[House Hearing, 113 Congress]
[From the U.S. Government Publishing Office]
21ST CENTURY CURES: MODERNIZING CLINICAL TRIALS
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HEARING
BEFORE THE
SUBCOMMITTEE ON HEALTH
OF THE
COMMITTEE ON ENERGY AND COMMERCE
HOUSE OF REPRESENTATIVES
ONE HUNDRED THIRTEENTH CONGRESS
SECOND SESSION
__________
JULY 9, 2014
__________
Serial No. 113-157
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
Printed for the use of the Committee on Energy and Commerce
energycommerce.house.gov
______
U.S. GOVERNMENT PUBLISHING OFFICE
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COMMITTEE ON ENERGY AND COMMERCE
FRED UPTON, Michigan
Chairman
RALPH M. HALL, Texas HENRY A. WAXMAN, California
JOE BARTON, Texas Ranking Member
Chairman Emeritus JOHN D. DINGELL, Michigan
ED WHITFIELD, Kentucky FRANK PALLONE, Jr., New Jersey
JOHN SHIMKUS, Illinois BOBBY L. RUSH, Illinois
JOSEPH R. PITTS, Pennsylvania ANNA G. ESHOO, California
GREG WALDEN, Oregon ELIOT L. ENGEL, New York
LEE TERRY, Nebraska GENE GREEN, Texas
MIKE ROGERS, Michigan DIANA DeGETTE, Colorado
TIM MURPHY, Pennsylvania LOIS CAPPS, California
MICHAEL C. BURGESS, Texas MICHAEL F. DOYLE, Pennsylvania
MARSHA BLACKBURN, Tennessee JANICE D. SCHAKOWSKY, Illinois
Vice Chairman JIM MATHESON, Utah
PHIL GINGREY, Georgia G.K. BUTTERFIELD, North Carolina
STEVE SCALISE, Louisiana JOHN BARROW, Georgia
ROBERT E. LATTA, Ohio DORIS O. MATSUI, California
CATHY McMORRIS RODGERS, Washington DONNA M. CHRISTENSEN, Virgin
GREGG HARPER, Mississippi Islands
LEONARD LANCE, New Jersey KATHY CASTOR, Florida
BILL CASSIDY, Louisiana JOHN P. SARBANES, Maryland
BRETT GUTHRIE, Kentucky JERRY McNERNEY, California
PETE OLSON, Texas BRUCE L. BRALEY, Iowa
DAVID B. McKINLEY, West Virginia PETER WELCH, Vermont
CORY GARDNER, Colorado BEN RAY LUJAN, New Mexico
MIKE POMPEO, Kansas PAUL TONKO, New York
ADAM KINZINGER, Illinois JOHN A. YARMUTH, Kentucky
H. MORGAN GRIFFITH, Virginia
GUS M. BILIRAKIS, Florida
BILL JOHNSON, Ohio
BILLY LONG, Missouri
RENEE L. ELLMERS, North Carolina
_____
Subcommittee on Health
JOSEPH R. PITTS, Pennsylvania
Chairman
MICHAEL C. BURGESS, Texas FRANK PALLONE, Jr., New Jersey
Vice Chairman Ranking Member
ED WHITFIELD, Kentucky JOHN D. DINGELL, Michigan
JOHN SHIMKUS, Illinois ELIOT L. ENGEL, New York
MIKE ROGERS, Michigan LOIS CAPPS, California
TIM MURPHY, Pennsylvania JANICE D. SCHAKOWSKY, Illinois
MARSHA BLACKBURN, Tennessee JIM MATHESON, Utah
PHIL GINGREY, Georgia GENE GREEN, Texas
CATHY McMORRIS RODGERS, Washington G.K. BUTTERFIELD, North Carolina
LEONARD LANCE, New Jersey JOHN BARROW, Georgia
BILL CASSIDY, Louisiana DONNA M. CHRISTENSEN, Virgin
BRETT GUTHRIE, Kentucky Islands
H. MORGAN GRIFFITH, Virginia KATHY CASTOR, Florida
GUS M. BILIRAKIS, Florida JOHN P. SARBANES, Maryland
RENEE L. ELLMERS, North Carolina HENRY A. WAXMAN, California (ex
JOE BARTON, Texas officio)
FRED UPTON, Michigan (ex officio)
(ii)
C O N T E N T S
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Page
Hon. Joseph R. Pitts, a Representative in Congress from the
Commonwealth of Pennsylvania, opening statement................ 1
Prepared statement........................................... 2
Hon. Michael C. Burgess, a Representative in Congress from the
State of Texas, opening statement.............................. 2
Hon. Frank Pallone, Jr., a Representative in Congress from the
State of New Jersey, opening statement......................... 3
Hon. Lois Capps, a Representative in Congress from the State of
California, opening statement.................................. 4
Hon. Fred Upton, a Representative in Congress from the State of
Michigan, opening statement.................................... 5
Prepared statement........................................... 5
Hon. Marsha Blackburn, a Representative in Congress from the
State of Tennessee, opening statement.......................... 6
Hon. Henry A. Waxman, a Representative in Congress from the State
of California, opening statement............................... 7
Hon. Diana DeGette, a Representative in Congress from the State
of Colorado, prepared statement................................ 125
Hon. Cathy McMorris Rodgers, a Representative in Congress from
the State of Washington, prepared statement.................... 151
Witnesses
Robert J. Meyer, Director, Virginia Center for Translational and
Regulatory Sciences, University of Virginia School of Medicine. 8
Prepared statement........................................... 11
Answers to submitted questions............................... 153
Aaron S. Kesselheim, Assistant Professor of Medicine, Harvard
Medical School, and Director, Program on Regulation,
Therapeutics, and Law (PORTAL), Division of
Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's
Hospital....................................................... 20
Prepared statement........................................... 23
Bill Murray, President and CEO, Medical Device Innovation
Consortium..................................................... 32
Prepared statement........................................... 34
Jay P. Siegel, Chief Biotechnology Officer and Head of Scientific
Strategy and Policy, Johnson & Johnson......................... 45
Prepared statement........................................... 47
Answers to submitted questions............................... 159
Roy S. Herbst, Ensign Professor of Medicine and Chief of Medical
Oncology and Associate Director for Translational Research,
Yale Cancer Center............................................. 60
Prepared statement........................................... 63
Sundeep Khosla, Dean for Clinical and Translational Science, Mayo
Clinic......................................................... 79
Prepared statement........................................... 81
Answers to submitted questions............................... 163
Paula Brown Stafford, President, Clinical Development, Quintiles. 90
Prepared statement........................................... 92
Submitted Material
Letters to the Editor of July 3, 2014, responses to ``New FDA
Breakthrough-Drug Category--Implications for Patients,'' New
England Journal of Medicine, submitted by Mr. Pitts............ 112
Article of July 3, 2014, ``New FDA Breakthrough-Drug Category--
Implications for Patients,'' Jonathan J. Darrow, et al., New
England Journal of Medicine, submitted by Mr.Pallone........... 118
Article of July 7, 2014, ``Ideas for Renewing America's
Prosperity,'' by Peter W. Huber, The Wall Street Journal,
submitted by Mr. Burgess....................................... 129
21ST CENTURY CURES: MODERNIZING CLINICAL TRIALS
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WEDNESDAY, JULY 9, 2014
House of Representatives,
Subcommittee on Health,
Committee on Energy and Commerce,
Washington, DC.
The subcommittee met, pursuant to call, at 10:01 a.m., in
room 2123, Rayburn House Office Building, Hon. Joseph R. Pitts
(chairman of the subcommittee) presiding.
Members present: Representatives Pitts, Burgess, Whitfield,
Shimkus, Murphy, Blackburn, Gingrey, McMorris Rodgers, Lance,
Cassidy, Guthrie, Griffith, Bilirakis, Ellmers, Barton, Upton
(ex officio), Pallone, Capps, Green, Barrow, Castor, and Waxman
(ex officio).
Staff present: Clay Alspach, Chief Counsel, Health; Gary
Andres, Staff Director; Matt Bravo, Professional Staff Member;
Leighton Brown, Press Assistant; Noelle Clemente, Press
Secretary; Paul Edattel, Professional Staff Member, Health;
Sydne Harwick, Legislative Clerk; Robert Horne, Professional
Staff Member, Health; Carly McWilliams, Professional Staff
Member, Health; Chris Sarley, Policy Coordinator, Environment
and the Economy; Heidi Stirrup, Policy Coordinator, Health;
John Stone, Counsel, Health; Ziky Ababiya, Democratic Staff
Assistant; Eric Flamm, Democratic FDA Detailee; Debbie Letter,
Democratic Staff Assistant; Karen Lightfoot, Democratic
Communications Director and Senior Policy Advisor; Rachel Sher,
Democratic Senior Counsel; and Matt Siegler, Democratic
Counsel.
Mr. Pitts. Subcommittee will come to order.
Chair will recognize himself for an opening statement.
OPENING STATEMENT OF HON. JOSEPH R. PITTS, A REPRESENTATIVE IN
CONGRESS FROM THE COMMONWEALTH OF PENNSYLVANIA
Part of the work of our 21st Century Cures Initiative is to
identify existing roadblocks to speeding treatments and cures
to patients. One of these barriers is the current clinical
trial process. Among the regulatory and administrative burdens
associated with clinical trials are the expanding cost and
size. While it takes on average approximately 14 years and $2
billion to bring a new drug to the market, a large portion of
that cost is spent in recruiting and retaining subjects for
clinical trials. It is often difficult to identify potential
participants due to a shortage of centralized registries, low
awareness of the opportunity to participate in clinical trials,
low patient retention, and lack of engagement among community
doctors and volunteers.
Widespread duplication of effort and cost also occurs
because research is fragmented across hundreds of clinical
research organizations, sites, and trials, and information
regarding both the successes and failures of clinical trials is
rarely shared among researchers.
Finally, in many cases, researchers have been slow to
utilize technology such as electronic health records and Web-
based platforms in their trials, which is also a barrier to
greater collaboration and information sharing. This expensive
and antiquated clinical trials model is simply not acceptable
in the 21st century. We can and must do better because patients
deserve better.
Researchers and physicians are going to have to strengthen
the recruitment and retention of volunteers for their trials,
adopt new technologies, and above all, collaborate to build
efficient and effective clinical trials.
I would like to thank all of our witnesses for being here
today. I look forward to hearing of their ideas.
Prepared statement of Hon. Joseph R. Pitts
Part of the work of our 21st Century Cures initiative is to
identify existing roadblocks to speeding treatments and cures
to patients. One of these barriers is the current clinical
trial process.
Among the regulatory and administrative burdens associated
with clinical trials are their expanding cost and size.
While it takes, on average, approximately 14 years and $2
billion to bring a new drug to the market, a large portion of
that cost is spent in recruiting and retaining subjects for
clinical trials.
It is often difficult to identify potential participants,
due to a shortage of centralized registries, low awareness of
the opportunity to participate in clinical trials, low patient
retention and lack of engagement among community doctors and
volunteers.
Widespread duplication of effort and cost also occurs
because research is fragmented across hundreds of clinical
research organizations, sites, and trials, and information
regarding both the successes and failures of clinical trials is
rarely shared among researchers.
Finally, in many cases, researchers have been slow to
utilize technology, such as electronic health records and web-
based platforms in their trials, which is also a barrier to
greater collaboration and information sharing.
This expensive and antiquated clinical trials model is
simply not acceptable in the 21st century. We can and must do
better because patients deserve better.
Researchers and physicians are going to have to strengthen
the recruitment and retention of volunteers for their trials,
adopt new technologies, and, above all, collaborate to build
efficient and effective clinical trials.
I would like to thank all of our witnesses for being here
today, and I look forward to hearing their ideas.
Mr. Pitts. I yield the remainder of my time to Dr. Burgess,
vice chairman of the subcommittee.
OPENING STATEMENT OF HON. MICHAEL C. BURGESS, A REPRESENTATIVE
IN CONGRESS FROM THE STATE OF TEXAS
Mr. Burgess. Thank you, Mr. Chairman, for the time. And
thanks to our panelists for being here this morning. Certainly
look forward to a good and lively discussion.
In many ways, randomized clinical trial, this country has
set the gold standard for clinical trials, the rigorous
investigative approach that we require. It does not mean that
you can't make changes nor that you should not make changes to
keep up with emerging science and new techniques in
investigational review all the while keeping a close and
careful eye on patient safety. Failure to adapt could see what
was once considered to be the standard of excellence in
regulation quickly look out of place and out of touch with the
field to which it applies.
Evidence A, Exhibit A is personalized medicine and the
ability of the human genome to play a role in that. We are
approaching a time when treatments could be tailored for a
person's specific genetic code. There is no way such a
revolutionary approach to treatment could be evaluated in the
same way as a single-molecule drug meant for large populations.
Mr. Chairman, I certainly appreciate the subcommittee
asking the question, how can we build in more flexibility? How
can we stimulate innovation into the trial process so that
these cures, which are just over the horizon, can become the
reality of therapies for our patients?
These changes must ultimately retain the integrity needed
to ensure that the end product is safe and effective. We cannot
be caught off guard and risk watching innovative therapies
suffocate at the hands of a regulatory system that has not kept
up or further cripple the regulatory system by the approval of
products that inherently are unsafe.
I welcome the testimony of our witnesses today. I will
yield back to the chairman.
Mr. Pitts. Chair thanks the gentleman.
Now recognize the ranking member of the subcommittee, Mr.
Pallone, 5 minutes for an opening statement.
OPENING STATEMENT OF HON. FRANK PALLONE, JR., A REPRESENTATIVE
IN CONGRESS FROM THE STATE OF NEW JERSEY
Mr. Pallone. Thank you, Chairman Pitts. Today we continue
our work on the 21st Century Cures Initiative, and the input
from these hearings is valuable to our discussion. One of the
primary lessons we have learned thus far, and I expect we will
continue to hear today, is that discovering cures and effective
treatments is complicated and difficult. But in the end when
medical advances reach patients, we must ensure that they are
safe and effective. And so I welcome today's discussion on
clinical trials, which is a foundation of our drug and device
regulatory system as well as the challenges and opportunities
there are for modernization of the system.
Clinical trials give researchers, drug, and device
developers and doctors a way to translate scientific advances
into treatments for patients. While not every trial is a
success, with every trial more knowledge is gained about drugs
and devices that can be used to aid in the development of a
future drug.
I think we would all agree that NIH and FDA are world
leaders. They have proven that they have the ability and
authority to integrate the newest science into their policies
and approaches. The NIH-supported Human Genome Project has
opened up a world of potential new drug treatment. The ground-
breaking public-private collaboration of the Lung Cancer Master
Protocol, or Lung-MAP, which we will hear about from our
witnesses today, represents an innovative approach to clinical
testing.
Meanwhile, just last year, three-quarters of the new drugs
approved by FDA were approved in the U.S. before any other
country.
But there is nothing wrong with always striving to be
better. The clinical development phase is the longest and most
expensive period of product development, so it is important
that we explore new tools, standards, and approaches that can
be taken to assess the performance of medical advances.
Throughout this initiative, the question remains how
Congress can advance these goals. The effort is a worthy one.
It has been a great way for members and the public to explore
and understand the complexity of issues that goes into
discovery, development, and delivery of medicine.
But I have to caution my colleagues that when it comes to
science, too much or too little is a hard balancing act
especially to dictate in statute. We can't be the science
experts. The greatest role Congress can play is ensuring that
our Federal agencies have the flexibility and resources to
apply the best regulatory science available.
On Friday, the subcommittee will hold another and related
hearing on the engagement of the patient perspective during the
development process. And I am glad that FDA will appear before
this subcommittee then to talk about a number of innovative
approaches they are taking in their recent regulation of drugs
and devices.
I think that, Mr. Chairman, I think it is an exciting time
in science and there are some amazing stories to be told. But
despite this progress, there is more that can be done. But
again, these are complicated issues that I hope we will
continue to examine very carefully.
I would like to yield my last 2 minutes to Congresswoman
Capps.
OPENING STATEMENT OF HON. LOIS CAPPS, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF CALIFORNIA
Mrs. Capps. Thank you to my colleague for yielding me time,
and I thank you, Chairman Pitts and Ranking Member Pallone, for
holding this important hearing.
I appreciate that this subcommittee wants to take action on
this issue. It is a large one. Questions: How do we design a
more modern clinical trial? How do we include the right mix of
participants so the data are meaningful? How do we ensure that
the data analyses performed actually look at differences on
gender and ethnicity? How could postmarket surveillance and
future passive data monitoring help inform our current system?
These are just a few of the many critical questions, and I
encourage the subcommittee to have additional hearings so that
we can truly focus on the many issues under the umbrella of
modernizing clinical trials.
This is an issue very near and dear to me. For almost 10
years, I have worked to improve clinical trials and especially
those involving women and children. And we have made some
progress in recent years, and this has been with the passage of
FDASIA and my own National Pediatric Research Network Act.
But, as you all know, there is much more work to do. And so
I thank you all for being here. And I look forward to your
testimony. And that is all I have to say on--I could yield back
to the ranking member or just yield to any of my colleagues. I
will yield back.
Mr. Pitts. Chair thanks the gentlelady. Now recognize the
chairman of full committee, Mr. Upton, 5 minutes for an opening
statement.
OPENING STATEMENT OF HON. FRED UPTON, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF MICHIGAN
Mr. Upton. Thank you, Mr. Chairman. You know, at our first
21st Century Cures roundtable we learned that there are
treatments for only about 500 of the more than 7,000 known
diseases that affect our Nation's patients. We have also heard
about the increasing time and expenses involved in bringing new
drugs and devices to market, and we learned that the costs and
regs surrounding clinical trials are a primary contributor to
this delay. This means that new treatments and cures cost more
and they are getting to patients more slowly. That system is
simply unsustainable.
So here in the U.S., it is incredibly complicated to
navigate the processes involved in simply getting a trial up
and running. Particularly for small companies. Overall, the
size, duration, costs, failure rates are higher than ever. In
some cases, trials are being moved overseas as a direct result
of those challenges. This leaves patients in the U.S. waiting
longer for cures and treatments, and it also takes those jobs
away from folks here at home. Safety is always the top
priority. And I know, I know that we can do better. We must
work together to remove any needless administrative or
operational burdens that do not benefit patients.
In addition, we would like to learn more about recent
advances in technology and data collection that can help
modernize our system, encourage better participation, and
certainly allow for continued learning about the risks and
benefits of new drugs and devices in the real world.
How can we take what we learn in the development and
delivery phases and translate that back to new, innovative
discovery in this cycle of cures? How can we leverage patient
registries in innovative new protocols, like the Lung-MAP
trial, as well as other collaborative efforts into more
advances into molecular medicine? Electronic health records,
increased data sharing, and patient-reported outcomes will
undoubtedly play a critical role in this regard. Ultimately, it
is going to accelerate and modernize the discovery,
development, and delivery cycle.
So today's hearing is yet another opportunity to discuss
what can we do to further our journey on the path to cures.
Prepared statement of Hon. Fred Upton
At our first 21st Century Cures roundtable, we learned that
there are treatments for only 500 of the more than 7,000 known
diseases affecting our Nation's patients. We have also heard
about the increasing time and expense involved in bringing new
drugs and devices to market. We've learned that the costs and
regulations surrounding clinical trials are a primary
contributor to this delay. This means new treatments and cures
cost more and are getting to patients more slowly. This system
is simply unsustainable.
Here in the U.S., it is incredibly complicated to navigate
the processes involved in simply getting a trial up and
running, particularly for small companies. Overall, the size,
duration, costs, and failure rates are higher than ever. In
some instances, trials are being moved overseas as a direct
result of these challenges. This leaves patients in the United
States waiting longer for cures and treatments and also takes
good jobs away from folks here at home. Safety is always the
top priority, and I believe we can safely do better; we must
work together to remove any needless administrative or
operational burdens that do not benefit patients.
In addition, we would like to learn more about recent
advances in technology and data collection that can help
modernize our system, encourage better participation, and allow
for continued learning about the risks and benefits of new
drugs and devices in the real world. How can we take what we
learn in the development and delivery phases and translate that
back to new, more innovative discovery in the cycle of cures?
How can we leverage patient registries and innovative new
protocols like the Lung-MAP Trial, as well as other
collaborative efforts, into more advances in molecular
medicine?
Electronic health records, increased data sharing, and
patient-reported outcomes will undoubtedly play a critical role
in this regard. Ultimately, this will accelerate and modernize
the discovery, development, and delivery cycle.
Today's hearing is another important opportunity to discuss
what can be done to further our journey on the path to cures.
Mr. Upton. And I would yield to Marsha Blackburn.
OPENING STATEMENT OF HON. MARSHA BLACKBURN, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF TENNESSEE
Mrs. Blackburn. Thank you, Mr. Chairman. And I want to
welcome all of you. We appreciate that you are here as we look
at modernizing clinical trials.
Federal law requires that medications proposed for human
use be safe and efficacious. That means that our constituents
can expect medicines to do exactly what they are advertised to
do and that any side effects are going to be clear and apparent
to these patients. And the major mechanism by which medicines
are found to be safe and efficacious are the phase III clinical
trials, which test the drugs against placebos and the other
known treatments. We all appreciate that process. And what we
want to do is look at how we are going to be able to modernize
this process as we go through the trials with large groups of
people, sometimes thousands, with the intent of finding the
side effects that could harm even a small percentage of
individuals.
The large groups also make the statistics work, giving
greater assurance that the drug does do what it is purported to
do. The importance of the phase III trials is reflected in the
statutory language in the FD&C Act. The FDA generally requires
drug companies to sponsor at least two such clinical trials for
a new drug. I would be interested to hear from you: Do you
think that is enough? Too much? How should that be changed?
Also, the phase III trials are the gold standard for drug
approval. They have their limitations. How would you address
those limitations? Today we are going to look at that gold
standard and the limitations of the phase III trials. And hear
of your base to build upon what we have learned in order to
speed safe and efficacious treatments to patients.
I thank you for your time, and I yield back to the
chairman.
Mr. Upton. Yield back.
Mr. Pitts. Chair thanks the gentlelady.
Now recognize the ranking member of the full committee, Mr.
Waxman, 5 minutes for an opening statement.
OPENING STATEMENT OF HON. HENRY A. WAXMAN, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF CALIFORNIA
Mr. Waxman. Thank you, Mr. Chairman.
The topic of this hearing is an important one. Clinical
trials are the bedrock of modern medical product development.
We rely on clinical trials to demonstrate that our drugs and
devices are safe and effective, and we rely on the willingness
of people to volunteer to participate in these trials. So of
course, we want to ensure that clinical trials are conducted
using the most modern tools and technology that science has to
offer.
We also need to ensure that clinical trials are conducted
in the most efficient manner possible. That is why NIH and FDA
have been leaders in working with academia and industry to
identify areas in which the clinical trial process can be
improved. These improvements could include encouraging the use
of centralized institutional review boards, developing
standards for harmonizing the collection and exchange of data,
and maintenance of patient registries to facilitate the
recruitment of patients for clinical trials. And I look forward
to hearing more today about such efforts.
How Congress can help advance these goals is a complicated
question. The 21st Century Cures Initiative is useful because
it is shining a light on some important issues surrounding how
drugs and devices are developed and ultimately delivered to
patients.
There are some clear areas where Congress could legislate.
We should ensure that both FDA and NIH have the resources they
need to remain the gold standard in observing clinical trials.
But when it comes to legislating how clinical trials are
conducted, we need to proceed with great caution. Congress
should not be in the business of dictating the kind or level of
evidence needed to permit drugs and devices to go on to the
market. That decision is solely the task of the scientific
experts at the Food and Drug Administration. We should not
force FDA to prematurely accept novel technologies. Our job
should be to ensure that FDA has the regulatory authority
needed to make use of the latest scientific advances.
When FDA testifies on Friday, the agency can tell us about
how it is applying novel approaches to clinical trials in their
regulation of drugs and devices. I would also like to know
whether the agency believes it has the authority necessary to
adopt new approaches and whether other new statutory powers are
necessary. In this area, we need to be careful not to try to
fix things that are not broken. That could harm a system that
is already working. We should create policies that foster
scientific advances. But we should not enact regulatory
policies based on how far we wish scientific development has
progressed.
I thank you, Mr. Chairman. And I am willing to yield my
time to anyone who might want it. Otherwise, I yield it back.
Mr. Pitts. Chair thanks the gentleman. That concludes the
opening oral statements of the members. All members' written
opening statements will be made a part of the record.
We have one panel today with seven witnesses. And I will
introduce them in the order that they present their testimony.
First, Dr. Robert Meyer, Director, Virginia Center for
Translational and Regulatory Sciences, University of Virginia
School of Medicine; Dr. Aaron Kesselheim, Assistant Professor
of Medicine, Harvard Medical School, Director, Program on
Regulation, Therapeutics, and Law Division of
Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's
Hospital; Mr. Bill Murray, President and CEO, Medical Device
Innovation Consortium; Dr. Jay Siegel, Chief Biotechnology
Officer and Head Scientific Strategy and Policy, Johnson &
Johnson; Dr. Roy Herbst, Chief of Medical Oncology, Yale Cancer
Center; Dr. Sundeep Khosla, Director, Center for Clinical and
Translational Science, Mayo Clinic; and Ms. Paula Brown
Stafford, President, Clinical Development, Quintiles.
Thank you for coming. You will each have 5 minutes to
summarize your testimony. And your written testimony will be
placed in the record.
Dr. Meyer, we will start with you. You are recognized for 5
minutes for an opening statement.
STATEMENTS OF ROBERT J. MEYER, DIRECTOR, VIRGINIA CENTER FOR
TRANSLATIONAL AND REGULATORY SCIENCES, UNIVERSITY OF VIRGINIA
SCHOOL OF MEDICINE; AARON S. KESSELHEIM, ASSISTANT PROFESSOR OF
MEDICINE, HARVARD MEDICAL SCHOOL, AND DIRECTOR, PROGRAM ON
REGULATION, THERAPEUTICS, AND LAW (PORTAL), DIVISION OF
PHARMACOEPIDEMIOLOGY AND PHARMACOECONOMICS, BRIGHAM AND WOMEN'S
HOSPITAL; BILL MURRAY, PRESIDENT AND CEO, MEDICAL DEVICE
INNOVATION CONSORTIUM; JAY P. SIEGEL, CHIEF BIOTECHNOLOGY
OFFICER AND HEAD OF SCIENTIFIC STRATEGY AND POLICY, JOHNSON &
JOHNSON; ROY S. HERBST, ENSIGN PROFESSOR OF MEDICINE AND CHIEF
OF MEDICAL ONCOLOGY AND ASSOCIATE DIRECTOR FOR TRANSLATIONAL
RESEARCH, YALE CANCER CENTER; SUNDEEP KHOSLA, DEAN FOR CLINICAL
AND TRANSLATIONAL SCIENCE, MAYO CLINIC; AND PAULA BROWN
STAFFORD, PRESIDENT, CLINICAL DEVELOPMENT, QUINTILES
STATEMENT OF ROBERT J. MEYER
Mr. Meyer. Thank you, Chairman Pitts, Ranking Member
Pallone, and members of the committee.
As stated, I am Dr. Bob Meyer, and I direct the Center for
Translational and Regulatory Sciences at the University of
Virginia. I am, by background, a pulmonary physician, and
previously held senior leadership roles within the Center For
Drug Evaluation and Research at FDA as well as in Merck
Research Labs, where I headed global regulatory strategy,
policy, and drug safety, and was a key participant in their
late-staged development committee, which the committee that was
responsible for the oversight of late-stage development trials
within Merck's portfolio.
While I am now academics, I think I have a very real and
tangible experience with regard to clinical trials challenges
from both a regulatory and industry perspective, and,
therefore, I am pleased to be here today.
Modern clinical development programs are large, complex,
and usually global in scope and in conduct. And are
increasingly expensive to conduct.
Compounding this rising cost is the fact that the success
rate for drugs entering into phase III to achieve final
regulatory approval is falling, and the rate is now
approximating only 50 percent.
There are myriad of drivers that have contributed to the
growth and larger, longer, and more complex phase III trials,
including regulatory demands. However, I think it is important
to focus beyond FDA in the considerations on how to address
some of these issues. And let me speak to a few of these. I
would say that I am going to keep this statement short because
I believe many of these points will be more eloquently made by
others on the panel.
The first consideration that I would raise is better trial
standardization. In phase III programs, there is a large amount
of time expended getting from study concept to the first
patient enrolled. And the sponsors usually recapitulate these
efforts for each program as if each one is a wholly new effort.
This then raises two important points for consideration.
First is the enhanced development of effective, lasting,
durable clinical trial networks. Networks can bring
efficiencies such as having identified patient populations and
qualified and ready clinical sites that can reduce some of the
time and effort spent in study startups. There are efforts
towards clinical trial network development in certain disease
areas, such as the National Cancer Trials Network. However,
this model is not as widespread as it should be or could be,
particularly taking into account the varied areas of unmet
medical needs.
Second concept is the development of master protocols. Such
master protocols could serve as the basis for use by different
investigators or sponsors with minimal modification, save for
the details of the particular test product.
An added benefit of wider use of shared standardized
protocols is this would also enhance the ability to interpret
these trials in cross-study comparisons to assess relative
efficacy, safety, or other attributes considered important to
physicians, patients, and payers, since the patient populations
and end points would be highly similar.
Another consideration is the increasing complexity and
design of modern clinical trials. This trend to increasing
complexity is reflective of the fact that modern trials are
designed to address an increasing number of demands from
differing regulatory demands across the globe, differing payer
expectations, differing market claims sought, the use of new
exploratory science or end points within the trials, and
interest and input of key opinion leaders who participate in
the design of the trials.
I believe sponsors could benefit from further concerted
efforts to simplify trials by using multidisciplinary groups
within the company and outside the companies tasked to maximize
the value of the trial while minimizing the complexity and
cost.
I also believe FDA could aid in this effort in the end of
phase II advice. But to do so they would need to recruit more
experienced industry personnel with practical clinical trial
design in the operations experience because this kind of
expertise is rare within the agency.
An additional consideration in reducing clinical trial
expenditures is moving further away from the paradigm of face-
to-face clinical evaluations as the gold standard for patient
evaluation. There is an increasingly sophisticated ability to
assess patient status and accrue sophisticated clinical data
via new technologies.
So in light of the other expertise on the panel, let me
close by saying these efforts to think about how we can
modernize clinical trials are critically important. However, I
think that the evaluation of safety and efficacy is a critical
safeguard to patients within the U.S. And I think the way that
this currently is done within the U.S. is, in fact, the gold
standard not only within the U.S. but across the globe. And I
would urge that the increasing daunting costs and the
challenges of medical clinical trials are addressed in a way
that preserves the assurance that drugs on the market are safe
and effective.
We must seek a way to deploy practice, into practice the
efficient modern clinical trials, incorporate new technologies
and science where appropriate and validated while maintaining
the integrity of the regulatory progress.
Thank you for this opportunity to participate in the
hearing.
[The prepared statement of Mr. Meyer follows:]
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Mr. Pitts. Chair thanks the gentleman.
Now recognizes Dr. Kesselheim for 5 minutes for an opening
statement.
STATEMENT OF AARON S. KESSELHEIM
Mr. Kesselheim. Thanks very much, Subcommittee Chairman
Pitts, Ranking Member Pallone, and members. I am Aaron
Kesselheim. I am a physician, lawyer, and health policy
researcher at Harvard Medical School. And it is an honor to
have the opportunity to share my thoughts with you about
modernizing clinical trials and helping expedite access to new
prescription drugs and medical devices.
About 50 years ago, Congress decided that new therapeutics
should have their efficacy and safety demonstrated before they
could be widely used by patients. This wasn't a capricious
attempt by legislators to prevent patients from getting the
treatments they need, but a rational response by public
servants to major public health tragedies caused by the lack of
such proof.
When Congress originally gave FDA this power, it did not
require any particular kind of test. All that is statutorily
required is that manufacturers provide substantial evidence
that the drug will have the effect it purports to have, with
``substantial evidence'' being defined as adequate and well
controlled investigation.
Unfortunately, some manufacturers will not subject their
healthcare products to studies meeting even these minimal
criteria without the FDA standard-setting authority. Take a
look at the dietary supplement market if you don't believe me.
Indeed, in the decade after these regulations were put in
place, FDA regulators removed hundreds of drugs that failed to
show sufficient evidence of effectiveness upon clinical study.
To meet these criteria, the FDA prefers randomized trials
with blinded assignment and placebo or active comparator
controls. And so does the world scientific community. It's
worth recalling that a randomized control trial was once an
innovation. The basic requirements for conducting these trials
became recognized and codified slowly over the course of the
20th century after decades of debate and consideration, leading
to consensus about their most important characteristics.
At the same time, subjecting a new product to a formal,
randomized control trial or testing a hard clinical end point
could delay availability of promising products to some patients
in life-threatening circumstances. Fortunately, as currently
written, the law gives the FDA flexibility to accept data short
of traditional randomized trials to approve therapeutics for
important unmet needs or where randomization may be ethically
or practically impossible.
These products may get assigned by the FDA to special fast
track, or accelerated approval pathways, or receive
congressionally authorized designations that signal their
special status, like ``orphan drug'' or ``breakthrough drug''
or ``humanitarian device.''
Studies conducted by myself and others show that products
with these designations are often provided with expedited
review by the FDA, many receiving approval based on
uncontrolled studies and small populations.
Expedited approval pathways and special designations are
common at the FDA. In 2012, 26 of the 39 new drugs approved
qualified for at least one such program. And the FDA now
approves about two-thirds of new drugs earlier than its
counterparts in Europe.
When medical products are approved without being subject to
randomized trials testing real clinical endpoints, it puts
patients at increased risk. Medical history is littered with
drugs and devices approved on the basis of unvalidated
biomarkers that have their indications later withdrawn or
altered, or cancer drugs, originally approved on uncontrolled
trial later demonstrated in better controlled trials finally
conducted a decade later to actually increase the risk of
death.
In 2012, the multi-drug resistant tuberculosis drug,
bedaquiline, was approved on the basis of two short-term trials
testing about 200 patients after being granted accelerated
approval status, fast track, orphan drug status, and priority
review. In these studies, the drug was only shown to improve
the questionable surrogate endpoint of converting sputum from
tuberculosis positive to negative. But two-and-a-half times as
many patients died from tuberculosis in the bedaquiline group
than the control group. Patients with tuberculosis want to be
cured, they don't want to die with cleaner sputum.
How do patients and individual physicians now make sound
benefit/risk determinations about this drug or others like it
in the absence of more conclusive scientific data?
The prospect of approving more drugs on the basis of trial
designs that diverge from traditional randomized trials also
puts pressure on the timely conduct of confirmatory clinical
trials and postapproval surveillance systems. But studies show
that manufacturers' commitments to continue studying their
products after approval may be delayed or incomplete.
Once a drug is FDA approved for a certain indication,
convincing patients to subject themselves to further randomized
trials of the drug for that indication can be challenging
because patients can receive the drug outside the trial. It is
no wonder that the FDA gave the makers of bedaquiline until
2022 to complete confirmatory trials of that drug's
effectiveness in tuberculosis.
In summary, the prospect that researchers can design new
ways of conducting clinical trials of investigational drugs is
exciting. And I hope that the best of these truncated designs
are proven to provide the same level of confidence as standard
randomized controlled trials.
But the FDA already has the flexibility in its laws and
regulations to accept innovative study designs short of
randomized trials and validated biomarkers that can accelerate
the testing of truly important new drugs and medical devices.
The fast track process reduced clinical development time of
a new drug from 8.9 to 6.2 years; accelerated approval drugs
have an average of just 4.2 years of development.
And the FDA already exercises its flexibility to a
remarkable extent. If regulators and others in the medical
community are still skeptical about certain biomarkers and
clinical trial designs, it is probably because the science
supporting them is still in its infancy; in which case, forcing
approval of the drugs or devices to which they are applied
would be dangerous and counterproductive for the very patients
we are all trying to help. Thank you.
[The prepared statement of Mr. Kesselheim follows:]
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Mr. Pitts. Chair thanks the gentleman.
Chair now recognizes Mr. Murray, 5 minutes for an opening
statement.
STATEMENT OF BILL MURRAY
Mr. Murray. Chairman Pitts, Ranking Member Pallone, and
subcommittee members, thank you for the opportunity to testify.
My name is Bill Murray, and I am president and CEO of the
Medical Device Innovation Consortium. During my 25 years in
this industry, I have had the opportunity to lead multibillion-
dollar global businesses as well as two early stage companies.
These innovative businesses were founded on technology
developed in the United States. In recent years, however, these
businesses have faced a more difficult regulatory and
reimbursement environment in the United States which is
challenging our country's position as a global leader in
medical device innovation.
I applaud the committee's bipartisan leadership in
initiating the 21st Century Cures Call to Action and its
commitment for finding solutions to help the U.S. healthcare
industry maintain global leadership.
MDIC is a public-private partnership between Government
agencies including FDA, CMS, and NIH, non-profits, and
industry. MDIC is focused on the medical device ecosystem. We
collaborate on advancing regulatory science, by which I mean
the tools, standards, and approaches that regulators and
innovators use in the development and review of medical
devices. We believe that improving regulatory science will
offer concrete ways to make patient access to new medical
technologies faster, safer, and more cost effective.
Clinical trials are amongst the biggest challenges. The
time, complexity, and cost of conducting clinical trials, along
with the uncertainty of outcomes, makes them a challenge for
both regulators and innovators. And based on a survey of over
200 medical device technology companies, it takes an average of
6 \1/2\ years and $36 million before a new class 3 device even
reaches the pivotal study.
We need new approaches if we are to continue fostering
innovation. MDIC's goal is to improve the safety and
effectiveness of products being introduced to the market,
reduce clinical trial timelines and costs, and give U.S.
patients earlier access to beneficial technologies.
MDIC's work includes several high priority initiatives.
First, MDIC is working to improve the design of clinical
trials. Medical device clinical trials are increasingly
complicated. MDIC is examining current trial designs to better
understand how much of the collected data are used and the ways
in which clinical trials may be unnecessarily complex. We are
exploring possible alternative trial designs that still supply
high quality data on the safety and effectiveness of medical
devices.
MDIC is also supportive of FDA Center for Devices and
Radiological Health, efforts to balance pre- and postmarket
data requirements. Providing the reasonable threshold for
clinical data during the pre-market process while continuing to
collect data in the postmarket setting is a win for patients
and innovators.
Second, MDIC is investigating ways to reduce the barriers
to conducting early feasibility studies in the United States.
These first in human studies are a critical step in the
approval process of many new medical devices. But increasingly,
they are performed outside the United States. The reasons for
this include economic incentives offered by other countries for
companies to invest abroad, but they also include concerns the
regulatory approval process is slower, less predictable, and
less flexible than the United States. As a result, U.S.
patients often have to wait longer for access to new medical
devices.
CDRH recognizes this issue and has taken initial steps to
address it through a new policy in 2012. MDIC is building on
that work by exploring new methods and tools that support early
feasibility studies, such as incorporating validated
computational modeling and simulation data into the assessment
process. We feel strongly that American patients should be the
first to benefit from cutting-edge American technologies.
Third, MDIC is conducting research to better understand the
data on patient preferences about the benefits and risks of
medical devices. Supported by funding from FDA, MDIC is
developing a catalog of scientifically valid ways to measure
patient perspectives, and we are developing a framework that
can support the use of the data in the regulatory process.
Fourth, MDIC is convening experts to help the medical
device industry harness the power of computational modeling and
simulation. Currently, medical devices lag behind such fields
as aerospace and automotive in the use of modeling and
simulation tools. The development and use of regulatory-grade
tools has the potential to revolutionize the field, enabling
developers to generate more ground-breaking ideas, test them
with greater confidence, and bring them to patients more safely
and quickly, while reducing the costs of clinical trials.
Moreover, modeling and simulation may soon play a larger role
in the treatment planning and the realization of personalized
medicine in the clinic.
MDIC is making progress on these important initiatives, but
more needs to be done. We encourage Congress to support efforts
to strengthen regulatory science and facilitate public-private
partnership collaborations to improve the innovation
environment in the United States.
Thank you again for the opportunity to testify about MDIC's
collaborative efforts to support medical device innovation that
will benefit patients. I will be happy to answer any questions.
[The prepared statement of Mr. Murray follows:]
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Mr. Pitts. Chair thanks the gentleman.
And now recognize Dr. Siegel, 5 minutes for an opening
statement.
STATEMENT OF JAY P. SIEGEL
Mr. Siegel. Thank you, Chairman Pitts and Ranking Member
Pallone and members of the committee.
I have been working on clinic trial improvements for over
30 years from the diverse perspective of a senior U.S.----
Mr. Pitts. Is your mic on? Thank you.
Mr. Siegel. I have been working on clinical trial
improvements for over 30 years, from the diverse perspectives
of a senior USFDA official, an industry R&D leader at Johnson &
Johnson, and a participant in many broad collaborations,
including the International Collaboration for Harmonization,
the Society for Clinical Trials, and the Clinical Trials
Transformation Initiative.
I applaud and thank the committee for the 21st Century
Cures Initiative and today's focus on clinical trials
modernization.
Our clinical research enterprise is critically important
for medical progress, but was largely designed for conditions
that prevailed years or decades ago. We have before us new
tools and opportunities to modernize it and thereby to usher in
a new era of efficient translation of scientific advances and
to medical advances in 21st century cures.
I will briefly discuss four of these opportunities: Use of
electronic health records, use of biomarkers, creation and use
of clinical trial networks and consortia, and engaging patients
as collaborators in the research process.
The adoption of electronic health records provides the
potential to collect data efficiently in the settings in which
health care is being delivered, creating a learning healthcare
system. Large scale registries of patients with a shared
condition can be constructed, allowing studies of disease
course, risk factors, biomarkers, and treatment effects. The
powerful tool of randomization could be applied to such
cohorts, creating large simple clinical trials in the care
setting. The resultant enhancement of the ability to learn
about the effects of medicinal products while in clinical use
could allow earlier availability of important new therapies
with assurance that additional information would be collected
reliably and efficiently after approval.
Full realization of the promise that electronic health
record enhanced research holds will require addressing several
needs, including standardization, interoperability, and data
quality of the systems; research into how best to compile and
use the data; and reassessment of the regulatory frameworks
that protect patients.
The rapidly increasing ability to collect and analyze
genomic, proteomic imaging and other information allow
incorporating that information into clinical trials as
biomarkers. One valuable use of biomarkers in clinical trials
is as surrogate end points, which, if reasonably likely to
predict clinical benefit, can support the accelerated approval
of new therapies. The success of accelerated approvals in
bringing important new drugs to patients in need sooner,
together with the ability to measure many new biomarkers,
suggests that wider usage of biomarkers for accelerated
approval would be beneficial. In the FDA Safety and Innovation
Act of 2012, Congress encouraged such wider usage.
Use of biomarkers for patient subgrouping and response
monitoring can crucially enhance several other aspects of
clinical research, including personalized medicine research,
disease prevention research, and adaptive clinical trials.
Government, in partnership with academia, patient groups, and
industry, can create and operate clinical trial networks that
provide a rapid and efficient means for assessing promising new
therapies.
Networks have already led to substantial advances in
clinical research, and there is potential to address more
disease, to create broad consortia, and to utilize powerful new
tools, such as electronic health record-based trials and
ongoing biomarker-driven adaptive design trials, such as Lung-
MAP.
Patients bring to clinical research valuable perspectives
and insights and often strong motivation to contribute.
Enhanced participation of patients in the design and conduct of
clinical trials can be expected to improve many aspects of
trials. Patient-reported outcomes together with patient-
informed risk/benefit assessments should play a larger role in
clinical trials and product development.
Additionally, efforts to involve more patients in clinical
research will help unleash the power of a learning healthcare
system while helping ensure that our medical knowledge is
derived from the experience of a more diverse and
representative population.
Mr. Chairman, I thank you and the committee for your
invitation and your attention.
[The prepared statement of Mr. Siegel follows:]
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Mr. Pitts. Chair thanks the gentleman.
Now recognize Dr. Herbst, 5 minutes for an opening
statement.
STATEMENT OF ROY HERBST
Mr. Herbst. Good morning, Chairman Upton, Ranking Member
Waxman, Subcommittee Chairman Pitts, Ranking Member Pallone,
and members of the subcommittee. Thank you for inviting me
today to share my experience regarding innovative clinical
trials for cancer patients. I am Dr. Roy Herbst, and in my role
as chief of oncology at Yale, I care for patients with lung
cancer, conduct and collaborate on basic research, and work on
clinical trials from phase I, first in human, to phase III.
Over the last 2 years, I have been working with the Friends of
Cancer Research, which was founded and is led by Ellen Siegel,
the National Cancer Institute, SWOG, a cancer cooperative
group, and the FDA on an innovative public-private partnership
approach to clinical trials. And I am honored to be invited to
participate in this important hearing today.
Cancer is the second most common cause of death in the
United States, with over half a million Americans expected to
die of this disease in 2014. Cancer is a disease that is
accompanied by much pain and suffering, loss of life and
productivity. Despite advancements in surgery and drug therapy,
many cancers remain incurable. Lung cancer, the number one
cause of cancer death, is one such disease. And, as a
specialist in this area, I often see patients with advanced
disease who have very limited treatment options. For this
reason, together with my colleagues in the field, we strive to
develop new therapies for these patients so that we may provide
them with a cure or at least with more quality of life and time
with their families. I am working hard to personalize care; I
want to match a patient's tumor profile with a best treatment,
with the overarching goal to find ways to provide more active,
less toxic, and more cost-effective therapies.
I am happy to say we are making progress. Due to the
country's investment in research, in 2014, we can now sequence
every gene in a tumor, including the 25,000 protein-coating
genes. This is amazing technology and science. However, it
remains limited. Why? Because, one, it is still only available
to a minority of patients; two, it is expensive and often not
covered by insurance; three, the informatics and data-
interpretation challenges are overwhelming; and, most
importantly, we still do not know how to translate this
information into therapeutic benefit.
Hence, clinical trials are essential for this process and
the need to modernize for the molecular age is very important.
Often clinical trials are limited by numerous challenges,
including the startup time, accrual expense, and the need to
identify and define subpopulations of patients that makes trial
enrollment difficult.
Developing a potential therapy from the initial discovery
stage through clinical testing and regulatory approval is a
complicated, expensive, and often inefficient process that can
take up to 15 years.
Let me give you an example. In recent years, we tried to
study a drug that affects 10 percent of patients with lung
cancer. That meant we had to screen 100 patients at Yale to
find 10; only six of those patients were then eligible with
good enough status to go on the trial; we treated two. That is
totally unacceptable, it is not good for the patients, it is
not good for the clinical trial, it is not going to advance our
cause.
With this in mind, the Lung Cancer Master Protocol, known
as Lung-MAP, is an innovative, groundbreaking clinical trial
designed to facilitate efficiencies and advance the development
of targeted therapies for squamous cell lung cancer of the
lung, one of the worst types of this cancer. The concept of a
lung map was developed at the 2012 Friends of Cancer Research
Brookings conference on clinical cancer research, and at the
same time, by the National Cancer Institute Lung Cancer
Steering Committee.
Since the release of that initial concept paper through the
intense collaboration of many, Lung-MAP was initiated and
opened in a very rapid year and a half. The goal is to develop
a biologically driven approach, building on the NCI-funded
Cancer Genome Atlas, TCGA, to identify targets.
In Lung-MAP, a master protocol will govern how multiple
drugs, each targeting a different biomarker, will be tested as
potential treatments for lung cancer. Each arm of the study
will test a different drug that has been determined to target a
unique genetic alteration. The use of cutting-edge screening
technology will help identify which patient is a molecular
match to each arm. This will create a rapidly evolving
infrastructure that can simultaneously examine the safety and
efficacy of multiple new drugs. We want to get the right drug
to the right patient at the right time. This is good for
patients because it allows them, with as many as 500 sites to
be opened around the U.S., to have access to the drugs and
allows us to study effects so eventually they can become
approved and be available to even more people around the world.
One of the benefits of the Lung-MAP, enrollment efficiency.
Grouping these studies under a single trial reduces the overall
screen failure that is great for patients. Operational
efficiency, a single master protocol can be amended as needed
as drugs enter and exit the study without having to stop and
restart; cost efficiency, as a result of shared services,
utilization of existing infrastructure and avoiding redundancy,
this public-private partnership will operate at cost
substantially less than individual trials.
This consistency among trials, predictability on the
outcome, full transparency with an oversight committee and a
drug selection committee benefit to patients, and seamless
movement from phase I to II trial design. In fact, the FDA was
very closely involved with the idea for this whole concept.
My time is running short. But I will tell you that I hope
this committee can help us and with the issue of biomarkers,
how to develop better biomarkers for these trials, how to
regulate the diagnostics for these trials. Certainly the
public-private partnership that we have developed is one that
needs to be enhanced and helped and incentivized.
And, of course, finally resources. We have been working
with the NCI. And the budget is flat at best. And certainly we
want to bring more of those drugs to patients.
So as I conclude, Lung-MAP is a public-private partnership
where each sector has committed to do business differently.
Together we believe that Lung-MAP can demonstrate a new model
for high quality drug development in less time at less cost for
more people, and most importantly, improve the lives of
patients with lung cancer. I am happy to report the first
patient on the study enrolled at Yale yesterday. The shared
goal of accelerating the pace in which new drugs are developing
is a driving force behind this partnership. We know that this
committee shares that goal, and so we thank you for taking on
this important 21st Century Cures Initiative. Thank you.
[The prepared statement of Mr. Herbst follows:]
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Mr. Pitts. Chair thanks the gentleman.
And now recognize Dr. Khosla, 5 minutes for an opening
statement.
STATEMENT OF SUNDEEP KHOSLA
Mr. Khosla. Good morning. My name is Sundeep Khosla. I am a
practicing endocrinologist and Dean for Clinical and
Translational Science at Mayo Clinic in Rochester, Minnesota. I
am also the principal investigator at the Mayo Clinic Clinical
and Translational Science Award, or CTSA, from the National
Center For Advancing Translational Sciences, NCATS, at NIH. I
salute the 21st Century Cures Initiative, and am please to
share some thoughts on the opportunities and challenges we face
in bringing new treatments to patients.
Mayo Clinic has facilities in six States and provides care
for more than 1 million people annually from all 50 States and
135 countries around the globe. In addition to clinical care,
Mayo has a robust research program, including clinical trials.
Over the years, Mayo has conducted pivotal clinical trials in
many areas, including diabetes, osteoporosis, heart disease,
and cancer. Mayo Clinic won a Nobel Prize in Physiology and
Medicine in 1950 for the discovery of cortisone and its
clinical applications. Conducting clinical trials is an
extremely high priority for Mayo.
With the Congressional investment in NIH over the past
several decades and the NIH-supported human genome project, we
are now in a truly exciting era where there are more
possibilities for understanding diseases and developing new
drugs and new treatments than ever before.
With these opportunities, however, have come significant
challenges. To address these challenges, NIH Director Collins
created NCATS in December 2011 to catalyze the generation of
innovative methods and technologies that will enhance the
development, testing, and implementations of interventions that
tangibly improve human health across a wide range of human
diseases and conditions.
As astutely recognized by this committee, the clinical
trials process needs modernization. NCATS is seeking to do just
that by funding CTSAs at 62 sites around the country, thus
essentially creating a network of potential clinical trial
sites. The vision is that high priority clinical trials funded
either by NIH or by industry could be run very efficiently
through all or part of the 62-site network.
While implementation is not easy, there are three changes
that would facilitate the work of the NCATS clinical trials
network. One is institutional review board, or IRB reciprocity,
between as many of the sites as possible. Because each
institution has its own IRB, there are frequent and often
lengthy delays in multi-center clinical trials as each IRB
reviews and eventually approves a clinical trial protocol.
Reciprocity between as many sites as possible would mean
that once the IRB at the primary site approved the protocol,
that approval would be accepted by the remaining sites.
Second, there needs to be much greater interoperability of
electronic health records. This could allow, for example, study
investigators to rapidly search for study participants across
all 62 CTSA sites.
Third, for a national network of clinical trial sites to
truly function efficiently, there needs to be greater
harmonization of regulations. For example, an investigator
today must contend with different regulatory requirements from
the Office for Human Research Protections, the FDA, and the
Office for Civil Rights, all within HHS. Further complexity is
added by State laws that may go beyond the Federal
requirements.
What can Congress do to help facilitate clinical trials at
the national level? I have four suggestions:
First, continue to support the efforts of NCATS and the
CTSAs through ongoing and, if possible, enhanced funding.
Second, help develop policies that encourage IRBs to have
greater reciprocity with other institutions.
Third, urge HHS to accelerate progress towards
interoperability of electronic health records.
Finally, develop policies for greater harmonization of
regulations across Federal agencies and across States.
Responsibility for modernizing clinical trials falls also
on the shoulders of individual academic medical centers. Here
are three ideas academic medical centers could consider to
modernize clinical trials:
One, work to shorten the time required for study initiation
through more streamlined contract negotiation with industry and
for IRB approval.
Two, because disagreements over the use of biospecimens
often cause considerable clinical trial delay, work to develop
a simplified biospecimens policy that is broadly accepted
across sites and companies.
Third, develop better electronic capabilities to enhance
recruitment, screening, enrollment, and tracking of study
participants.
In summary, the opportunities for bringing new treatments
to patients have never been greater, yet significant challenges
remain. Congress can help this effort by supporting discovery
science, NCATS, and the CTSA system, and by removing roadblocks
in the clinical trials process. Together Government, the
private sector, and academic medical centers must all step up
and do all we can to rapidly deliver discoveries to the people
who need them.
Thank you for your opportunity to testify today.
[The prepared statement of Mr. Khosla follows:]
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Mr. Pitts. Chair thanks the gentleman.
And now recognize Ms. Stafford, 5 minutes for an opening
statement.
STATEMENT OF PAULA BROWN STAFFORD
Ms. Stafford. Good morning, Chairman Pitts, Ranking Member
Pallone.
Mr. Pitts. Make sure your button is pressed. Thank you.
Ms. Stafford. Good morning, Chairman Pitts, Ranking Member
Pallone, and members of the Health Subcommittee. Thank you for
the opportunity to appear before you today. My name is Paula
Brown Stafford. I am president of Clinical Development at
Quintiles, the world's largest provider of biopharmaceutical
development and commercialization services. We have more than
29,000 employees globally, including nearly 10,000 here in the
U.S. We are engaged every day in helping bring better medicines
to patients faster.
To give you a sense of our scope, over the past 10 years,
we have enrolled nearly 1 million patients in clinical trials
at over 100,000 investigative sites like Yale, Mayo Clinic.
Our experience and our role as a facilitator of the process
gives us a unique vantage point on where the challenges and
opportunities are in the drug development process.
We all agree the development process is too expensive, in
excess of a billion per NME, and takes too long. Generally,
that is 7 to 10 years. And, yes, patients are waiting.
Modernizing clinical trials is critical if we are to meet
the goals we share of delivering medicines faster at less cost
to patients who need them.
Quintiles works closely with our biopharma customers and
the FDA to find better ways to design and execute studies to
meet this goal, and we have had many collaborative successes to
date, yet there is more to be done.
My remarks will focus on three areas for further innovation
and a number of recommendations where Congress can help
accelerate meaningful improvements.
First, with nearly 80 percent of total drug development
time and cost spent on clinical trials, we must focus on
patients, creating better ways to find the right patients for
the right clinical trials. The bulk of time to conduct a
clinical trial is spent in finding patients that meet the
increasingly complex inclusion/exclusion criteria of trials
today. Improving data collection and accessibility would
facilitate more rapid identification of patients suitable for
clinical trials. Without new approaches and better access to
data, patient recruitment will become increasingly difficult,
especially as we work to develop cures that are more targeted
or personalized based on genomics.
Second, there is much more room for improving the process
of conducting clinical trials, reducing the timeline for each
trial by eliminating redundancies and inefficiencies,
particularly in what is known as the startup phase, where it
can take up to 18 months just to get to a point where a study
is open for patient enrollment.
Also standardization of clinical trials. The protocols, the
data collection requirements would help to reduce repetitive
activities that happen across trials.
Among private sectors, the Clinical Data Interchange
Standards Consortium, CDISC group I chaired from 2012 to 2011,
has recently even created data standards for a number of
therapeutic areas, including multiple sclerosis, Alzheimer's,
and asthma.
The third area is pathways. Alternative development
pathways could speed the introduction of new therapies to
address serious unmet medical needs as an alternative to the
traditional three-phase clinical trial paradigm. Great strides
have been made by the passage of FDASIA--the anniversary is
today, 2 years ago today. Also the creation of the breakthrough
therapy designation and other expedited drug approval pathways.
However, these have largely addressed FDA review time, which
was 10 months, but not the much longer development time, which
is 10 years.
So how can Congress help? A number of recommendations.
One, Congress could encourage the FDA to set goals for more
frequent use of master protocols and adaptive designs. Both of
these approaches allow multiple drugs to be evaluated in the
same trial, identify affected and non-affected populations
faster. And Quintiles has recently submitted a proposed master
protocol for diabetes, CVOT, to the FDA, and are expecting
comments later this month.
Congress could take steps to improve the quality and
accessibility of the data to researchers and thereby improve
the speed and accuracy of identifying the right patients for
the right trial. Among these steps are incremental improvements
to linkages between EHR and clinical research databases, better
interoperability among EHRs, and examining where there are
misinterpretations of HIPAA and other data privacy regulations
that may be inadvertently hampering the use of de-identified
data to improve research.
Congress should explore ways that the FDA and the NIH could
encourage the use of central IRBs, which, in our experience,
can cut the time to even start an individual investigative site
for more than 100 to 45 days.
And Congress could encourage FDA to pilot alternative
development pathways, similar to the adaptive licensing
approach that the EMA is now piloting. The tools and science
are in place to support alternatives whereby treatments could
be tested and approved for limited use while ongoing studies
would still be required.
Chairman Pitts, members of the subcommittee, I ask you and
your colleagues to support these recommendations because at the
end of the day a spouse, family member, a friend, or even you
may benefit from the next drug discovery that a modernized
clinical trial system brings forth.
Thank you.
[The prepared statement of Ms. Stafford follows:]
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
Mr. Pitts. Chair thanks the gentlelady.
And thanks all the witnesses for very thoughtful testimony.
And we will begin questions and answers.
At this point, let me ask you for a unanimous consent
request to submit for today's hearing record four items:
Letters to the editor of the New England Journal of Medicine
questioning a number of assertions made in an article Dr.
Kesselheim and others had published in the same publication on
March 27. And these letters include a letter from Mark
McClellan of the Brookings Institution and Ellen Sigal of the
Friends of Cancer Research, a letter from the Infectious
Diseases Society of America, and a letter from the Leukemia and
Lymphoma Society.
Without objection, so ordered.
[The information follows:]
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
Mr. Pitts. I will now begin the questioning and recognize
myself, 5 minutes for that purpose. And I will start with you,
Dr. Siegel.
Despite advances in science and technology, the duration,
cost, and failure rates of clinical trial costs have grown
exponentially, leading to delayed access and higher costs for
patients. How can we reverse these trends?
Mr. Siegel. Well, I think there is a number of topics that
have been touched on today that could help address the issues
around duration and cost and failure of clinical trials. Those
would include the establishment of networks that can allow one
to plug in, either through trials such as Lung-MAP or through a
series of trials, new therapies, and to relatively standardized
approaches, with standardized startups and experienced
investigators and standardized protocols. The better use of
biomarkers and integrating them into trials, genomic and
proteomic information to identify patient groups at risk, to
identify early responders and the use of those sorts of data to
adapt trials while in conduct also offer the opportunity to
reach either success or failure faster with a product, and
thereby to reduce the cost of product development.
Mr. Pitts. How can we improve the process by which FDA
qualifies novel drug development and review tools such as
biomarkers and patient-reported outcome measures, and what
would this mean for modernizing clinical trial designs?
Mr. Siegel. Is that directed to me?
Mr. Pitts. Yes, Dr. Siegel.
Mr. Siegel. It should be clear, first of all, that any
sponsor or company or investigator can propose for any trial
the use of a patient-reported outcome or a biomarker regardless
of whether or not a patient, the FDA has qualified it. The
qualification process allows a broader use and acceptability
and is intended for use when many groups want to come together
and bring together the data that demonstrate the utility of a
biomarker or a tool for a particular purpose. It does appear
that that process has been relatively scantily used. I think
with the creation of more consortia and networks focused on
diseases, there is an opportunity to use it more. I do not have
expertise in how the process might be improved.
Mr. Pitts. OK. Mr. Murray. What part of the clinical
research process consumes the most time for medical devices,
and what are the major reasons device trials are moving
overseas?
Mr. Murray. There are a couple reasons. As I mentioned
during my testimony, early feasibility studies in getting to
the point of actually having the device ready to start a
pivotal study takes on average 6 \1/2\ years and $36 million.
That is because there needs to be assessments done during the
early phase. Medical devices are physical constructs and
oftentimes can only be evaluated effectively in humans. So
those early feasibility studies are extremely important. So
streamlining that early feasibility process, IRB reviews, legal
reviews for innovative new technologies can take very long, and
having a process that is more consistent and more predictable
in an environment where each site has unique and different
requirements will help reduce the delays.
Additionally in today's environment we have the situation
where a lot of scientifically valid data is already available
outside the U.S., and the opportunity to incorporate that data
and use it for informed decisions in the U.S. could radically
reduce the cost.
Mr. Pitts. To pursue that a little bit, given the current
reality, what can Congress do to help FDA accept the data
collected outside the U.S. to ensure American patients are
getting access to the American innovations sooner?
Mr. Murray. One of the opportunities is to look at
rebalancing the pre- and postmarket requirements. If you look
at reducing slightly the confidence interval in the premarket
perspective, for example, if the confidence interval in a trial
were modestly reduced from 95 percent, say, to 90 percent in
the premarket phase, that could radically reduce by as much as
half the size of the clinical trials required; and as long as
there is appropriate controls and mechanisms in place to
continue to monitor those patients post market, that would
encourage more products to be approved and could reduce the
time to market.
Mr. Pitts. Ms. Stafford, how can real world data enable us
to learn more about the benefits and risks of a product, both
in the clinical trial setting and once a product goes to
market, and how can electronic health records and increased
data sharing play a role in this regard?
Ms. Stafford. One way that it can help in terms of using
the EHR is actually in the feasibility of a trial and using the
data that we have in the real world to help us design the best
trial possible and using that data up front to even help us
identify and find the right patients for the trials based on
prior experience with similar drugs or like therapeutic areas.
And real world is our ability to, it really goes into the
master protocol or the adapted design and really bringing in
data sooner and helping to make these decisions sooner based on
the real-world information that we have.
Mr. Pitts. My time is expired. The Chair recognizes the
ranking member, Mr. Pallone, for 5 minutes of questions.
Mr. Pallone. Thank you, Mr. Chairman. I would ask unanimous
consent to enter into the record an article from the New
England Journal of Medicine by Drs. Darrow, Avorn, and
Kesselheim, and also a statement by Ms. DeGette.
Mr. Pitts. Without objection, so ordered.
[The article and the prepared statement of Ms. DeGette
follow:]
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
Mr. Pallone. Thank you. I wanted to start with Dr.
Kesselheim. Some of you have cited the need to use novel or
alternative trial designs as a way to modernize the way
clinical trials are conducted, and I want to learn more about
one of these in particular, the use of surrogate end points. We
have heard a lot about this recently, most notably with the
situation surrounding two drugs, Avandia and Avastin, and these
drugs were allowed on the market based on a surrogate end point
through FDA's accelerated approval pathway.
So I would like to ask you, Dr. Kesselheim, to explain to
us a bit more about what surrogate end points are because I am
not sure I totally understand what they are and how they are
used in accelerated approvals. Specifically, what are the
benefits of using surrogate end points? What are the drawbacks
or concerns, and how has FDA relied upon surrogate end points
appropriately, or have they relied on surrogate end points
appropriately in your view?
Mr. Kesselheim. Well, a surrogate end point is when we are
testing a new drug or a patient wants to take a new drug or get
a medical device, they are most interested in extending their
lives or improving their symptoms or other kinds of real
clinical end points. A surrogate end point is an end point that
is not one of those end points but might predict that end point
ultimately. So in the case of a diabetes drug, instead of a
drug showing that it improves life span or reduces
cardiovascular events, it might change the hemoglobin A1C
value, which is a biomarker and a surrogate end point that may
predict ultimately down the line what happens. The goal of
using surrogate end points is to try to shorten the span of
clinical trials that are necessary to test a new product.
The problem is when a surrogate end point isn't connected
to the final clinical end point and then doesn't predict the
final outcome of the drug, and if a drug is approved on the
basis of a surrogate end point, then patients may experience
bad outcomes even though their A1C is slightly improved or in
the case of the tuberculosis drug, even though their sputum is
slightly cleared, more cleared of tuberculosis.
So surrogate end points, in order to be used as a basis for
new drug approval, need to be validated by being linked
clinically, and that is a very difficult and long process and
can vary depending on the particular surrogate end point. You
know, just take statins, which is a cholesterol-lowering drug,
and most people understand, most people agree now that lowering
your LDL cholesterol is a surrogate end point towards
ultimately lowering your cardiovascular risk. Unfortunately
there are some cholesterol-lowering drugs like statins that do
a good job of that and then are connected to with surrogate end
point does predict clinical outcomes. There are other
cholesterol-lowering drugs like Ezetimibe which lowers your LDL
but then is not necessarily connected to improved health. And
then there are other cholesterol drugs like Torcetrapib, which
is a drug that raised your HDL level that again which was
thought to act as a valid surrogate but then ultimately did not
end up demonstrating actual clinical effects.
Mr. Pallone. But what about whether you think that the FDA
has relied upon these appropriately?
Mr. Kesselheim. So I think that the FDA has a very
difficult job and relies on surrogate end points in certain
limited circumstances where either, A, the surrogate end point
has been validated or B, there is a great unmet clinical need.
And that was as in the case that you mentioned, the Avastin for
metastatic breast cancer case, where everybody believes we need
more therapies for metastatic breast cancer, and this appeared
to be a good surrogate.
Unfortunately it later turned out that it wasn't, and it
increased mortality of patients with breast cancer. And the
problem was at that stage it was very difficult for the FDA to
then withdraw the indication and now to try to change clinical
practice away from using the product because the surrogate end
point had sort of caught on.
Mr. Pallone. It is difficult for the FDA to know when they
are valuable or not, in other words?
Mr. Kesselheim. Right.
Mr. Pallone. Let me just ask one more. I am running out of
time. Dr. Meyer, you noted that you would caution against
shifting confirmatory efforts to the postapproval setting. Can
you just expand upon that a little, and what is your view on
how FDA has approached the reliance on surrogate end points.
Mr. Meyer. OK. So as far as the proposals to shift the
regulatory decision-making more towards the end of phase II
relying on real world data for efficacy, I don't think we are
at a point with the science where we can rely on that. The kind
of evidence we want for assuring effectiveness of a drug at the
present time I think can only come through well-conducted,
generally randomized trials. I think the fact that half the
drugs that fail from phase III to approval fail for efficacy
reasons is a good example that even at the end of phase II
where there is a lot of promise, that may not be confirmed by
randomized control trials.
As far as the FDA's reliance on surrogates, I think on the
main, they do a reasonable job on it. I agree that they are in
a tough position there, but I think for the most part, they are
very judicious about it, and while they may not always get it
right, I think the public health balance is such that you would
want them to do well most of the time, and I think they do well
most of the time.
Mr. Pallone. Thank you. Thank you, Mr. Chairman.
Mr. Pitts. The Chair thanks the gentleman. I now recognize
the chairman emeritus of the committee, Mr. Barton, 5 minutes
for questions.
Mr. Barton. Mr. Chairman, I have not been here for the--I
listened on TV, but I wasn't here in person, so I am going to
pass, but I appreciate your courtesy. I think this is a good
panel, and I think the issues they are putting before your
subcommittee are excellent, but I appreciate your courtesy.
Mr. Pitts. The Chair thanks the gentleman and now
recognizes Dr. Burgess, vice chair of the subcommittee, for 5
minutes.
Mr. Burgess. Thank you, Mr. Chairman. And again, thanks to
our witnesses for being here today.
Mr. Chairman, before I get to questions, I just want to add
another unanimous consent request that yesterday's Wall Street
Journal, the article by Peter Huber, they did a collection of
articles about how things could change in this country to
improve things. In addition to the Tax Code and two-parent
families, here was an article by Peter Huber about unleashing
molecular medicine dealing with the very issue that we have
before the committee today. I would like to put that into the
record.
Mr. Pitts. Without objection, so ordered.
[The information follows:]
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
Mr. Burgess. Dr. Herbst, let me ask you a question. You
touched on it, but you didn't get much chance, so perhaps you
could expound on it a little bit, the use of the laboratory
developed tests, I think you put it, the regulating diagnostics
for clinical trials?
Mr. Herbst. Right. So this is a big challenge because right
now for genetic testing there are 20,000 perhaps tests you know
that look at 4,000 conditions. There are many different tests.
So how are we going to regulate and develop the right tests to
use? In the master protocol we have done is we are using a next
generation sequencing platform which is allowing us to look at
250 different genes prior to the trial and then assort those
patients to one arm of the trial. So that is an example of
where we have designed the test in with a trial; hopefully the
whole principle of regulation will then occur, that we will
approve the drugs with the test. So that is the hope.
Mr. Burgess. Now, with the FDA reauthorization that we did
2 years ago, and thank you, Ms. Stafford, for recognizing that
achievement. Nobody else paid any attention to the fact that
there was a bipartisan, bicameral work done by Congress in an
election year that actually worked, so I appreciate the
recognition. When we did that, did that allow for the type of
flexibility that you are requiring for these laboratory
developed tests? Do you think as you use this next generation
sequencing, that you will be able to get through the regulatory
requirements that you need to?
Mr. Herbst. I believe so. It is a challenge because this is
a new paradigm to do a multiplexed series of tests and then use
the data from that to put patients on trial, but the benefit we
have in this large public-private partnership of the master
protocol is we are working very closely with the FDA and with
the branch that regulates these diagnostics and getting advice
from them. We are working closely with our pharma partners, and
we are working closely with the group that we have chosen to do
the diagnostic tests, so hopefully we are meeting all the
requirements of that should this work and should a drug
actually show efficacy, we can then get these tests approved.
But I think it is important to look very carefully at what test
is being done, the method, the validity, the reproducibility of
those tests because there are so many different ways of testing
for the same thing.
Mr. Burgess. Correct. That was actually one of the
unanswered questions in FDASIA, so I would appreciate your
feedback to this committee. If you find it is working well or
not working well, we actually need to hear from you on that,
because we never actually came and closed the loop on that and
came to a conclusion.
Dr. Siegel, let me ask you a question and your company, and
this is a little off topic for you because you were primarily
talking about drug approvals, but on the device side, Johnson &
Johnson just achieved finally a FDA approval for a device
called SEDASYS that assisted in the administration of analgesia
and anesthesia for people who are undergoing minor procedures.
Minor, by definition, is someone else's procedure, but
undergoing procedures that are not open procedures. Can you
speak a little bit to the difficulty, because that was a, what,
17-, 18-, 19-year-old regulatory process that this device
required, and it seemed pretty simple and straightforward. Can
you speak to that at all? Are we better now than we were the
last 17 years?
Mr. Siegel. I think that SEDASYS is an excellent device and
an important medical advance. It did raise important questions
because in a sense, it is replacing the use of
anesthesiologists in some cases, or at least it had the
potential to replace use of anesthesiologists with a
technology-guided approach to delivering anesthesia and
ensuring that the patient is safely monitored. And that I think
raised a lot of safety questions with the FDA. So I think the
FDA had some legitimate concerns. I think it would be fair to
say that there were times in the process where those could have
been handled, communicated better, handled a bit more
expeditiously so that the process would not have drawn out as
long as it did.
Mr. Burgess. Well, the idea behind giving people a
predictable pathway going through this process was largely
because of the experience that your company had, and I hope
FDASIA actually has dealt with that.
Time is short, but Ms. Stafford, let me ask you, you have
it in your written testimony. You didn't get a chance to really
get to it, but the sharing of precompetitive data, how is that
working out? How is that approached? Can you give us some real
world examples of how that works?
Ms. Stafford. Thank you. It is a very good question. In
terms of the precompetitive data, it is having access to
electronic health records so that we are able to take that data
and de-identify it. We don't want to know who the patients are,
but we want to know how to find the physicians who have those
patients and enroll them. The biggest time driver in this
process when we talk about these 7 to 10 years of development
is actually finding the patients. And when we talk about why do
we go outside the U.S., it is partly to find the patients in a
time frame in order to be able to get these products to market.
And so the precompetitive, if you will, data is really
having access to data to help us find the right patients for
the right trials in as rapid a time as possible. Right now on
average, you know, anywhere from 10 months to 4 years, and, you
know, there have been trials that have been put together, and
there has been some proposals put forward and the ability to
use data and to recruit the patients into a trial in 14 days.
And just think about the amount of time that would be cut out
of the trial from 4 years to finding patients down to 14 days
because we have the data that gives us access to identify the
patients.
Mr. Burgess. Mr. Chairman, I have additional questions, and
I would ask unanimous consent to be able to submit those for
the record. I will yield back.
Mr. Pitts. All right. The Chair thanks the gentleman. I now
recognize the gentlelady from California, Ms. Capps, for 5
minutes of questioning.
Mrs. Capps. Thank you, Mr. Chairman. And I thank you all
for your testimony today. You know, providers and patients
alike are relying on clinical trial data to ensure that we are
getting the right treatment at the right doses at the right
time. However, for too long these trials have not necessarily
been representative of the population at large. And, Dr.
Kesselheim, I have a couple questions to ask you about this,
but I wanted to just highlight where I am going with my
questions. Women have been excluded, assuming that women are
``men with hormones.'' Even lab rats in the past have all been
male, and recent past. And diverse ethnicities have been
underrepresented. And even when these groups are included in
trials, often there are too few participants in these groups to
analyze the effects on them or the analysis are simply not run
or reported. More and more we are hearing about how disease
manifestations can diverge based on gender. Recently there was
a 60 Minutes story examining how some drugs affect women and
men differently.
The story highlighted an example of the drug Ambien which
metabolizes differently in women than men. Because of this,
women have been unsuspectingly receiving high doses of the drug
for over 20 years. This FDA change was followed by a report
entitled Sex-Specific Medical Research, Why Women's Health
Can't Wait, which provides compelling evidence for the further
inclusion of sex and gender in scientific research.
And the FDA's own August 2013 report, which was initiated
by the inclusion of my Heart For Women Act in the FDASIA
legislation, shows that there is still much work to be done to
make sure that women are fully represented in clinical trials
and that the safety and effectiveness of information is readily
available.
And to you now, Dr. Kesselheim, Brigham and Women's has
been a leader in research on sex differences of disease. Can
you tell us more specifically about the importance of ensuring
proper analysis of drugs and devices on a diverse population?
And what more can NIH, FDA, and private companies do to ensure
that we don't have another Ambien situation?
Mr. Kesselheim. Thank you very much for bringing that up. I
think it is a really important point, and I think the essential
issue that your question goes to is the generalizability of the
study and for a clinical trial for a newly approved drug or
device to be truly generalizable, which is to say useful in the
patients in which the drug will be used after approval, it
needs to have representation of both sexes, people of different
minority groups, without relation to their financial status or
their sexual orientation or any kinds of things. The problem
is, is that as we move in this conversation towards talking
about more efficient trial designs and other kinds of processes
to try to shrink the premarket study, what that inherently does
is it reduces the number of patients in which a drug or device
is tested in and so makes it even harder to achieve the kinds
of goals that you are talking about and that have been
recognized as being a problem in medical device trials of women
underrepresented in device in trials of cardiovascular devices
or in trials of new drugs that will then be used in those
patient populations.
It is the same for older patients, and it is the same for
younger patients. I think that Congress, just as it can put,
encouraged the FDA to take up, you know, innovative clinical
trial designs, can also encourage the FDA to make sure that the
trials that are being delivered to it are fully representative
of the patient population in which the drug or device will be
used.
Mrs. Capps. Great. And I want to get another topic in real
quickly for you because your written testimony also touches on
the Sentinel system under development by the FDA to conduct
postmarket passive surveillance of drugs and devices to spot
issues like adverse drug interactions quicker. And I believe
that the Sentinel program holds great promise. That is why I
worked to get the Assurance for Effective Devices Act included
in FDASIA to continue progress on the program and ensure it
would be designed for drugs and devices. So can you discuss--
there is only a little time left--how the Sentinel program
could be complement to the data derived from premarket clinical
trials?
Mr. Kesselheim. Well, the Sentinel Initiative as you
describe is a very promising pathway to try to get signals of
safety issues for newly approved drugs and soon devices as well
after they are approved. The problem is that the essential work
in the Sentinel system of distinguishing the signal of the
safety event from the noise of everything else that is going on
with the drug in this postapproval observational setting is
really very, very hard. So in the last 6 or 7 years, the
Sentinel Initiative has been focused on the methods used to try
to do this and has made relatively slow, steady, little
progress, but steady progress, in trying to assess these kinds
of methods.
There is still much, much more to be done before we can
rely on the Sentinel Initiative for any sort of real active
surveillance, and I think that that is far in the future, but
unfortunately at this point my understanding is that the
funding of the Sentinel Initiative is still up in the air, so I
would encourage Congress to continue to fund it. But I would
also not get people's hopes up that the Sentinel system is
going to provide this great white knight from a post market
surveillance point of view for drugs that are approved on the
basis of limited pre-market study. I think the FDA itself still
refers to the Sentinel Initiative as the mini Sentinel pilot
program now 6 or 7 years out from its creation.
Mr. Pitts. The Chair thanks the gentlelady. I now recognize
Dr. Murphy from Pennsylvania for 5 minutes of questioning.
Mr. Murphy. Thank you. I want to ask particularly about a
couple of the issues related to psychiatric drugs. Certainly,
many medications you have brought up with regard to some
recommendations for advancing the speed of these are important,
but in particular, with 60 million Americans affected in some
level with psychiatric illness, 10 or 11 million with severe
psychiatric illness, and about 3.6 million who are not in
treatment in part because of whatever the reason be with
medication, et cetera. Would there be some change in the
recommendations you would make to advance or speed up research
with regard to psychotropic drugs, and I will open that
question to anybody. Nobody has any? Go ahead.
Mr. Meyer. Yes, I will at least try to touch on that. I
agree that it is an area of great unmet medical need. I think
the problem has been a couple of fundamental issues. One is how
poor some of the neuroscience is in predicting targets that are
amenable to becoming drugs, or targets for drugs. The second,
though, is that these trials are exceedingly difficult to
conduct, and, in fact, if one looks at drugs for antipsychotics
and/or depression, even very well-conducted clinical trials
often fail for effective drugs. So it is probably one of the
more problematic areas to think about new paradigms of drug
evaluation at the current time. I do think where the hope is
for the future is really a better fundamental understanding of
neurobiology to identify true opportunities for targets.
Mr. Murphy. Let me add to that. Ms. Stafford, you also
mentioned I think in your written testimony about issues
involving, we should be looking at some of the EU standards,
and perhaps that would help expedite. I know right now part of
the discussion is also in terms of TTIP in looking at this
Transatlantic Trade Agreement, and those standards, I believe,
should become part of that. Do you have any insights for us
that you can provide with regard to some of the differences
between the American FDA and the EU standards for advancing
clinical research?
Ms. Stafford. Yes. I was specifically talking about the
adaptive licensing pilot that was started in March, April of
this year, so it is early stages in terms of Europe. And, you
know, the FDA is having that discussion as well, so I don't
think that they are too far behind, but I think encouragement
to also pilot, there are a lot of different terms for this,
progressive authorization, adaptive licensing, et cetera, and
so, you know, that is the one major area that I was speaking
to.
Mr. Murphy. Thank you. I also have a question with regard
to the HIPAA laws and how the interpretation of those may
interfere. I know some other members asked questions on this,
but I also have some further comments of this, of how perhaps
there are some barriers in what HIPAA laws are preventing us
from getting information that would be extremely valuable in
advancing research. I would open that up to anybody if anybody
would like to comment on changes. Dr. Siegel?
Mr. Siegel. I think since the time those laws were passed,
we have had a lot of experience with them, and we have new
types of information that can be collected in laboratories, and
I think it is time for a relook. It is important that privacy
be protected. I believe it can be done in ways that also
facilitate the advancing of research. And I know that HHS
actually had about 3 or 4 years ago an advance notice of public
rulemaking that looked at both the IRB process for patient
safety protection as well as the process for privacy
protection. There is a lot of opportunity, I think, both to
increase patient protections, while at the same time, allowing
better availability of important medical information, whether
it is minimal or no risk to patients.
Mr. Murphy. Thank you. Dr. Herbst, do you have a comment on
that?
Mr. Herbst. I guess one of the benefits of doing the
genomics in the context of a clinical trial is then you
actually have the informed consent from the patient. You are
matching them to the therapy, and then you have their consent
to do the discovery within the trial, hopefully identifying new
targets for the future.
Mr. Murphy. Do you think some of this is misinterpreted now
by researchers or by physicians who are just afraid to go
anywhere with it because of the HIPAA laws?
Mr. Herbst. I think people are concerned, appropriately so,
and they file them, and you do have to look very carefully at
what consent you have whenever you are asking a question with
tissue. But, no, I think people are very aggressively trying to
study what they can, reconsent patients when they can also, so
that we can match genomic markers to activity.
Mr. Murphy. Thank you. Dr. Khosla.
Mr. Khosla. Yes. I just wanted to add when you talk about
clinical trial networks and consortia, I think that is where
the HIPAA laws may need to be modified, particularly in what
Ms. Stafford was referring to in terms of kind of the pre-trial
process. So before the subject has signed any consent forms,
the electronic health record would need to be searched to
identify participants at a given site. Currently that data
can't leave that particular medical center to be merged into
data from other centers.
So modifying that to allow that in a way that still
protects patient privacy but allows for better ascertainment of
potential participants at different sites would be very
helpful.
Mr. Murphy. Thank you. So the HIPAA laws as they stand,
they were designed to help protect patients from exposure of
confidentiality? They weren't designed to hamper research in
other movements. I thank you very much. I yield back.
Mr. Pitts. The Chair thanks the gentleman. I now recognize
the gentleman from Texas, Mr. Green, 5 minutes for questions.
Mr. Green. Thank you, Mr. Chairman, and Ranking Member
Pallone and for our witnesses here today.
In a time of historic opportunity offered with big data and
scientific advances and technological developments it is
important to examine the ecosystem of clinical trials. Before
us is the prospect of transitioning from reactive systems
centered on large patient populations, large clinical trials,
and one-size-fits-all approach to a proactive system, they can
target smaller, specific patient populations, advance
personalized medicine, and revolutionize the way we prevent,
treat and cure disease.
Dr. Siegel, clinical trial development in the area of
antibiotics has been increasingly difficult in recent years
because of the FDA trial design requirements. For instance, FDA
requirements at trial study infection sites in the body versus
the deadly pathogens that cause these infections that make
conducting trials in the United States near impossible in large
part because of the small population associated with these
illnesses. How important is it to trial design successful
trials, is an FDA empowered to accept alternative trial
requirements based upon the unique nature of the disease and
the patient population? By the way, I am sharing this question
from Congressman Gingrey and I who have legislation working on
it. So is there something that we can do that would make it
easier on the smaller populations?
Mr. Siegel. Well, clearly infectious diseases are a major
medical problem and threat to our country because of the rapid
emergence of resistance and of new infections and because
industry efforts in this area have somewhat decreased, in part
because of difficulties in pathways. But I think the issue
before us is the pathways that have traditionally been used and
the way these drugs have been studied is, in fact, to develop
them rather broadly for use, broad spectrum antibiotics for use
in large populations. And as your question presumes, what is
needed is a better effort to focus on specific needs to develop
drugs that can be used in specifically the populations that
need them so that resistance is less likely to emerge, and to
have innovative pathways that will allow that to happen and
allow there to be ample incentives for investment in developing
those therapies. I do think that there have been both
legislative and regulatory moves in recent years in that
direction, and I think that that is very welcome to, in fact,
ensure that there are both incentives and pathways for more
targeted treatments of critical infectious diseases.
Mr. Green. Anyone else? Dr. Meyer.
Mr. Meyer. Yes, thank you. I have actually worked on this
issue, published on this issue, and actually I would say that
FDA has shown some movement. I think one of the quandaries for
FDA, however, is if they accept a smaller data set on a limited
population for, say, a particular infectious agent, they don't
really control the practice of medicine, and the issue for them
is if they are reasonably assured that it works in that
population but they don't want it broadly used either because
of poor antibiotic stewardship and/or uncertainties about its
general efficacy and safety, they don't have a good means for
doing that. So I think that is part of the consideration that
might be thought through in terms of approaching antibiotic
drug development especially.
Mr. Green. And I agree in the real world of practicing
medicine, but the FDA can put restrictions and advisories and
things like that, so physicians may not, you know, use that
particular drug for things that may not be proven on the label,
but I know they don't have that ability in all the doctor's
offices.
So, Dr. Siegel, your testimony brings up the potential for
continued recognition of surrogate end points by the FDA as
having great promise for continued drug development in the
United States. Over the past few hearings and roundtables, you
have heard of the dire lack of new diagnostic tests for many of
today's illnesses and conditions. As the adage goes, if you
want to cure something, you first need to be able to identify
what it is. Dr. Siegel, since such tests operate largely
against predetermined end points, could early FDA recognition
of diagnostic end points for the purpose of clinical trial
design improve the efficiency and success of those clinical
trials?
Mr. Siegel. First, I want to say on record that the FDA
program for accelerated approval has been a tremendous success.
There is a large number of drugs, especially in cancer and HIV
infection, that have come to patients much sooner, a large
number of effective drugs that have come to patients sooner and
a large amount of increased investment in those areas. There
have been cases, as has been pointed out, where subsequent
studies have shown that those surrogate end points did not
predict benefits.
That, in my mind, is the evidence of the success of the
program, the ability to learn in the postmarking situation,
and, in fact, we have found when you just look at the numbers
and the implications of the drugs involved, the benefits of
those programs have tremendously outweighed the risk, the
downside suggesting that more use, even though it would
incorporate more risk, would be appropriate.
Diagnostic tools are critical to do that, diagnostics to
identify the right populations and as you indicate, to measure
end points. The use of diagnostics have been limited. The
technological advances in proteomics and genomics and
informatics offered the powers of explosive use--Dr. Herbst
referred to some of that use in Lung-MAP--in all aspects of
clinical trial designs. And I think that investment in research
in that area and investment in ensuring that we know how to
integrate in both the research process, the product development
process, and the regulatory process, we know how to integrate
the development and the regulation of diagnostics with drug
products is important since historically they have been done by
separate organizations or companies.
Mr. Green. Mr. Chairman, I know I am over time, and I
appreciate it. This is such a great panel with so much
information, if you all have responses to not only my questions
but other ones, please share them with us. And I thank you, Mr.
Chairman.
Mr. Pitts. The Chair thanks the gentleman, and I now
recognize the gentleman from Illinois, Mr. Shimkus, 5 minutes
for questions.
Mr. Shimkus. Thank you, Mr. Chairman. I too appreciate you
coming and have been in and out, but actually have been around
in these little anterooms and stuff. But I want to start with
Dr. Khosla. In your testimony you state, and I am just going to
quote, ``The current clinical trial model of placebo-
controlled, randomized, double-blinded clinical trial may not
be the most effective model, particularly for early phase
studies.'' And then in the case of antibiotics, when you use--I
am really struggling with this, and I have actually been
looking on my phone for the Hippocratic oath and issues. So if
you are using a double-blinded, placebo-controlled test, and
you have someone, and I use the term ``emergent condition,''
and they are, maybe because it is a test you are using a
placebo, doesn't that really cause ethical problems and
challenges?
Mr. Khosla. Yes. I think you raise a very important point,
which is the use of placebos in trials where effective medical
therapy exists, and I should clarify that there have been
enormous changes over the years in what is allowable and
ethical to use as a placebo. So historically, for virtually all
diseases, there were randomized controlled-placebo trials. More
and more in my own area of expertise, for example, in
osteoporosis, where we now have effective drugs to prevent or
treat osteoporosis, instead of a placebo, often there is a
standard-of-care drug that is used, and the burden of proof is
to show noninferiority or superiority to the current best
treatment.
So that is a great point that you raise, and it is in the
context of where there may or may not be effective alternative
therapies available.
Mr. Shimkus. I am going through this because one of the
statements, and this is a modernized version. I will prevent
diseases whenever I can. Prevention is preferable to cure. I am
to care adequately for the sick. And when we are in a system
like that, obviously we are not if it is placebo.
Mr. Siegel. It is important to note that the use of placebo
in a clinical trial doesn't mean that the patient is not
receiving a treatment. For example, with a new cancer drug if
there is already two drugs being given, and a new drug comes
along, some patients may receive all three. The others may
receive the first two, but also a placebo so that there can be
blinding as to which treatment, but they are still getting
fully standard treatment. Placebos can be very important in
research but should not be equated with lack of treatment.
Mr. Shimkus. Seems like this started some comments, and so,
Mr. Murray, please.
Mr. Murray. Yes. So medical devices, it is a very important
moral and ethical question. And there are instances for
breakthrough medical devices where there is not an existing
therapy, and you do a surgical procedure, especially with an
active device that is not turned on, so the person is not
receiving therapy. That, I think, adds to the conundrum, if you
will, and I think it becomes a major challenge that is unique
for medical devices especially in those breakthrough areas
where there is a treatment-resistant diseases with no other
options.
Mr. Shimkus. So let me go back to Dr. Khosla real quick. As
far as in this process that we just discussed, any other FDA
reviews or reforms that you would suggest that would be helpful
in this process?
Mr. Khosla. Well, I think it really comes on a case-by-case
basis depending on the particular disease being studied because
for certain diseases there are effective cures, and you are
really looking for a drug that might be better or have fewer
side effects, and in that case, clearly the use of a placebo
isn't warranted. In other instances, there really isn't a good
alternative and the standard of care may involve, you know, for
example, just giving nutritional supplements like vitamin D or
calcium. And in those instances using an active drug against
that standard of care is appropriate. So it is a major ethical
issue. It is something, though, that is very specific to each
disease entity and the alternates that are available.
Mr. Shimkus. Great. Thanks. And for my final minute, let me
go to Dr. Siegel, and you talked about proteomics, if I
pronounced that right, and molecular diagnostics and genomic
sequencing. So what do you believe Congress needs to do to
address and ensure that the potential for, I guess the
terminology is precision medicine can be realized by both
developers and clinicians?
Mr. Siegel. I think the potential to utilize those
technologies in the development of precision medication is
critical. I don't know that there is a specific legislative
need to change the rules or the way drugs are developed. I
think that we have what we need in that regard. I do know,
however, as we have seen with breakthrough therapies, that
congressional attention to an issue, highlighting an issue,
congressional exhortations, congressional direction of how
Federal agencies invest and spend their money can have a big
impact, and I think in those areas certainly enabling FDA and
NIH to help enable those technologies and those developments
could be very important.
Mr. Shimkus. Thank you. And I know, Chairman, you probably
have asked and will mentioned that there will be opening record
for questions. There may be follow-up questions based upon your
response. We would solicit and then we would forward to you. If
you would do that, Mr. Chairman, I would appreciate it.
Mr. Pitts. Yes, we will have follow-up questions. The Chair
thanks the gentleman. Now I will recognize the gentlelady from
Florida, Ms. Castor, for 5 minutes of questioning.
Ms. Castor. Thanks to the panel for sharing your insights
today. Dr. Meyer, I know you were formerly at the FDA and you
have worked in industry, so I would like to get your insights
based on that experience on a couple of questions. We have
heard a lot today about various ways that clinical trials can
be modernized, everything from increased use of technologies
like electronic health records to increased use of alternative
trial designs like surrogate end points and adaptive trial
designs. A lot of what has been mentioned I would assume is
outside the purview of FDA. I imagine a lot goes on in the
development of drugs and devices that doesn't and shouldn't
involve FDA at all. I would like to hear your view on that. Do
we have the right balance for the modern era?
Mr. Meyer. So I think some of what we have been hearing is
outside the purview of FDA. For instance, the use of electronic
health records for precompetitive screening of patients and
understanding who the patient populations might be. That really
is preregulatory as well. I think the expansion of the use of
surrogates is clearly within the FDA's purview. I think the
difficulty there, though, is not with the FDA. It is really
identifying biomarkers or other assays that will be validated
to predict outcomes. That is no easy task, and it sometimes
takes a very, very long time. If you take for instance,
Alzheimer's disease, everybody would like to be able to do much
smaller, much more focused trials, but to date, the biomarkers
we have have not predicted benefit. So there is no choice but
to do large, long trials.
I think the other thing that I would say is that the FDA
does, I think at times, have some reluctance to accept things
like a patient-based electronic assessments. And I think that
is something that they could be encouraged to do. I am not sure
it needs legislation, but for instance, if you are a pulmonary
patient and you are able to have a very reliable home
spirometer and measure your air flow every single day, that is
a very rich data source. But if FDA insists that those patients
go into the clinic and be assessed in the clinic, that is
actually inhibitory to patient enrollment to some degree, but
also I think it produces a more expensive and complex trial.
Ms. Castor. Mr. Murray, do you think that the current
regulatory scheme is meeting the entrepreneurial spirit that is
out there? And I will give you a great example. In my home town
of Tampa, we have a fantastic new center called the Center for
Advanced Medical Learning and Simulation by the University of
South Florida. I was so proud of it, I took Mr. Pallone to
visit, and I know Mr. Bilirakis has been there where we are
bringing together the medical engineers, the academics, the
folks that can work through the business cycle, have the 3D
printers right there so they take the device right to the 3D
printer right into a computer analysis of whether it works or
not. Does this regulatory scheme currently, is that going to be
acceptable for the advances in technology and devices?
Mr. Murray. Excellent question. The genesis of MBIC was the
recognition primarily from Dr. Jeff Shuren at CDRH and the
commissioner that medical device technology is advancing at a
rate that we have never seen before. You see it in the consumer
and the mobile and the social media side, but you are seeing
that translate over to health care as well. So there was a
recognition that tools methods and approaches used needed to
evolve, and to do that we are working collaboratively in the
precompetitive space. And you mentioned 3D printing. That is an
example where you are going to see the realization of
personalized medicine where using computational modeling and
simulation, people will be able to have tailored custom devices
that fit them and meet their needs specifically.
Where we are going right now, and I think the opportunity
and the need, and we talked about this in terms of HIPAA and
data, but there is a tremendous amount of data that is
available out there in terms of patients' post approval of
devices, and if you will, if you had the opportunity for, we
have right now donor selections, if we had people that would be
data donors instead of organ donors, and they would allow their
data to be used, I think we could improve by orders of
magnitude the quality and richness of those models and
simulations to even improve more on the technology that is
going to realize personalized medicine advancements.
Ms. Castor. Thank you very much.
Mr. Pitts. The Chair thanks the gentlelady. I now recognize
the gentleman from New Jersey, Mr. Lance, for 5 minutes of
questioning.
Mr. Lance. Thank you very much, Chairman Pitts. In the
various testimony of members of the panel, you have discussed
the challenges in attempting to coordinate the work of multiple
institutions before and during clinical trials. Varying
regulations and protocols make it difficult, I think, for
institutions to communicate one with another. If institutions
that are attempting to coordinate have difficulty doing so,
what about those that are not working together, and what
methods are currently in place, if any, to reduce redundancies
in clinical trials, and what steps would the panel recommend to
ensure we are not doubling up on research or making the same
mistakes over and over again. Dr. Siegel, yes.
Mr. Siegel. Well, there has been a lot of advances recently
in terms of transparency of research results and rapid
publication, and there has been a lot of growth of consortia,
TranCelerate Pharma as an industry consortia, various other
broader groups to enable better communication and cooperation.
I think that you have heard from several members of the panel.
One area, though, of better shared learning and cooperation
that we see already but could see more of are disease-specific
clinical trial networks and trials, such as Lung-MAP or
organizations which bring together broad expertise. And one of
the nice things about some of the newer approaches to that is
that there are organizations that are not just, say, academic
centers coming together with perhaps Government support, but
are also incorporating patient and industry expertise and input
to enable better addressing of some of the operational problems
as well as the scientific problems that they need to face.
Mr. Lance. Thank you. Dr. Herbst.
Mr. Herbst. Yes. I would agree with that. And just sharing
our experience for the Lung-MAP trial, we are looking to accrue
a thousand patients a year, and this is throughout the United
States, really focused at the community, places that normally
don't have access to these types of trials. So it really
requires using the National Clinical Trials network, and that
network uses a central IRB. We heard about that from the panel,
so that this trial doesn't have to go through a different IRB
at each site, which can take weeks in some cases. So that is
very helpful. I agree with Dr. Siegel, the commitment and
working with all the partners, the Pharma partners especially,
you know, the National Clinical Trials Network is being
supplemented by the public-private partnership that we are
working with. We need to all work together with the FDA as well
because this would all be a failed effort if at the end of the
day, these drugs and marketers couldn't go for approval of the
drug. I think one thing we all have to also consider we heard a
little bit about surrogate end points is quality of life and
patient-reported outcomes and how we are going to build those
into the trials and work with patient advocates and with those
groups early on.
Mr. Lance. Thank you. Yes, Doctor.
Mr. Khosla. I just wanted to reemphasize what I had
mentioned in my testimony, which is that NIH is investing in
these clinical translational science awards across the Nation,
and so this is a preexisting network where there are going to
be best practices incorporated over time. There is hopefully
going to be increasing IRB reciprocity, so many of the
obstacles that we have heard about hopefully will be reduced or
eliminated. And it isn't disease specific, so it would be open
to any disease for which there is a trial ongoing.
Mr. Lance. Thank you. To the panel, is there something more
we should be doing here on this committee and at the Federal
level to make sure that this occurs in the greatest way
possible for the benefit of the better health of the American
people? Yes, Dr. Herbst.
Mr. Herbst. Getting back to the whole idea of the public-
private partnership, I think it is essential. In my, opinion
that is one of the reasons the Lung-MAP is working well. Any
way the committee could work to incentivize that to move
forward the precompetitive measure. The fact that we have five
different companies deciding to put their hat into our trial
versus doing a trial themselves. I would hope that at the end
of the day, they will see this is the only way to find these
small populations of patients. But they are taking a risk, and
ways to sort of incentivize, to promote, to give them credit
for that, I think would be important.
Mr. Lance. Thank you. Yes, sir?
Mr. Murray. And again, on public-private partnerships, but
in particular with our partnership which includes NIH, CMS,
FDA, the ability to have a flexible collaborative environment
in that precompetitive space, it is oftentimes very
structured--I think its FACA, if you will, that becomes an
important consideration. So we have to be able to foster and
encourage these kinds of partnerships in that precompetitive
arena.
Mr. Lance. Thank you. Yes, sir?
Mr. Kesselheim. Another thing that I would add is that I
guess I am a little bit less optimistic than Dr. Siegel is
about where things stand right now in terms of data
transparency and the ability to share clinical trial data, and
I think that this committee and Congress can do a lot to try to
encourage and put in place systems and structures to allow
sharing of clinical trial data to try to prevent redundancy in
testing of new drugs and to try to allow different groups to
learn from data that is currently right now held as a trade
secret by many companies.
Mr. Lance. Thank you. My time has expired, and it is been a
very interesting and informative hearing. Thank you, Mr.
Chairman.
Mr. Pitts. The Chair thanks the gentleman. I now recognize
the gentleman from Louisiana, Dr. Cassidy, for 5 minutes of
questioning.
Mr. Cassidy. Dr. Siegel, the sharing of the data, it is
proprietary data, so is the obstacle to the sharing the company
releasing it? I am just asking.
Mr. Siegel. Obviously you need to have some protection of
proprietary information in order for innovation to occur, in
order to have incentives for innovation. However, when clinical
trial data get to the point where what is learned about that
data could be used to protect the safety of patients if it is a
drug that is already approved or there----
Mr. Cassidy. I accept that, but just in terms of expediting
other research. I am just intrigued. Sounds like a great idea
but will the companies agree to it? Do you follow what I am
saying? I am not arguing either point. I am just asking.
Mr. Siegel. We have put in place through an agreement with
Yale a third-party review that will enable much greater access
to our clinical trial data where needed for important medical
research in patient safety, and we believe that that is not
incompatible at all with protecting innovation and allowing----
Mr. Cassidy. I think it was the Michael J. Fox Foundation
that, in order to receive their grant, you had to collaborate
prior to peer review publication. Maybe I have that wrong, but
nonetheless it seems like a nice concept. I don't know the
practicality of NIH. Does NIH require that? I don't believe
they do, do they? Anybody.
Mr. Kesselheim. I am not 100 percent sure. I would also
support what Dr. Siegel has said about his company and its
innovative relationship with Yale is actually quite a good
model for other companies, but it is relatively rare at this
point. I think that the NIH when it funds research, you know,
should be held to the same standard as when companies fund
research as well. But when research on products that are
available in the market is done on patients, there is really no
reason why that research shouldn't be available for further
study and for greater learning by everybody.
Mr. Cassidy. Dr. Herbst.
Mr. Herbst. I will just add that Yale and NCI Comprehensive
Cancer Center, and I do know that the new regulations for
recompleting those grants do require even more collaboration
between centers, so hopefully through that we will bring the
Pharma partners, too.
Mr. Cassidy. Dr. Khosla, you and others mentioned having a
centralized IRB, but that is already allowed. The Western IRB
is the central IRB for many others. Now, would Mayo cede
their--knowing how prestigious Mayo is, would they cede their
IRB approval to a centralized western IRB, for example?
Mr. Khosla. I think the answer to that is that is a culture
change that is occurring at many academic medical schools.
Mr. Cassidy. So let me ask, that is merely a culture
change. There is nothing regarding statute or regulation. I am
asking because it seems like there is a certain institutional
pride that some institutions do not wish to cede. That truly
seems more a culture issue than statute or regulation. Is that
correct?
Mr. Khosla. Correct.
Mr. Cassidy. Believe me, I am from that culture. I
understand the hideboundness of it. Now, you also said
something which I found intriguing. Dr. Herbst shook his head
yes, that if you are doing the screening with genetic markers,
that material, that information has to remain domiciled with
the institution, and yet Southwest Oncology Group, I am just
asking, you have multiple institutions. If one of them has
certain biomarkers, they cannot share that with the
centralized, whoever is overseeing the entire study framework.
Whatever you learn cannot be shared with that centralized
authority.
Mr. Herbst. Actually yes and no. First of all, the patient
gets their data, so that is very important. So we are making
this screening available to patients where they might not have
had it or afforded it. And then, of course, the excess tissue
does get banked through the cooperative group structure. That
is not part of the national system.
Mr. Cassidy. Now is that statute or legislation? Does that
require an act of Congress? Oh, my gosh.
Mr. Herbst. No, no. The groups have tissue banks and the
tissue goes in the tissue banks, and with petition anyone, it
is a public bank, can petition the swag at some point if they
have a study and they want to use this tissue.
Mr. Cassidy. Dr. Khosla, I think what you said is that if
you do biomarkers, those results remain at the institution and
cannot be shared with others. Did I hear that correctly.
Mr. Herbst. No. Maybe you misheard me. This all goes
centrally. In fact, the whole beauty of this is we are
profiling at 500 different places with the same technique where
it all goes through a central database. And that is the beauty
of it. The point I was trying to make is we have very broad
consent on these patients all very carefully through the IRB so
that we are both putting patients on the drugs that we know now
may or may not work. We are also able to discover new targets
so the next four or five drugs that will come into the Lung-MAP
we will be able to be more informed in what we choose.
Mr. Khosla. So just to clarify, what I was referring to was
the preparatory to research phase so before the patient's
actually been enrolled in the study to search the electronic
health record, identify patients at a site, that information,
before that patient has signed a consent form, can't leave that
site.
Mr. Cassidy. That is OK. I used to do clinical research,
and I had 10 patients who I knew were interested in a trial. We
knew from looking at their study. It is just that they had not
had the formal testing. I don't see that as an impediment so
much, and I forget if we did this. If it is illegal, I didn't
do. But nonetheless, I would say listen, I have 10 patients
whom I think we can enroll as soon as we start. There would be
some sort of signal, knowing that it didn't guarantee, but it
suggested it might happen. Is that an impediment?
Mr. Khosla. It is an impediment to the extent what when you
have these national clinical trials networks, it is sort of an
ongoing process to recruit both a site investigator and the
study participants. And so if you know up front where the
patients are, then you can seek out individual investigators at
those sites. So in that sense, it is an impediment.
Mr. Cassidy. I yield back. Thank you for your generosity.
Mr. Pitts. Chair thanks the gentleman. I now recognize the
gentleman from Virginia, Mr. Griffith, for 5 minutes for
questioning.
Mr. Griffith. Thank you, Mr. Chairman. I appreciate that. I
am going to pick up on that real quick. There is a company out
of Richmond that I have been real excited about. It is not in
my district, but it is close enough. It is the The Health
Diagnostic Laboratories, and what they do is do all the stuff
on your blood looking mainly at heart disease and diabetes. I
am sure they can add to their form a consent in advance,
because what they are doing is tracking biomarkers and giving
counseling to the people they have done the blood work on,
obviously with the oversight of the physician. But they are
giving counseling and trying to help folks avoid heart disease
and diabetes, and a lot of times those biomarkers are
overlapping.
And just seems to me that that might be a good place.
Because they have got folks all over the country that they Fed
Ex in their blood samples to and they--I call it they ``Henry
Forded'' blood lab work. And it is really exciting stuff. And
it just seems to me that might be something you all can look at
and find a way, particularly if they get consent from their
patients in advance, you might be able to track some of the
biomarkers that you are looking for or some of the other things
that you all are looking for that you then can get rid of that
impediment that you were talking about by having a whole slew
of folks automatically identified who may have already given
advance consent at least to be contacted.
Ms. Stafford. I was going to say, I think the operative
word is ``consent.'' And as several of us have discussed, it is
a matter of designing your consent up front that allows you
that capability. And, you know, for instance, we have a tool, a
technology, MediGuard.org where we have about almost 3 million
patients that we have data, we have a relationship with. But we
consent them, with them to participate in real world research
with us, et cetera.
So I think it is about the consenting and what you put in
that up front.
Mr. Griffith. Absolutely. I would never want anybody's
information being shared without their consent.
What do you find in your getting the consent up front? What
do you find? It was about 5 or 10 percent that say they don't
want their data being passed along?
Ms. Stafford. I don't have the metric. But it is
interesting how many people want to be in the conversation. How
many people are members of different, you know, groups like the
ADA, American Diabetes Association or multiple sclerosis, and
where they find their communities and how interested they are
in research opportunities.
And so our database is really, you know, do you want us to
communicate with you? Because they are all very interested in
being part of research.
Mr. Griffith. And you all mentioned it earlier in your
testimony today that, you know, the technology and things are
moving so much faster than it used to move, and it is exciting
and really has great opportunities.
I want to switch gears a little bit, although it does
connect. You know, I think about these issues of developing new
treatments. And I have to tell you, I align with the mindset of
those who support right-to-try laws that are being passed in
the States. And I have introduced similar bills, two such
similar bills here for patients whose doctors have exhausted
current medical options, have been told that the end of life is
nearing. My feeling is, why should the Federal Government
interfere if the patient wishes to spend their own money on
experimental treatment plans? I have this saying, if I'm dying
anyway, why do I need to be protected by the FDA? Because death
is near. And all treatment options have been tried.
That being said, I think the issue of benefit/risk
framework should be brought forward in the earlier stages of a
study of a new treatment by allowing an informed and
responsible access to medications after the establishment of
safety could allow for a faster translation of the science and
technology from lab to clinic while insuring safety benefiting
patients, and at the same time, leveraging our Nation's
leadership and investment to advance science and technology.
One of the bills I have introduced, the Patient Choice Act,
does this by creating a provisional approval process after drug
safety has been established to allow patients to have access to
new treatment while the efficacy is still being tested. This is
similar to how things are moving in Europe.
I think this makes sense. I think it makes sense to empower
a patient, as we have been talking about today, particularly
faced with the dilemma of a terminal disease, to help move the
ball down the field in the area of medical science and medical
knowledge about fighting to save their own life with
experimental drugs if they choose to do so. And even if they
fail, the satisfaction of knowing that they may have helped
save someone else's life.
So then the question comes, because I know that a number of
you, particularly Dr. Meyer, are generally opposed to this kind
of a concept. But when you are faced with the subset of that
terminal patient, and their doctors have indicated that the
current medical options have been exhausted, how do you tell
that person that they can't spend their own money to try
something that may not work but that might hold some promise?
Dr. Meyer.
Mr. Meyer. So I would actually like to address that very
point. Because actually from my experience at the FDA, it is
usually not the regulators who are standing in the way of that.
It is actually more often the companies. And there are a couple
of considerations around that. Often they cannot charge, and
going through the mechanisms to charge are very arduous. And
they have to prove what their investments have been.
The other thing is that it ends up dirtying their data, if
you will. So you mentioned the patient maybe having an
altruistic view of even if I don't benefit, maybe others will.
But unless they are in a trial of some sort and their data
collected in a rigorous fashion, they may not, in fact,
contribute meaningful data to the evaluation.
So I very much am sympathetic to that view that those
patients who have no other options, and there is a promising
drug out there, should get access to it. But I think it really
requires a thoughtful look at the ecosystem around that, if you
will. And, you know, what is the problem, what is the fix.
Mr. Griffith. Mr. Chairman, I know my time is up. I know
Mr. Murray wants to respond as well. But I have to yield back
at this point.
Mr. Pitts. Go ahead, Mr. Murray.
Mr. Murray. Thank you. I just would say patient choice we
believe is an important aspect, and also the consideration for
devices in that discussion. And to the extent that there are
methods and methodologies to streamline how a patient may pay
for a procedure, because that is a difficult aspect in this,
especially if it is in a clinical trial, and how adverse data
might be considered if it is not in a controlled environment.
Mr. Pitts. Chair thanks the gentleman.
Now recognizes the gentlelady, Mrs. Ellmers, from North
Carolina, 5 minutes for questioning.
Mrs. Ellmers. Thank you, Mr. Chairman. And thank you to our
panel.
Ms. Stafford, I have the great honor and opportunity to be
representing North Carolina and, certainly, your operation and
organization there, the world headquarters right there in
Durham. And I just have a couple questions for you. Again,
obviously, our goal is to try to make the system work more
efficiently so that we can get these very important drugs to
market in a much quicker, efficient manner that is safe for all
of our constituents.
My understanding, as we have learned about the clinical
trial path that the sponsors who are collecting the data, they
have to collect so many end points--I mean, dozens of end
points--to demonstrate that the drug is safe and that it works.
My question to you: In your opinion, how much data do we need,
and are we collecting too much data? Is the data we are
collecting truly efficient, or are we collecting so much data
that it is just over in abundance? And can we find a process to
narrow that down if that is the case?
Ms. Stafford. Thank you for your question. And of course, I
am wearing my North Carolina blue, just to say.
Mrs. Ellmers. Yes.
Ms. Stafford. Anyway, it is a very good question. And
actually, I am a statistician by training. And I have seen in
my almost 30 years in this industry now, we collect too much
data. There is too much collected. And a lot of that comes from
the multiple voices at the table.
And I do think that having the conversation up front, and I
think the FDA wants to work with us on this with the industry.
But there are a lot of key opinion leaders in the design of the
trials, which includes many academic centers and scientists who
have different opinions. And they want to prove that the drug
is efficacious and safe, but they also want to explore what
don't we know about the drug, what extra information can we get
that is beyond really the investigation of that product.
Mrs. Ellmers. Again, what I think you are saying here is,
what we need to do is narrow the scope so that we can come up
with the information. And certainly more information is great,
and that can be used in many ways after the fact. But I agree.
So would you say that up front, straightforward, more
transparency and focus on the actual goals that are trying not
to be put forward initially?
Ms. Stafford. Most panel members here talked about the
trial design. And I think it all comes into the design and
trying to focus the design. And, as you say, the scope and
focus that scope and not enter into too much interesting
extraneous data which end up taking time to collect the data.
Once you have that data, what do you do with it?
Mrs. Ellmers. Then you have to do something with it.
Ms. Stafford. It is just very costly, so trying to focus
the scope of the trial design is my recommendation.
Mrs. Ellmers. Very good. You know, there again, what we are
faced with, or--we are seeing more of the trend toward global
clinical trials. And, here for our committee, we are looking at
ways that--we want to show incentives so that some of those
clinical trials can be here and kept in the United States.
Can you make one or two suggestions on how we can achieve
that goal so that we are doing more of those clinical trials or
we are kind of returning back to a process where we are doing
them here in the United States?
Ms. Stafford. I think we are having that discussion today
in terms of ensuring that the U.S. is at the forefront of
innovation around clinical trials. And that as long as we are
the leader today in clinical research, we need to maintain that
by being innovative and by modernizing the clinical trial and
by being in a position to stay that leader. You know, drug
development is no longer a one country, one continent, or one
region. But we can certainly ensure that we keep our heritage
as the clinical research leader by continuing this innovation
discussion.
Mrs. Ellmers. Thank you. And I saw some other nodding
heads. Dr. Herbst, would you like to comment?
Mr. Herbst. Yes, I would agree. You know, I am a medical
oncologist. Many of us who work in cancer have very busy
clinics. There is limited infrastructure. You know, flat or
declining public money. We are bringing some of the private
money in. But really anything we can do to streamline the
process, you know, the burden on the staff. You ask a few more
questions, that means a coordinator or a nurse has to spend
some time. You know, fewer, you know, rooms available. We want
to put more patients on trial. Putting 5 percent of patients in
this country on clinical trial is way too low. We have to do
20, 30, actually everyone should go on a trial in these
incurable diseases, and to do that we really need as efficient
as possible.
Mrs. Ellmers. And, Dr. Khosla, do you agree with that?
Mr. Khosla. Yes.
Mrs. Ellmers. Thank you.
Thank you, Mr. Chairman.
Mr. Pitts. Mr. Murray, you wanted to add something?
Ms. Murray. I would just state briefly for medical devices,
the just-in-case perspective of what is going to be required at
panel for breakthrough devices and not knowing up front what a
panel might ask. So bringing that part of the process forward
would be very helpful. And also allowing for more flexibility
in the early discovery. So when a new device comes out, you
learn something in allowing for adaptive trial designs that
incorporate and don't necessarily poison the data for the
overall trial.
Mrs. Ellmers. Thank you very much, Mr. Chairman, for
extending my time a little bit there.
Mr. Pitts. Chair thanks the gentlelady.
Now recognize the gentleman from Florida, Mr. Bilirakis, 5
minutes for questions.
Mr. Bilirakis. Thank you, Mr. Chairman. I appreciate it.
I want to thank the panel for their testimony today as
well. And I appreciate you holding the hearing, Mr. Chairman.
So very important.
Dr. Herbst, I am impressed with your multi-stakeholder
partnership that resulted in the Lung-MAP program. Lung cancer
has a 5-year survival rate of less than 20 percent. The work
that NCI-designated cancer centers do is tremendous, as far as
I am concerned. In the Tampa area, we have the Moffitt Cancer
Center, as you know, which is the only NCI-designated cancer
center in Florida. They have a partnership which has resulted
in the Oncology Research Information Exchange Network, ORIEN.
In my understanding, it is the world's largest clinically
annotated cancer tissue repositories and data for more than
100,000 patients who have consented to the donation for
research.
In your testimony--this is my question--in your testimony,
you mention the importance of partnerships to accelerate
clinical trials as well as the need to examine the incentives
structure and process to facilitate data generation, sharing,
and collaboration. Could you briefly elaborate on this and how
this should be done, please. Can you elaborate?
Mr. Herbst. Right. And I do compliment Tampa on their work.
They were one of the leaders initially in doing this
personalized medicine network and bringing it together. And we
are basically doing the same thing. The Lung-MAP is really, it
is a truly national effort. And, as I mentioned, it came from
an NCI panel and from work at the Friends-Brookings meeting.
And the thing that is very nice about it is, we are working
closely with the FDA, with the foundation for the NIH, and
others. We really want to really bring these drugs and this
testing throughout the Nation to the community. So the idea
basically is to pick and do profiling in one specific way at
all the different centers. Within 10 days. You know, because
patients can't wait, they have advanced disease. You are right.
This is even worse than what you mentioned because this is
squamous cell lung cancer, mostly a smoker's lung cancer, where
there really are no other therapies to offer these patients.
The most advanced, widespread disease.
And then we are randomizing patients to either the standard
of care or to one of these new drugs based on the molecular
profile. And we have five different drugs. So the way this has
worked has really been a good concept, something that the
academic community, the clinician community around the country,
and the drug companies and the private payers see as a very
important way to move forward. And we have all worked together.
And it has taken a large amount of collaboration, meetings. It
really is a partnership. And I sit here now, but there are
hundreds of people who have been involved in this process. And
I am very proud of how we have all worked together. And we are
doing it for the patients.
And the other thing that is very important is advocacy
community has been involved with us from the very beginning.
And they have advised us on some of the issues regarding
disclosure and forms and consent forms. And we have really
worked--this is really focused on the patient and bringing more
drugs to patients quicker.
And I just want to add, the FDA has been so supportive of
this process. Of course, these trials all have to go through
the standard phase II, phase III criteria. In fact, they are
very strict criteria. But we have had advice as we move along:
How do you integrate the markets into the trial? So I would say
this is something that has to be emulated. And other diseases
are already working on this. There is a trial in colon cancer
that is moving forward, breast cancer, and others as well.
Mr. Bilirakis. Terrific. Very encouraging. Thank you,
Doctor.
Dr. Siegel, you raised the issue of providing greater voice
for patients in clinical trials. You mentioned that the
investigators only use objective outcome measures--the
investigators, but not information from patients like, how did
they feel, how are they progressing? How could investigators
and regulators use qualitative data when making decisions?
Mr. Siegel. Well, thank you for that question. I think it
is an important one. It is easier, I think, and that is
probably why there is a history of using things that can
objectively be measured in the lab or life or death. But beyond
what the exception of life or death, usually what is most
important is how a patient feels.
There is a science behind how to do that. If you are not
careful about how you do that, you can introduce a lot of bias,
you can use tools that mis-weigh and that don't really
represent patient outcomes.
So that has been part of the reluctance to--or maybe the
slowness in incorporating patient-reported outcomes. With that
said, I think we are at a place where they can and should be
incorporated much more broadly in almost all areas of clinical
research.
Mr. Bilirakis. Thank you very much. Another question for
you, Dr. Siegel. Can you explain in laymen's terms what
adaptive clinical trials are, how they are different from
traditional clinical trials, how has FDA viewed adaptive
trials? I believe they have released guidance just a few years
ago. And have adaptive trials been used in Europe? And what
lessons can be learned from Europe?
I am not sure if that has been covered, because I had to
step out. But if you could elaborate, I appreciate it.
Mr. Siegel. Not in any depth.
So more traditional trials, you design the trial and how
you are going to conduct it and how you are going to analyze it
up front. And then at the end, you unblind the data and you do
your analyses.
That offers the advantage of avoiding a lot of biases that
can lead to inaccurate assessments of treatment effects.
In adaptive trial designs, you learn as you move on. You
use biomarkers or actual outcomes in patients, if they are
available fast enough, to understand what are the more
promising therapies, perhaps, maybe putting more patients onto
those therapies, changing randomization, substituting changing
or selecting among doses. Or even select changing entry
criteria. You could change almost any part of a trial.
A lot of scientific work has gone into how to utilize
adaptive trials, because if done wrong, there are opportunities
to introduce bias. But they allow real-time learning from what
is happening within a trial. Therefore, they can be extremely
powerful tools in drug development.
The FDA has been out in a leadership position in terms of
providing guidance as to how they could be used in the
regulatory setting. There is, of course, some conservatism
because of the scientific challenge.
But it is an opportunity to accelerate our ability as you
have heard about from Dr. Herbst, to accelerate our ability to
learn within clinical trials. And I think it is one that is
very much underutilized.
Mr. Bilirakis. Very good. Thank you.
I yield back, Mr. Chairman.
Mr. Pitts. Chair thanks the gentleman.
That concludes the first round of questioning.
This has been another exciting, informative, important
hearing. A lot of members have follow-up questions. So we will
send those to you within 10 business days.
I remind members they have 10 business days to submit
questions for the record. I ask the witnesses to please respond
to questions promptly. Members should submit their questions by
the close of business on Wednesday, July 23rd.
Without objection, subcommittee is adjourned.
[Whereupon, at 12:18 p.m., the subcommittee was adjourned.]
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