[House Hearing, 113 Congress]
[From the U.S. Government Publishing Office]






            21ST CENTURY CURES: MODERNIZING CLINICAL TRIALS

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

                                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
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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

                              ----------                              
                                                                   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

                              ----------                              


                        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:]
    
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    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:]
    
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    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:]

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    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:]
   
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    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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