statement of Senator Roberts
Senator Roberts. Well, thank you, Mr. Chairman.
Back to the subject at hand.
Thanks to the panel. I am pleased to see the increased
reporting, more timelines, stronger commitments to patient
engagement, and independent third-party reviews.
With the combined 30 percent increase for fees proposed for
next year, as Senator Burr so aptly described, that is over 100
percent for the biosimilars alone. I hope you are all prepared
for the increased workload which will be required to turn this
investment into increased and improved treatment options for
the patients.
We certainly, here on the committee, do not want to slow
down approvals as these are important therapies to get on the
market. We have heard a lot of frustration and confusion with
how to proceed in their absence.
I appreciate that in the commitment letter that you gave
us, there are specific timelines laid out on the
interchangeability. Your agreement states that the FDA will
publish draft guidance by the end of this year, and finalize
within 24 months after the close of the comment period. That
puts us into 2020. That is 10 years after the biosimilars
pathway became law. That is a long time, even for Senators.
Dr. Marks and Dr. Woodcock, why is this taking so long?
Either one.
Dr. Marks. Well, I can start and I can let Dr. Woodcock
continue.
In part, it was necessary to develop--the guidance took
time to develop in order to develop the science behind this.
There were issues with developing the science of determining
that things were bioequivalent. There were issues in
determining what constitutes the scientific criteria that
things would be interchangeable.
Taking into account stakeholders' comments on these, and
so, it did take some time to get things, but I think we are
committed to moving ahead very expeditiously toward trying to
get out our required guidance and to continue to move ahead
with this important program.
Senator Roberts. Not an easy task, I know.
Please, doctor.
Dr. Woodcock. We would expect to finalize the guidance
ahead of schedule. That is what I would expect.
Senator Roberts. Thank goodness.
Dr. Woodcock. I would expect that there is going to be,
there is a great deal of controversy on this, obviously,
because it is a point of great financial import to both
innovators and the biosimilars.
The patients are very interested in this. All professional
groups are interested in this. So there is a great deal of
commentary on what the standards should be.
We are committed to getting this done as quickly as
possible and it should not, it will not impede the availability
of biosimilars on the market. It is simply switching at the
pharmacy that is the interchangeability piece.
Senator Roberts. In 2015, only 9 percent of generic drug
applications were approved in the first cycle review.
Dr. Woodcock, before the Energy and Commerce committee, you
stated that you think that this number is either 20 or 25
percent of the new agreement. You would consider that a
success.
In the commitment letter, I see the pre-application program
for complex products as a good step to improve early
communication for companies with the agency and approve on
review success. But that is only for complex products.
Can you share any other efforts within this agreement that
would be beneficial for noncomplex products to receive the
first cycle review approvals?
Dr. Woodcock. Certainly, we recognize that even more
communication than we have instantiated in the first generic
drug review program will be necessary to bring up that first
cycle approval rate. And it is in our best interests, as well
as the interests of the companies and the public, to get these
on the market as quickly as possible.
We have put in place more communications at every step of
the way, including if people do not get a first approval, there
can be a conversation about what was wrong, what needs to be
fixed, and so on. We hope this will improve first cycle
performance faster than we did in PDUFA.
Senator Roberts. Mr. Chairman, I would like to acknowledge
your aversion to acronyms. And I would like to acknowledge your
penchant for country and western music. I would like to
acknowledge the considerable fervor that has been shown on the
minority side. I do not know if this is the best I can do. I
will work with you later.
``We met in PDUFA,
But she was very aloofa.
But our bios were similar,
So we got married in GDUFA.''
[Laughter.]
What do you think?
The Chairman. I think we should go onto Senator Warren.
[Laughter.]
As much as I respect your country music.
Senator Roberts. I think that is probably a very good idea.
The Chairman. Thank you, Senator Roberts.
Senator Warren.
Statement of Senator Warren
Senator Warren. Thank you, Mr. Chairman.
You have called us here today to discuss the FDA User Fees
program, and it is vitally important, and I am going to work
hard to make sure that this makes it through Congress.
I join my democratic colleagues and--I am just going to be
blunt about this--I have no idea why we are having this
healthcare hearing today, 48 hours before the House Republicans
try to ram through a bill that is going to rip health insurance
away from 24 million people, raise insurance premiums for
seniors by $12,000 a year, and eviscerate the Medicaid program
to the tune of $880 billion. There is no indication that the
Senate will hold a hearing on this bill. Not now, not ever.
If Republicans want to gut our healthcare system, they
should have the decency to talk openly about it, not jam
through a bill that will devastate the entire country's
healthcare system with zero debate.
We have three distinguished witnesses here from the Food
and Drug Administration. None of this is their fault. I do have
some questions I want to ask them, so I am going to do that.
But they are among the thousands who work hard at the FDA to
get innovative treatments to patients, while also protecting us
from dangerous drugs, from deadly devices, and from poisoned
foods.
Dr. Woodcock, on his third day in office, President Trump
announced a governmentwide freeze on hiring. Does a hiring
freeze help or hurt the FDA's ability to do these jobs?
Dr. Woodcock. We are actively working through the issues of
hiring with the Administration. We were able to move forward on
certain select positions within the User Fee programs and to
hire to meet also the needs of the Cures Act.
Senator Warren. That was not the question I asked.
The question I am asking you is: does a hiring freeze make
it easier or harder for you to do the things you are supposed
to do? Protect us from dangerous drugs, from deadly devices,
and from poisoned food.
Dr. Woodcock. Clearly, the FDA needs adequate staff in
order to conduct its public health mission.
Senator Warren. All right. That is the whole point of these
User Fees is that it is supposed to add positions to do drug
and device review, not plug holes that are created by a hiring
freeze.
Let us be honest. We have to say there is no way that a
hiring freeze is going to help the FDA do its job.
The President's budget also proposed to, quote, and I will
read it here, ``Replace the need for new budget authority at
the FDA with an increase in medical product user fees.'' As I
read this, I think this is just a fancy way of saying that
Congress should cut the guaranteed funding going to the FDA.
Dr. Woodcock, if Congress cuts funding going to the FDA,
does that make it harder or easier for the FDA to do its job?
Dr. Woodcock. I am not position to discuss budgetary
matters at this time.
Senator Warren. Well, I get that you are not here to
describe the budget, but I am asking you a question. If the
President wants to cut money going from Congress to the FDA, is
that a good idea or a bad idea from the point of view of the
FDA doing its job?
Dr. Woodcock. Again, I am not able to comment.
Senator Warren. Well, look. I really do not get what the
plan is here. I certainly hope that we are not going to blow up
our User Fee negotiations and risk an FDA shutdown because the
President does not think that the Government needs the Food and
Drug Administration.
I am not seeing much evidence that this Administration
actually wants the FDA to work. If they did, they could start
by reversing the hiring freeze and backing off this announced
reckless plan to undermine FDA funding.
Let us be clear, if the Republican bill to gut American
healthcare becomes law, all the miracle cures and speedy FDA
approvals in the world will not matter to the tens of millions
of Americans who will not be able to afford them when they get
sick.
On behalf of the thousands of people in Massachusetts and
millions of people around this country who are terrified about
that, Mr. Chairman, I look forward to having a Senate hearing
where we can discuss those issues.
Thank you.
The Chairman. Thank you, Senator Warren.
I will take my 5 minutes now, if that is all right with
Senator Cassidy and Senator Scott.
Senator Scott. We serve at your pleasure, Sir.
The Chairman. No, you do not really.
Senator Scott. I concede your right.
The Chairman. I appreciate your courtesy.
We scheduled this hearing on March 3 because of what would
happen if we do not do our job here. I am going to ask you a
question in just a moment of what the consequences would be to
patients all over the country if by July 27 we do not decide
what we think about these Agreements and you have to fire 5,000
people. What the consequences will be to the enormous advances
that we laid in place for the 21st Century Act. I will ask you
that in just a minute.
As far as the FDA hiring freeze, I can answer that
question. That is a problem. That needs to be lifted as soon as
it can be because one of the major advances of the 21st Century
Cures Act was to give the FDA new authority to hire the people
it needed and pay them what needed to be paid to them so they
could approve the drugs that we complain are not getting
through the investment and regulatory process and into doctors'
offices.
I can give my opinion on that and that is my goal. I hope
the Administration will quickly recognize the importance of
that.
Insofar as the amendments to the Affordable Care Act,
without dwelling on that, because I want to spend the time here
on this important Act, I think we can do two things at once in
the U.S. Senate.
It is true there. We proceeded on two tracks when we passed
the Affordable Care Act. One was the part that required 60
votes. There were plenty of hearings there.
One was the reconciliation track. There were almost none
there. In fact, there was no train that ran through the
Congress faster than the Obamacare reconciliation bill. It went
through in 8 days. Budget to the floor, budget to the floor in
the Senate, and then back to the House, and out to the
President.
There has already been much more deliberations on the
current amendments than there were on that reconciliation in
2010.
On the part that requires 60 votes, which is the only way
we will get lasting, durable changes to our healthcare system,
there will have to be a lot of hearings. We had one a month ago
in what I consider the real humanitarian crisis, which are the
231,000 Tennesseans who will have zero healthcare options in
2018 if Congress does not act to fix the problems of what is a
collapsing, failing individual market caused by the Affordable
Care Act.
We proceeded on two tracks in 2009 and 2010. We are
proceeding on two tracks today. The track on reconciliation
actually has more deliberations than the one did in 2010.
Let me ask my question. What would be the impact if
Congress does not act by the end of July, 60 days before the
expiration of the current Agreements? What would be the impact
on the Food and Drug Administration if we fail to do that? I
will ask each of you that question.
Dr. Woodcock. We would have to follow the Government rules
for preparing to let go a large number of people, as you said,
across the User Fee programs because we would have to prepare
to issue notices of reduction in force if those User Fee
programs were not reauthorized, and we would not be getting the
money.
There are carryover balances that are carried within each
of the programs that allow for an orderly shutdown.
But I think your question is more what would the impact be?
The Chairman. Yes. What would the effect be on patients,
and on new drugs, and on lifesaving devices?
Dr. Woodcock. Peter, do you want to start?
Dr. Marks. We have literally hundreds of investigational
new drug applications that are a part of User Fee programs. The
ability to hold meetings in a timely manner, the ability to
make sure those approvals happen in a timely manner to get
products to patients with medical need would be adversely
impacted severely.
The Chairman. Dr. Shuren.
Dr. Shuren. We would lose about one-third of our people.
And it is not just that reviews will take longer, but the
industry, which now is starting to bring their innovative
technologies to the United States early, sometimes first, as
you heard with the artificial pancreas. They are going
elsewhere. I am already hearing from companies if the United
States does not work out right, it is not just Europe, it is
now China and elsewhere.
The Chairman. I am not exaggerating when I say that if we
do not act, if the President does not sign the bill by July 27,
I believe it is, then you have to take these steps.
Is that correct?
Dr. Woodcock. We must initiate them. Yes, we must do the
reduction in force that would start at the time.
The Chairman. So you send letters to employees saying,
``You are going to be laid off in 60 days.''
Is that right?
Dr. Woodcock. We would begin a process to do that, and we
have to identify the people. There is an elaborate system of
how you figure out who is what. But everyone would know this is
going on.
The Chairman. An application for a cancer therapy or cure
that might be before reviewers might be delayed?
Dr. Woodcock. Yes. We know right now, we have patients
living sort of hand to mouth, young people with brain tumors or
other cancers who are waiting for the next effective therapy to
come along as they develop resistance to current.
I heard from a Senate staffer, ex-staffer about this who
has lived a long time, been able to work because there have
been successive approvals of drugs for his cancer that have
kept him alive. And this would be repeated over and over.
Most concerning in the biologics area for the
pharmaceuticals, the gene therapies, the cellular therapies,
the very innovative treatments require oversight in the
investigational phase because any slip up there can last for 10
years and set the entire field back.
The Chairman. Thank you very much.
Senator Hassan.
Statement of Senator Hassan
Senator Hassan. Well, thank you, Mr. Chairman and Ranking
Member Murray.
And thanks to the witnesses for being here today as well.
I will join my colleagues on the minority side of the table
here just to reiterate that while I think it is extremely
important that we consider the User Fee Agreements--and I
appreciate the chance to speak with all of you today--like many
of my colleagues, I am troubled that the committee has not
been, and is not addressing, the issue that I hear most about
from Granite Staters right now.
I just came back from several days at home and wherever I
go, people want to understand what the implications of Trump
Care are for them. I hear from constituents all the time who,
because of the Affordable Care Ace for the first time, got
access to lifesaving treatment.
While what you all are doing and what we are talking about
here today is very important, without that underpinning of
insurance coverage for many of my constituents, this is a
little bit of an irrelevant conversation.
I hope that we will have a chance to convene hearings to
the Chairman's point that the U.S. Senate can do two things at
once. We could convene some hearings on Trump Care before we
have to vote on it, and I hope very much that we will do that.
Not only so we can make informed decisions, but so that all
Americans can be part of an open and transparent process
because the Trump Care bill, as it now stands, will hurt my
constituents. It will hurt our country.
As the committee in this body with jurisdiction over many
things in the Trump Care bill, that is the topic that I think
we should be focused on today.
With that being said, I do want to ask you all about a
couple of things and I will start, Dr. Woodcock, with you.
Too many Granite Staters, and people across our country,
are struggling with an opioid addiction and it is an epidemic
in my State. It killed approximately 500 people in the little
State of New Hampshire last year.
I commend the FDA for putting out its Opioid Action Plan
last year, but I want to be very clear that there is still much
more work that the FDA needs to do on this issue, and that it
continue to play a role in confronting and beating this
epidemic.
For example, there are several FDA-approved opioids with
so-called ``abuse deterrent formulations'' on the market. And
the User Fees that we are talking about today help pay for
review of these products.
The FDA acknowledges ``abuse deterrent'' does not mean
``abuse proof,'' and has acknowledged that these products can
still be easily abused by just swallowing a whole bunch of the
abuse deterrent drugs, for example.
Dr. Woodcock, is it appropriate to call these opioids abuse
deterrent if they can still be easily abused?
Dr. Woodcock. They cannot be abused as easily in certain
ways by snorting or by injecting, which are preferred by many
addicts because they give you an immediate high.
Senator Hassan. Right.
Dr. Woodcock. All right? What we are trying to do is move
up the scale and get more and more effective abuse-deterrent
technologies in place. These are Version 1.0. We acknowledge
that. They are still undergoing their evaluation to see, in
fact, how effective they are.
Senator Hassan. Just so I can understand. They are just as
addictive, though.
Dr. Woodcock. They are opioids, and so what we are trying
to do in addition to introducing more treatments for opioid
abuse is to introduce pain treatments that do not have these
liabilities. And we have approved a number of drugs for
specific conditions that now people are, like the neurologists,
are moving away from opioids for peripheral neuropathy, for
example.
Senator Hassan. Right. And I understand that, and that was
actually going to be--so thank you for anticipating one of my
questions. I am very glad you are doing that because I have
been talking with my constituents about this, both as Governor
and now as Senator for some time, and I think that is very
welcome news.
I do want to get back to one issue, though, which is the
use of the term ``abuse deterrent'' because experts have done
surveys now that show that 46 percent of primary care providers
think that abuse deterrent products are less addictive than
other opioids.
In light of this safeness conception, do you think calling
these products ``abuse deterrent'' is misleading or causing
providers to think that these products are less addictive?
Dr. Woodcock. It certainly seems as if more education is
needed, and that is something that we are working on very hard.
We are considering extending our educational program. Over
100,000 I think, practitioners of various kinds in healthcare
have been educated under our current program. But we would like
to extend that.
Much of the abuse, though, of opioids is not these high
potency extended release, but is actually the kind of drug you
get after you go for an in-and-out procedure, or you have your
tooth extracted. And the question is, do you really need 60
tablets with three refills?
Senator Hassan. Right.
Dr. Woodcock. The healthcare system is actually awash and
actually people's medicine cabinets are full of these products
that are not the high tech products. They are the simple
opioids. They are just as addictive.
Senator Hassan. Right. My time has passed, but I think to
that point, I would look forward to working with all of you on
the FDA taking a greater educational role.
Because one of the issues we have had with providers,
especially with licensing boards, is pushing them to change
their proscribing guidelines. So that somebody getting wisdom
teeth extracted are leaving with only 1 or 2 days' worth of
prescriptions rather than a month or two.
I would look forward to continuing to work with all of you
on that.
Thank you.
The Chairman. Thank you, Senator Hassan.
Senator Cassidy.
Statement of Senator Cassidy
Senator Cassidy. Thank you all for the good work that you
do. As a physician, I am very aware of the good work that you
do, so thank you.
Dr. Woodcock, you mentioned that the GDUFA II includes
preapproval meetings, but it seems, at least I am told, the
process still lacks clear guidance on what tests a complex
generic has to pass.
Also pre-NDA meetings are limited to applicants who have
already started investment and can meet the several
requirements. Rankly, this throttles out a small business, the
guy in his garage and the gal coming together seem a little bit
iced out by that, if you will. Only the bigger firm that
already has the pockets can address this.
I guess how does this make the process more transparent or
competitive? Thoughts?
Dr. Woodcock. Well, first of all, we are trying to commit
to having within several years of the brand product being
approved, having guidance out there that is basically a recipe
for how to develop the generic. For the vast number of
generics, that would be enough; that sort of cookbook.
For the complex ones, we do not know either, or completely,
how to make a copy. We do have small business assistance, which
is a separate program outside of what we are doing in the pre-
generic area. That might be an appropriate venue for somebody
who is just getting started and really does not know the ropes
at all. So that opportunity is also available.
Senator Cassidy. Because it does seem as if that is a
little bit of a hold up like Mylan and Advair, et cetera, in
terms of coming up with a generic. How would you pass FDA
muster?
Is there a way to actually give guidance without being
prescriptive because there is going to be somebody that may
have a better idea? Do you see what I am saying with that?
Dr. Woodcock. No guidance, actually, is prescriptive;
people are very confused about this.
Our draft guidance is not binding on us or on the
applicant, and neither is our final guidance. And so if
somebody comes up with a better way, we are happy to entertain
that.
The guidance is simply for those who are not clear what we
are thinking to make them clear about what we think would be an
acceptable way. But there are other ways that are certainly
acceptable. I agree with you. So they are not prescriptive.
Senator Cassidy. OK. Also, we have spoken in the past about
post-marketing surveillance. GAO just recently issued a report,
or I should say last year, that the FDA,
``Lacks reliable, readily accessible data on track
safety issues and post-market studies needed to meet
certain post-market safety reporting responsibilities,
and to conduct systemic oversight.''
Any response to that? Clearly and the reason I raise this,
of course, personalized medicine will increasingly--if we are
going to get it out the door, as we have spoken before--require
maybe we get it out the door, but there is a tension as to the
safety.
If the data systems are inadequate, how will we meet that
tension?
Dr. Woodcock. Well, they were talking about our tracking
system, so we can roll up all this and make reports. I think we
are pretty satisfied that our actual oversight of safety since
the Amendments Act has been really strengthened. It is very
robust.
In October 1, 2017, I hope we will enact a workflow
management system for new drugs. We still do not have that. We
do not have an I.T. system for the new drug review process.
We will be implementing that and over time, we will put
these track safety issues--tracking them, tracking other safety
issues and so forth. All will be put into this I.T. system that
we will be implementing, hopefully, in October 1 of this year.
That will then address the GAO concern.
It was really about our I.T. systems and the fact that--
which is true, I think, across much of Government--that they
are not up to what you would find in the private sector.
Senator Cassidy. Dr. Shuren, the FDA also has a similar
system, the NEST system, we have spoken of.
Will it be part of this October 1 rollout or do you feel
like you already can do adequate reporting?
Dr. Shuren. This is a differing system separate from what
came out on the drug report. But we do think that NEST is going
to provide complementary tools to what we have today.
Today most of our reporting is passive. It requires a
person that is going to have to identify if there is a problem
and then take the time to report it in.
NEST is going to allow us to move more toward an active
surveillance system where we can go through larger datasets
with analytical tools to try to find if there are associations
between the use of a device and particular safety problems.
Senator Cassidy. OK. Thank you. Yield back.
The Chairman. Thanks, Senator Cassidy.
Senator Whitehouse.
Statement of Senator Whitehouse
Senator Whitehouse. Thank you, Chairman.
I guess, Mr. Chairman, we are going to find out this week
whether the so-called Trump Care bill can get through the House
of Representatives and come over to the Senate.
If it does, I would like to recommend that we follow the
model that you led, that I thought was extremely successful on
the Elementary and Secondary Education bill where we had
hearings, and we worked together under your and Ranking Member
Murray's leadership. We put together a really significant piece
of legislation that has now passed into law.
Sometimes when we get together, the stuff we can agree on,
we can agree on because it is so much of a ``nothing burger''.
This, actually, was a very consequential piece of legislation
that we were able to agree on, and I can even remember your
reaction the day that we voted it out of committee unanimously.
I think we have a good model in this committee for treating
major legislation in a responsible way.
I would note that when we did the Affordable Care Act, this
committee was also very, very active. I was appointed to it on
a temporary basis at that point so that we could fill out a
seat where we had a vacancy. I participated in weeks of
hearings in this very committee on the Affordable Care Act. My
recollection is that we considered, and even adopted, more than
100 amendments, many of them bipartisan. In fact, I suspect
almost all of them were bipartisan in order to be adopted.
This committee was active, and had an active and vibrant
role in considering the Affordable Care Act.
This thing is coming out of the House at us. It looks like
it is a complete mess. It has never had a proper hearing other
than a kind of ``Midnight Spectacular'' that the House, I
guess, developed just for this particular bill to jam it
through.
At least speaking for Rhode Island, we are now calculating
if that mess were to pass into law, we would lose $30 million
in Medicaid. We would put people, 70,000 Rhode Islanders who
are on the Medicaid expansion, at risk. We have 30,000 Rhode
Islanders who are in the individual market as a result of the
Affordable Care Act. Ninety percent of them are enjoying tax
credits that come from it. It is supporting their ability to
afford healthcare.
One of our insurers, Neighborhood Health Plan, has dropped
its premiums. It is the low income serving insurer in Rhode
Island. In fact, they tried to drop their premiums even more
and our Insurance Regulator said, ``No, no, no. You can drop
them a little, but let us not go too far now.'' There may even
be more premium reductions coming.
Our exchange is working. The idea that this wreck of a
piece of legislation is going to be fired like a torpedo at my
State without my committee even having a chance to consider it
is pretty objectionable when you consider how well we did with
the SSA and how active this committee was with respect to the
Affordable Care Act.
I hope, frankly, I hope this thing dies over in the House
and gets the proper end that it deserves. But if it does come
over here, I would really encourage the Chairman and the
Ranking Member to find a way to have meaningful hearings on it.
To the witnesses, my recollection from our previous
conversations was that when I spoke to the Drug and the Device
sides individually, both of you said that we would be better
off with a third track. Neither side was willing to propose a
third track, but you did urge that we try to come up with a
third track. At least, that was my recollection of the State of
play.
We could not get that organized. In the 21st Century Cures
Act, instead, we asked for improved coordination between the
two tracks.
Can you tell me (A), how is improved coordination working?
And (B), if we could, would you still like us to develop a
third track? Is improved coordination Plan B, and should we
still be considering a proper, thought through, well-developed
third track for drug-
device combinations?
Dr. Woodcock. Go ahead.
Dr. Shuren. I do think coordination across the agency has
improved. The agency has created a Combination Product Policy
Council. It has now been changing processes, putting policies
in place to have much more coordinated activities.
For example, the agency has already modified how we consult
various centers, and we have timeframes that we have piloted,
and where we will have that fully stood up as a program fairly
soon. The early data on it is showing that it is helping.
In terms of your question about should we explore still
another pathway? Right now, our biggest focus is on
implementing 21st Century Cures and seeing what comes out of
that. We are always open to other ideas to make the programs
work better, and always happy to discuss other ideas.
The Chairman. Thank you, Senator. You took most of your
time on another subject, but that will be fine, if that is what
you want to do.
Dr. Woodcock. I agree with Dr. Shuren. Yes, I agree with
that.
The Chairman. Go ahead.
Senator Whitehouse. No, it will take too long. That is all
I needed to hear.
The Chairman. Give him an answer. He deserves it. Is that a
sufficient answer?
Senator Whitehouse. Sufficient to me, as long as there is
not pressure for us to develop a third way right now, that they
would rather work through this first. I think that is our
understanding.
The Chairman. Actually, if I might just add, that is of
interest to a great many of us on this committee. Being able to
let you work through the best ways to do it, before we jump to
a different pathway might be the more practical approach. I
appreciate the Senator's questions.
Senator Scott.
Statement of Senator Scott
Senator Scott. Thank you, Mr. Chairman.
Thank you all on the panel for your dedication and your
commitment to the welfare and the health of America and
American citizens. Appreciate that.
Dr. Woodcock, the PDUFA VI goals letter encourages the
adoption of a new drug discovery tools under the mid-provision.
This is important as I feel all too often the private sector
and researchers are innovating, but the Federal Government is
often behind on recognizing the value and impact of these
tools. In short, we are missing some opportunities.
A good example of an innovative tool in this space is
tissue bioprinting, which began at Clemson University in South
Carolina, of course, my home State. It is now being used by the
pharmaceutical industry, researchers, and the NIH.
The goals letter does not distinguish between ready to go
technologies, those that hold immediate promise and are already
being used, versus those technologies that are not yet quite
available.
How will the FDA differentiate and prioritize its selection
of technologies that help make drug development shorter and
less costly? And will you make efforts to understand tools that
are being used already when deciding which tools you should
consider?
Dr. Woodcock. Certainly. What we are contemplating is that
people will approach us with the tools that they would like to
get qualified for regulatory use.
Typically, though, academia has one sort of standard for
tools. We do not just publish papers on the tools. We have to
make decisions about human life. And that is a little bit
higher standard of rigor often.
If we are going to depend on a tool to make decisions about
what is going to happen, say, to somebody's kidney or maybe
their brain, its performance has to be pretty well-understood.
That is what our qualification process is about.
To answer your question, we expect people will approach us
with qualification proposals. That is happening now. We have a
program going on, and so we will give them advice. That is what
was contemplated in this program. We will give them advice
about what they need to do to get up to the standard that would
be needed to make decisions about human life based on that
tool.
Senator Scott. I think your answer, in many ways,
reinforces the necessity of using those tools that are already
in the market or ready to go to market as opposed to those that
are still in the development stage, actually.
These 3-D tissue models also promise to have a big impact
on drug safety and cost, which is what you were just
discussing.
Given that it often takes more than a decade and billions
to research and develop a new drug, we should make sure that we
are encouraging the use of any tools available that can help
sponsors identify potential toxicity issues early in the
clinical trials process. This not only improves drug safety,
but saves money as billions are lost every year in the last
stage clinical trial failures.
How do you plan to give product developers confidence that
you will accept the data being generated from these new tools?
Dr. Woodcock. That is what the qualification process is
about. In fact, right now, the C-Path Institute has a big
safety consortium, and they have tools before us just as you
said. Better safety tools to look at drugs earlier and
determine whether there is a safety signal. Some of those have
been qualified already for animal use and they are in the human
process right now.
Safety tools are about the most important, as you said. We
are also working with NIH and others to develop that evidence
standards to say, ``How much do you need to know to rely on
this, to keep somebody's kidneys safe or their heart safe, that
you make decisions on that?''
That along with the process that we have set in place will
enable people to have a clear path of how they develop these
tools into something that can be used for regulatory purposes.
Senator Scott. Thank you. Final question, Mr. Chairman.
The pioneering work of Clemson researchers in the field of
tissue bioprinting and the promise of that technology in the
drug development and review process is a great example of the
benefits of promoting a strong classroom to lab, STEM education
pipeline.
I am aware of the FDA's practice of collaborating with
academic institutions to create a CERSI in order to enhance the
regulatory workforce and promote innovation and regulatory
science.
Just this year, I believe, the FDA invested about $6.7
million in the creation of a CERSI with Yale and the Mayo
Clinic.
My question is, can you comment on the value of the CERSI
program in evaluating the safety and effectiveness of the
products the FDA regulates? And given the level of investment
in these Centers, how does the FDA plan to ensure
accountability from this program?
Dr. Marks. The CERSI programs have been a wonderful way for
our scientists to interact with other investigators. I think
they have helped to develop the evidence needed to look at
safety in various ways. I think they continue to blossom.
Just so you know, the CERSI's are not the only ways that
our investigators are involved with academic institutions. We
have many collaborations that are done as part of cooperative
research and development agreements across all of the Centers
that help us to have a critical interaction that keeps us at
the forefront of the science that we need to know in order to
speed the development of products.
Senator Scott. Thank you, Mr. Chairman.
The Chairman. Thank you, Senator Scott.
Senator Kaine.
Statement of Senator Kaine
Senator Kaine. Thank you, Mr. Chair and thanks to the
witnesses.
Mr. Chair, I echo the comments made by folks on our side
about the timeliness. This hearing is very important. This
topic is very important. But I would say there is kind of an
elephant in the committee room, which is, there is a matter of
both importance, but desperate urgency before Congress, which
is the House's consideration this week of the bill to repeal
Obamacare and propose a particular version of a replacement.
We are hearing that we may be asked to vote on that
promptly here without, possibly without committee consideration
on the floor.
When the Affordable Care Act was pending before this body,
I was not in the Senate, but I understand the HELP committee
held 13 hearings to really dig-in to the good, the bad, and the
ugly of what we should do.
Mr. Chair, you did a good job. I was really impressed with
the hearing that you called on the individual market, which is
a challenging area that we ought to be working together to
solve. That hearing was held before there was a plan on the
table, so we were not able to talk about whether this plan
addressed it.
There were four witnesses who were here that day at that
hearing and I asked them all the same question. They had all
had thoughts about how to fix the individual market. And I
said, ``Would it be a disaster for the individual market if we
repealed the Affordable Care Act?'' They all said, ``yes''. And
then I said, ``But we do need to fix it.'' They all said,
``yes''.
And I said, ``OK. If we are going to fix it, should we fix
it fast, careless, and secret? Or, should we fix it slowly,
deliberately, and transparently?'' They laughed at my question
because it was so obvious the answer was, of course, slow,
deliberate and transparent.
The notion of taking an action on a bill that might cause
24 million people to lose health insurance, and that is the
combined population, the combined population of about 16 States
does not do credit to a body that is often called the world's
greatest deliberative body.
I once heard Senator Franken say, though, sometimes the
world's greatest deliberative body spends more time
deliberating on whether it should be Senate bean soup or tomato
soup in the Senate dining room than on matters of great
importance.
Senator Franken. My version was much funnier.
[Laughter.]
Senator Kaine. Yes, well, as evidenced that I did not get a
laugh.
Anyway, this is something that if there is to be a world's
greatest deliberative body, could there be anything more
important to deliberate on than people's health?
On the issue before us, the President's budget submission
last week proposed a cut of the NIH budget to the tune of $6
billion. Often drugs that are developed through the FDA process
have been significantly assisted or sort of started with the
assistance of NIH funding.
Am I correct about that?
Dr. Woodcock. Generally what happens is NIH researchers who
get grants lay the foundation, the scientific foundation,
understanding the pathways, or the pathophysiology. And then
drugs are separately developed against that.
Senator Kaine. The title of this hearing deals with
innovation, improving medical product regulation and
innovation.
Would a budget cut of that size to the NIH hurt the
innovation that is one of the subjects of this hearing?
Dr. Marks. Unfortunately, we cannot speak to the budgetary
implications of that.
Senator Kaine. Well, boy, that is going to have me do a
followup question because you guys are here for expertise.
Do you have no opinion about whether there is a connection
between NIH funding and medical innovation?
Dr. Marks. I can say that clearly there is a connection
between NIH funding and medical innovation, and that
innovations from the NIH have supported the development of
important products that have benefited the lives of people in
the country.
Senator Kaine. So, as a general matter, reductions in NIH
funding would have the effect of reducing innovation as a
general matter?
Dr. Marks. I would have to leave you to surmise that.
Senator Kaine. Do you not have an opinion on that question?
Dr. Marks. I am sorry. I cannot speak to it.
Senator Kaine. Do you any of you have opinions on that
question, whether the reduction of funding to the NIH as a
general matter will reduce innovation?
[No response.]
Do I assume that none of you have opinions on that question
as professionals?
Dr. Woodcock. We are just not in a position to discuss it.
Senator Kaine. Let me ask a second question, a second
topic. Drug pricing is a serious concern for everybody here and
drug pricing of biologics is one of the matters that we are
very concerned about. They are innovative, but they can be
expensive too.
Of the 595 drugs paid for by Medicare Part B in 2015, only
eight biologics accounted for 40 percent of the total Part B
spending.
Talk to us about moving forward within the FDA on
biosimilars, regulatory guidance for biosimilars so that we can
potentially see, through the development of those products, a
reduction in drug pricing.
Dr. Woodcock. The Biosimilar User Fee program that is part
of the subject of today's discussion, of today's hearing,
supports our approval of new biosimilars in setting the
standards for those coming on the market.
They, of course, are more complex molecules than what is
approved under the generics program. And they have required an
entire set of scientific principles be developed, which we have
done. That has stimulated, really, a new industry to come forth
and develop products.
We have approved four biosimilars. We have about 13
applications before us, and there are 64 development programs
where people are working to show their biosimilar work to
various innovator drugs.
This is a rising industry. We recognize that it will take a
number of competitors to each brand product to substantially
bring the price down, if that is similar to the generic market.
Senator Kaine. Thank you. Mr. Chair, if I could just----
The Chairman. We have a vote at noon and we have one more
Senator who has to speak.
Senator Kaine. I am just troubled by the witnesses'
unwillingness to offer professional opinions. They are M.D.'s
and Ph.D.'s and I am new to the committee, but I am on the SASC
committee and our military witnesses all the time give us their
professional opinion, even when it differs from the
Administration. We never ask them about what they communicate
to the Administration. That would not be fair.
We do call professional witnesses before a committee with a
thought that they will give us their best expertise. I find it
impossible to believe that the individuals do not have an
opinion on the question of whether the funding of research has
a connection to medical innovation. And whether the cutting of
research funding would, as a general matter, reduce innovation.
The Chairman. Yes, in defense of the witnesses--both this
Administration and in the last one--the military officers have
a different role and give different answers.
The nonmilitary officers always are in a tough spot when
presented with questions like that because they have been
instructed by the Office of Management and Budget not to answer
the question. Maybe it should be different, but that has been
the tradition throughout both of the last, well, all the
administrations I know.
Senator Franken.
Statement of Senator Franken
Senator Franken. The answer is yes, reduction in NIH
funding would have a reduction in innovation. And I am an
expert. I am not.
By the way, the joke is that sometimes the Senate is not
even the most deliberative body in the Senate. Sometimes it is
the Senate dining room when it has to decide whether turnips
will be part of the winter vegetable medley. That was the
original joke, and it is not real funny, but I wanted to
deconstruct what a joke is, but we can do that at some other
time and this is why we need more research at the National
Institute of Comedy.
The hearing today is on the User Fee Agreements that
industry and the FDA forged to support the agency's operations
and approve performance accountability. This is really
important. That is very important and we should work on a
bipartisan basis, as this committee often does. I thank both
the Chair and the Ranking Member for that.
Frankly, I came in--I walked in. I had been at the Supreme
Court, the Gorsuch hearings. So I am sorry I got in here so
late.
I think what the Senator from Virginia was talking about
was that we really should be talking about ACA and about
healthcare reform. I am surprised that we are not doing that. I
thought that we had a very good hearing.
I agree with the Senator that we had a good hearing on that
and I thought the Chairman was absolutely right. That what we
should be looking at is the exchanges. I think that is what we
should be doing over here right now because we are in the
middle of this really seismic debate and battle. What I see in
the House that is being passed again, or being taken up in a
way that is not the way, I believe, the health bill should be
is what we should be talking about.
This past weekend, I was in Minnesota and I did roundtables
in Perham, MN at their hospital. Did a roundtable in Moorhead,
MN at the nursing home and my goodness, people are very scared
by what they are seeing and these are uniform. People were
crying at this. And so, so concerned and this is what we really
should be talking about, I think, right now, as important as
this issue is.
I want to thank Dr. Woodcock, who has testified for us and
Dr. Shuren especially. I want to tell you what a big difference
you have had in your role, in terms of the medical device
industry, they tell me uniformly that you have been a wonderful
partner.
Before, when I got here in 2009, the cultures were so
different and that you have worked so hard to help bridge that.
So thank you for that.
I really do, I just hope you are hearing me, Mr. Chairman,
that I think that we should be looking at those exchanges and
how to fix those. I think that is the first thing that we
really need to be doing. I am afraid that there is a bit of
trying to cause destruction by the way this is being taken up
now in the House and by the President.
I want to talk a little bit about, since we are here,
postmarket surveillance. I spent a minute on the theory of
humor, so I am sorry. I will try and make this quick.
One of the reasons the FDA launched NEST was to enhance
FDA's post-market surveillance activity. One early report
issued by the FDA explained that the purpose of NEST was to
enable,
``Active surveillance in near real-time using
routinely collected electronic health information,
quickly identify poorly performing devices, and
facilitate the development of new devices and new uses
of existing devices.''
While I am encouraged that the most recent MDUFA agreement
funds NEST, the funding is restricted to activities that just
promote premarket approval.
My understanding is that this User Fee funding would
complement work FDA has underway already to advance NEST's
post-market surveillance capabilities.
Is that true and can you provide me specific examples of
what you are doing currently to promote more active postmarket
surveillance through NEST?
Dr. Shuren. The answer is yes. And just to clarify, the
commitment letter for MDUFA talks about use of real-world
evidence in NEST. And because it is under MDUFA, the activities
that we would commit to, or the NEST coordinating center
commits to, has to be within the scope of MDUFA, which is
predominantly premarket review.
However, the NEST coordinating center beyond that is also
focused at activities that go more toward traditional
postmarket surveillance.
What we have been doing already is trying to leverage real
world data sources, for starters, for conducting some of our
required postmarket studies.
One of the challenges we face today is once we approve a
device, patients do not want to sign up in clinical trials. But
if we are already collecting that data as a part of routine
clinical care, and we can make good use of it to understand the
true benefit and risk profile of the device, that is a win for
everybody. We can do it at lower cost, and we can finally get
the answers we have been trying to get for years, and we are
starting to do that.
Senator Franken. Because I just cannot emphasize enough how
important, I think, postmarket surveillance is in terms of
people's safety and the efficacy of these devices.
Thank you, Mr. Chairman, for your indulgence.
The Chairman. Thank you, Senator Franken.
There are 10 minutes left before the close of the vote.
Senator Murray, do you have closing comments?
Senator Murray. I would just say this, and I will submit my
questions to the record.
Again, I just have to emphasize how concerned I am that a
major piece of legislation is being jammed through in the
House. It is going to come to the Senate, reportedly next week
with changes, again, before the Senate considers it or sees it,
rushed through in a few days and a few amendments. And we have
had no hearings in the Health Committee.
I, like all of my colleagues, am hearing from so many
people who are deeply concerned and frightened. This is a bill
that, I understand, impacts 20 percent of our economy,
healthcare. We should be having a hearing about the impacts of
that, whether it is Medicaid, taking away the Medicaid
expansion, or changes to that program. How is this going to
work?
I heard from Linda on Bainbridge Island. She spent 15 years
without direct healthcare coverage. Now has it. It is
affordable, and she has had cancer; so a preexisting condition,
critical to her.
Monica from Seattle, increased cancer risk, could not
afford preventive care. She needs that. Without coverage, she
said she would just not be here.
Kim from Tacoma, her daughter and husband both have
preexisting conditions, as do many Americans. They want to know
what this bill will do to them.
I am deeply concerned that this Health Committee has not
had a hearing and does not propose to have a hearing on
legislation that impacts virtually every American.
The Chairman. Thank you, Senator Murray.
Senator Warren. Mr. Chairman.
The Chairman. Senator.
Senator Warren. Mr. Chairman, I also have another, I just
have another question about a bipartisan bill that is being
introduced today while we have FDA witnesses in front of us.
The Chairman. Sure. Please, go ahead.
Senator Warren. Would you like me to do it now?
The Chairman. Why do you not do it now?
Senator Warren. I will try to do it, and I will try to do
it without being funny, so we do not have to laugh. OK. Thank
you.
Forty-eight million Americans, 48 million, have some level
of hearing loss and this includes half of all people in their
70s. If hearing loss seems like a boring problem, I want you to
think about what it means to be unable to participate in a
meaningful conversation with another person, unable to talk on
the telephone, or to hear a television or a radio.
People with hearing loss are more likely to experience
social isolation. They are more likely to experience
depression. They are more likely to experience dementia. They
are even more likely to fall, which is the leading cause of
death for people over the age of 65.
The good news is that many cases of hearing loss can be
corrected. Technology is advancing at an incredible speed.
Hearing aids are smaller. They are more effective than ever.
Dr. Shuren, do you know how many of those 48 million people
with hearing loss actually use hearing aids?
Dr. Shuren. It is about 20 percent.
Senator Warren. About 20 percent. Johns Hopkins researchers
think it is actually about 14 percent, even smaller, but
somewhere in that range.
The vast majority of people with hearing loss are literally
suffering in silence. And there are a lot of reasons for this.
Do you know, Dr. Shuren, what it costs to get a hearing
aid?
Dr. Shuren. About $2,000.
Senator Warren. For each aid, that is exactly right. Out-
of-pocket costs, it is not covered by Medicare, and most people
need two of those. So that is $4,000 to kind of get you in the
door on this.
Earlier this month, Senator Grassley and I wrote an op ed
in the ``Journal of the American Medical Association'' about
this problem. And this morning, Senator Grassley and I
introduced bipartisan legislation with Senators Hassan and
Isakson that would help reduce the cost by directing the FDA to
create a category of over the counter hearing aids.
Dr. Shuren, last December, the FDA announced, and I am
going to quote it,
``A commitment to consider creating a category of
over the counter hearing aids that could deliver new,
innovative, and lower cost products to millions of
customers.''
Can you walk us through quickly why over the counter
hearing aids could improve both access and affordability to
hearing technology for Americans with hearing loss?
Dr. Shuren. If we make it over the counter now, patients
would not have to go through a healthcare practitioner. They
could get it, let us say, from a pharmacy. Of course, as we
reduce the costs of technology to come to market, and we have
greater competition, we will see prices go down.
Senator Warren. That is good to hear. Better access, lower
prices.
It is good that the FDA is thinking about this. I am really
glad to hear this. The legislation that Senator Grassley,
Senator Isakson, Senator Hassan, and I have put together would
help make sure that it actually happens. That these devices,
when they are made available directly to consumers, that it is
done in a safe and effective manner.
This is my last question. Can you just say something about
the kinds of concerns you would want to be sure are addressed
in order to make sure that this is done in a safe manner for
people with hearing loss?
Dr. Shuren. Well, we would want to make sure that patients
understand how to use hearing aids, that we have good labeling
to explain the circumstances under which they should contact
their healthcare professional. We might also look at
performance characteristics; should there be any output limits?
Senator Warren. Right. I appreciate that.
We really do need to do this right. I know there are plenty
of cases where over the counter hearing aids will not be
appropriate. That is fine. But right now, there are millions of
Americans whose lives could be made so much better if they had
access to low-cost hearing aids.
This is a place where we could loosen up outdated
regulation and with a few consumer protections put in place, we
could actually let the market work to help bring better
products to people at lower costs.
Thank you very much.
The Chairman. Thank you, Senator Warren. Thank you for the
legislation.
I want to thank the witnesses for coming and thank you for
the work you do.
I think you can see from the attention on both sides of the
aisle, how much we appreciate your willingness to move ahead
with implementing the 21st Century Cures Act. Almost everybody
on this committee, really almost everybody in the Senate,
played some part in that because we saw the dramatic prospect
of what would happen with the artificial pancreas for persons
with diabetes, or a cure for HIV AIDS, or a way to identify
Alzheimer's before symptoms showed; all of these Dr. Collins
predicted before our committee, our Appropriations Committee,
would likely see in the next decade.
Our goal is to try to move those lifesaving cures and
devices more rapidly into patients' hands and into doctors'
offices. We want to do what we can to create an environment
where you are able to do that.
We mentioned the hiring freeze. I understand from staff
that the Administration is already working with FDA to try to
relieve the effect of that. I would encourage that and I will
continue to encourage the Administration to be selective about
a hiring freeze.
I understand about hiring freezes. When I was Governor, I
put one on when I first came in. But the FDA, Dr. Califf told
us that the single most important priority for him and the 21st
Century Cures bill was the ability to hire experts to do the
reviewing and to be able to pay them what it took to keep them
so they did not go work for the drug companies, or some
university, or somewhere else. So we want to make sure that we
do that.
I wanted to ask, quickly, Dr. Marks. You mentioned
regenerative medicine and I noticed how quickly you moved on
that.
Do you think that the fact that your accelerated pathway is
now available for regenerative medicine therapies or cures will
bring a number of these therapies and cures into the FDA for
more rapid approval and give people more confidence in the
safety of those therapies and cures?
Dr. Marks.
Dr. Marks. Thank you.
We are already receiving requests for the Regenerative
Medicine Advanced Therapy designation. And we very much look
forward to working with sponsors.
Normally, we cannot talk about unapproved applications. I
can tell you that there is a sponsor who issued a press release
yesterday that FDA had granted a Regenerative Medicine Advanced
Therapy designation.
I think we have tried to move quickly on this and we look
forward to continuing to move forward. We are thankful for the
legislation that was passed that has provided this pathway.
The Chairman. Dr. Shuren, Senator Whitehouse mentioned the
combination device-drug. I think we actually came to a pretty
good way to move forward with that, which is to give you the
opportunity to use your good judgment to talk across lines and
see what you can do within your existing authority. And then if
we need to do more, which we may very well need to do, you
could let us know that.
On guidance, Dr. Woodcock, I would make this observation. I
think you said correctly that guidance, not only does not bind
you, it does not bind anyone else. It is just guidance. But
different parts of the Government have not been as clear as you
have been.
I had a witness before me from the Department of Education
on title IX who said that she expected all of the universities
to follow her guidances as if it were the law. Well, of course,
that was not even the Obama administration's policy, and when I
talked to the Office of Management and Budget about that, they
said, ``We are doing our best to make it clear that guidance is
not a regulation, it is not a law.''
Maybe the FDA could explain that more clearly. That
guidances are to be helpful, to answer questions, and if you
have, the way you said it here, if you have a better idea, we
welcome the better idea. Because I think a great many people
are risk averse. They do not want to do anything that might
delay things a year or two.
Is there something else that you might be able to do to
make it clear what guidance is and what it is not?
Dr. Woodcock. Possibly. In the very front of every guidance
document, it has a disclaimer and it says it is binding on
neither party.
Maybe we could go further and really say in English,
because this was bureaucratese, ``If you have a better idea,
come talk to us.''
The Chairman. Yes, it might be that simple, just to put a
headline on it. Say, ``If you have a better idea, but in the
meantime, here are some suggestions.'' Because that is what
guidance really is supposed to be.
I appreciate my colleagues' concern about the Affordable
Care Act and the amendments that are going through it.
The decision to hold this hearing was a bipartisan
decision, and I am glad we held it. We are going to have
another one in early April despite the fact that we have to
confirm a Labor Secretary, and we have to consider the
Affordable Care Act, and have a lot of other things to do,
because it is hard to think of anything much more important
than moving lifesaving drugs through the FDA and into medicine
cabinets, and doctors' offices, and patients to save their
lives.
That was the decision of this Congress, and President
Obama, and Vice President Biden, and Speaker Ryan, and Senator
McConnell last year, and it is still our opinions today.
I would make only this observation about the process of
amending the Affordable Care Act, which I made earlier. There
are two tracks to that and there were in 2009 and 2010. I was
here.
The track that took 60 votes had lots of hearings, lots of
discussion, lots of amendments. And the track that takes 60
votes now will have hearings, amendments, and we will see what
comes out because only bipartisan solutions are durable.
The track in 2010 that went through the reconciliation
process went like a freight train through Congress. I have
never seen anything move more rapidly. It took 8 days, Budget
to House, Budget to Senate, back to the House, and onto the
President. And that includes the weekend.
It is a little bit of selective memory here in terms of
what is too fast when you are going through a reconciliation
process. Actually, I believe the House of Representatives has
done a very good job of discussing their legislation in public
and before the Energy and Commerce Committee, before the Ways
and Means Committee, before the Budget Committee, the Rules
Committee, and it will be on the House floor.
Then when it comes, if it is passed in the House, we will
see what happens in the Senate. If it goes to the floor, under
the reconciliation process, there will be ample opportunity for
amendment on the floor.
I thank the witnesses for coming.
The hearing record will remain open for 10 days. Members
may submit additional information for the record within that
time.
The HELP Committee will meet again tomorrow, March 22 at 9
a.m. to hear from Alex Acosta, nominee for Secretary of Labor.
Thank you for being here today.
The committee will stand adjourned.
[Whereupon, at 12:22 p.m., the hearing was adjourned.]
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