[Senate Hearing 114-717]
[From the U.S. Government Publishing Office]


                                                        S. Hrg. 114-717

        NOMINATION OF ROBERT CALIFF TO SERVE AS FDA COMMISSIONER

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

                                HEARING

                                 OF THE

                    COMMITTEE ON HEALTH, EDUCATION,
                          LABOR, AND PENSIONS

                          UNITED STATES SENATE

                    ONE HUNDRED FOURTEENTH CONGRESS

                             FIRST SESSION

                                   ON

        NOMINATION OF ROBERT CALIFF TO SERVE AS FDA COMMISSIONER

                               __________

                           NOVEMBER 17, 2015

                               __________

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                                Pensions
                                
                                
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          COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS

                  LAMAR ALEXANDER, Tennessee, Chairman


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


               David P. Cleary, Republican Staff Director

                  Evan Schatz, Minority Staff Director

              John Righter, Minority Deputy Staff Director

                                  (ii)

                            C O N T E N T S

                               __________

                               STATEMENTS

                       TUESDAY, NOVEMBER 17, 2015

                                                                   Page

                           Committee Members

Alexander, Hon. Lamar, Chairman, Health, Education, Labor, and 
  Pensions Committee, opening statement..........................     1
Murray, Hon. Patty, a U.S. Senator from the State of Washington..     3
Burr, Hon. Richard, a U.S. Senator from the State of North 
  Carolina.......................................................     5
Scott, Hon. Tim, a U.S. Senator from the State of South Carolina.     6
Whitehouse, Hon. Sheldon, a U.S. Senator from the State of Rhode 
  Island.........................................................    16
Isakson, Hon. Johnny, a U.S. Senator from the State of Georgia...    18
Warren, Hon. Elizabeth, a U.S. Senator from the State of 
  Massachusetts..................................................    20
  Prepared statement.............................................    22
Roberts, Hon. Pat, a U.S. Senator from the State of Kansas.......    23
Baldwin, Hon. Tammy, a U.S. Senator from the State of Wisconsin..    25
Cassidy, Hon. Bill, a U.S. Senator from the State of Louisiana...    27
Franken, Hon. Al, a U.S. Senator from the State of Minnesota.....    28
Hatch, Hon. Orrin G., a U.S. Senator from the State of Utah......    30
Bennet, Hon. Michael F., a U.S. Senator from the State of 
  Colorado.......................................................    32
Sanders, Hon. Bernard, a U.S. Senator from the State of Vermont..    33
Murkowski, Hon. Lisa, a U.S. Senator from the State of Alaska....    35
Casey, Hon. Robert P., Jr., a U.S. Senator from the State of 
  Pennsylvania...................................................    37

                                Witness

Califf, Robert M., M.D., Deputy Commissioner for Medical Products 
  and Tobacco, Department of Health and Human Services, Durham, 
  NC.............................................................     7
    Prepared statement...........................................     9

                          ADDITIONAL MATERIAL

Statements, articles, publications, letters, etc.:
    Response by Robert M. Califf, M.D. to questions of:
        Senator Alexander........................................    42
        Senator Enzi.............................................    50
        Senator Burr.............................................    50
        Senator Isakson..........................................    53
        Senator Isakson and Senator Murkowski....................    56
        Senator Isakson and Senator Murphy.......................    56
        Senator Collins..........................................    57
        Senator Hatch............................................    61
        Senator Roberts..........................................    64
        Senator Cassidy..........................................    68
        Senator Murray...........................................    71
        Senator Sanders..........................................    82
        Senator Casey............................................    86
        Senator Bennet...........................................    90
        Senator Baldwin..........................................    94
        Senator Murphy...........................................    96
        Senator Warren...........................................    99
    Comprehensive Clinical Trials Conducted by Dr. Califf........   112
    Drug price comparisons in the United States and Canada.......   117

                                 (iii)

  

 
        NOMINATION OF ROBERT CALIFF TO SERVE AS FDA COMMISSIONER

                              ----------                              


                       TUESDAY, NOVEMBER 17, 2015

                                       U.S. Senate,
       Committee on Health, Education, Labor, and Pensions,
                                                    Washington, DC.
    The committee met, pursuant to notice, at 10:05 a.m., in 
room SD-430, Dirksen Senate Office Building, Hon. Lamar 
Alexander, chairman of the committee, presiding.
    Present: Senators Alexander, Burr, Isakson, Collins, 
Murkowski, Kirk, Scott, Hatch, Roberts, Cassidy, Murray, 
Mikulski, Sanders, Casey, Franken, Bennet, Whitehouse, Baldwin, 
Murphy, and Warren.

                 Opening Statement of Senator Alexander

    The Chairman. The HELP Committee will come to order. Today 
we're reviewing the nomination of Dr. Robert Califf to serve as 
Commissioner of Food and Drugs.
    Dr. Califf, welcome. Congratulations on your nomination. 
Welcome to you and to your family members. We're glad they have 
been able to come up, some of them from Columbia, SC, and I 
enjoyed having the opportunity to meet with you in my office.
    If you're confirmed to lead the Food and Drug 
Administration as its Commissioner, you will be in charge of 
steering the agency responsible for the safety and 
effectiveness of our Nation's medical products and protecting 
our country's food supply. This is a huge job.
    The FDA affects nearly every single American almost every 
day and regulates about a quarter of all of our consumer 
spending in the United States, over $4 trillion annually. It is 
responsible for product areas as diverse as prescription drugs 
for humans and animals, medical devices, biologics, cosmetics, 
over-the-counter medications, food, and tobacco.
    It's a vital mission, and we all want to make sure that the 
right person is leading it. The President has nominated you to 
do that job, and like every full-time nominee, you've been 
through an exhaustive process to make sure that you don't have 
any conflicts of interest or other problems in your background.
    If you'll permit me, I had the privilege of coming before 
this committee about 24 or 25 years ago and sitting in the 
chair where you sit. It's not always a pleasant experience. One 
of the Democratic Senators said to me, ``Governor''--my family 
was sitting where yours is--said to me, ``Governor Alexander, 
I've heard some very disturbing things about you, but I don't 
think I'll bring them up this morning,'' and Senator Kassebaum 
leaned over and said, ``Well, Howard, I think you just did.'' 
And then he held me up for 3 months.
    I don't expect that would be happening with you, because 
like every full-time nominee, you've been through an exhaustive 
process to make sure of the conflicts of interest, as I said. 
Before the President announced your nomination, there was an 
extensive vetting process by the White House and the FBI.
    You submitted paperwork to the Office of Government 
Ethics--that's been carefully reviewed--including your 
financial information. They found several recusals, which you 
have committed to do, so there wouldn't be any remaining 
conflicts of interest that would prevent you from doing your 
job, in the opinion of the Office of Government Ethics. The 
form you submitted is public. It includes every source of 
income over $200 and every asset worth more than $1,000 and 
every potential conflict that the Office of Government Ethics 
determined would require a recusal.
    I'm going through this so people will know that nominees 
such as yourself do this. You've answered 37 pages of questions 
from our committee, including some confidential questions on 
financial information. You've responded to written followup 
questions. Your responses included over 3,000 pages of articles 
and lectures that my staff reviewed and that any member of the 
committee may review.
    You were nominated on September 17. Our committee staff has 
spent 2 months carefully reviewing everything you submitted, 
and my staff tells me that they haven't found anything that 
would call into doubt your ability to lead the FDA fairly and 
impartially.
    You come here with impressive qualifications; a leading 
cardiologist, professor at one of the Nation's top medical 
schools. You are an expert on clinical research and you've been 
recognized as an author of medical publications. You've had 
some experience managing large organizations, and you've been 
the founding director of Duke's Clinical Research Institute. 
I'm sure Senator Burr will go into some detail about your 
background when he has a chance to introduce you in a few 
minutes.
    You've conducted scores of important clinical trials. 
That's important to me, because it helps to have people in 
government who actually know what they're talking about because 
of the experience that they've had before. You understand how 
research gets done in the real world.
    I'm eager to hear your priorities about how you intend to 
manage such a large and diverse organization. I'd like to hear 
what you'll be able to do to ensure that affordable drugs are 
available to American patients. I hope you'll agree that drugs 
are--that your job is to see that drugs are safe and effective, 
but the FDA can help market lower drug prices by approving 
generic drugs and other products as quickly as it possibly can 
so there's more choice and competition in the market.
    Approval times have gotten worse instead of better. I'll be 
asking you about that and what you intend to do about it. 
Second, there has never been a more exciting time to lead the 
agency. We know more about biology and medicine than ever 
before, and that's not likely to stop anytime soon given the 
advancement of regenerative cell therapies, 3D printing, and 
the President's Precision Medicine Initiative.
    Your job, if confirmed, will be to make sure that the FDA 
regulation is appropriate. Too much regulation could reduce 
investments. Too little could make it difficult for drugs to be 
safe and effective. There is much work to be done. Sometimes it 
takes a decade to develop a drug. Sometimes it takes billions 
of dollars, literally.
    In this committee, we're working together in a bipartisan 
way to help get safe cutting-edge drugs, medical devices, and 
treatments into American medicine cabinets and doctors' offices 
more quickly, and we hope to move that soon. We're looking 
forward to hearing what you believe needs to be done to build 
the FDA's capacity and to fix the impact of its regulations so 
that the FDA is a partner in innovation and not a barrier.
    I thank you, and I look forward to hearing your testimony 
on these important issues.
    Senator Murray.

                  Opening Statement of Senator Murray

    Senator Murray. Thank you very much, Mr. Chairman, and 
thank you to all of our colleagues for being here today.
    Dr. Califf, thanks to you and your multigenerational family 
that is here with you today. I want to express my appreciation 
to all of you for accepting this nomination and continuing to 
offer your expertise--or offer your spouse or dad--in service 
of families and communities nationwide.
    As the Chairman said, the FDA Commissioner has a critical 
role to play in supporting health and well-being in our 
country. Whether you're in a grocery store or the medicine 
cabinet or the emergency room, families depend on the FDA to 
maintain the highest standards of product safety.
    As we talk about the future of the FDA and the many health 
challenges our country faces, it is important to note that 
valuable efforts have been made in recent years to strengthen 
the FDA and improve its services for patients and families.
    Last year, the FDA approved 51 new drugs and biologics, its 
highest number in almost 20 years. The agency consistently 
approves drugs more quickly than advanced regulatory agencies 
in other countries, while maintaining the high standards of 
safety and effectiveness. The FDA has also made strides toward 
implementing the Food Safety Modernization Act, helping to 
bring our Nation's food safety system into the 21st century.
    Despite these gains, the FDA faces significant challenges 
moving forward. There are several areas, in particular, where I 
hope to see continued progress. As someone who has seen 
personally the challenges that patients and families face due 
to chronic illness, I am very interested in making sure we are 
encouraging development of safe, effective treatments and cures 
for our most challenging unmet medical needs.
    So-called super bugs are another growing threat and an 
issue Chairman Alexander and I are working on closely. As we 
have seen in my State and across the country, where medical 
devices known as duodenoscopes have been linked to tragic 
outbreaks of antibiotic-resistant infections, we have got to 
find ways to prevent these infections and respond more quickly 
and effectively when any risk arises.
    Especially as technology continues to evolve, we need to do 
more to make sure that after products reach the market, the FDA 
has the effective tools it needs to monitor their safety, 
taking full advantage of information technology.
    We need to ensure that FDA continues to strengthen its 
generic drug and biosimilar programs. I also believe there is 
much more we can do to bring patients' voices into the process 
of developing new treatments and cures and ensure their 
priorities are consistently reflected in the FDA's work.
    In addition, our country faces urgent public health 
challenges that deserve our attention. To name a few, we need 
to move forward on making sure families have access to 
nutritional information and ensuring our food supply is both 
safe and healthy. We need to put all of the agency's tools to 
work to stop tobacco companies from targeting our children. We 
must do more to tackle widespread illnesses, such as heart 
disease and diabetes, that threaten so many people in our 
country.
    Like so many of my colleagues here today, I have heard time 
and again from families that the cost of prescription drugs is 
a significant financial burden. I believe the next FDA 
Commissioner has an important role to play in ensuring all 
patients and families have access to the prescription drugs 
they need.
    Another critical priority is ensuring the FDA always puts 
science over politics. As some here will remember, several of 
my colleagues and I fought long and hard to ensure that medical 
expertise, not ideology, governed decisionmaking on the sale of 
Plan B over the counter. Women and families have to be able to 
trust the FDA not to play politics with their health.
    As Congress and the administration work together to address 
these and many other health challenges in which the FDA plays a 
significant role, we need to recognize that our efforts will 
not be successful without additional support for the FDA. We 
must make sure the FDA has the resources and authority it needs 
to hire top experts in a highly competitive field and manage 
its growing workload as it navigates our increasingly global 
supply chain.
    Many of these are issues that our committee is currently 
debating as we negotiate bipartisan legislation to advance 
medical innovation for patients and families. After careful 
consideration and review, I am confident that Dr. Califf would 
contribute leadership and expertise as we work to find new ways 
to advance medical innovation for patients and families and 
improve health and well-being across the country. He is a 
strong nominee for the FDA Commissioner.
    Dr. Califf has an impressive history of leadership and 
management experience, in particular, at Duke. He would bring 
to this new role a record of advancing medical breakthroughs on 
challenging illnesses through clinical trials. Our review of 
his record demonstrates a longstanding commitment to 
transparency in relationships with industry and to working to 
ensure academic integrity.
    Dr. Califf has made clear he will continue to uphold these 
values and prioritize a strong, independent FDA as 
Commissioner.
    I have approached this nomination focused on the best 
interests of families and communities in Washington State and 
across the country and in making sure the FDA puts them first 
in all its work, from drug and device approvals to ensuring 
that a child's peanut butter sandwich is safe to eat.
    As we work toward these goals, I believe Dr. Califf would 
be a valuable partner. I encourage my colleagues to join me in 
supporting his nomination, and I look forward to working with 
all of you to strengthen health and well-being for the families 
and communities that we serve.
    Thank you, Mr. Chairman.
    The Chairman. Thank you, Senator Murray.
    Senator Burr will introduce Dr. Califf.

                       Statement of Senator Burr

    Senator Burr. Mr. Chairman, thank you, and thank you to my 
colleagues.
    Dr. Califf, welcome. Thank you for sharing your family with 
us. Your parents are here. Your bride is here. Your children 
are here, and your granddaughter is here.
    Welcome, Brooke. Hope you get an extra credit at school for 
being here.
    Dr. Robert Califf is a North Carolinian whose career has 
been distinguished by his unwavering commitment to patients as 
a respected clinician, researcher, and advisor. I'm 
particularly pleased to have the opportunity to introduce him 
here today. Dr. Califf has been nominated to serve as the next 
Commissioner of the Food and Drug Administration, and my 
colleagues and I look forward to hearing from you today.
    Dr. Califf is currently serving as the Deputy Commissioner 
of Medical Products and Tobacco for the FDA since February of 
this year. In this role, he's responsible for overseeing and 
directing the Centers for Drug Evaluation and Research, the 
Centers for Biologics Evaluation and Research, the Centers for 
Devices and Radiological Health, the Centers for Tobacco 
Products, the Office of Special Medical Programs within the 
agency.
    Prior to his work at the FDA, Dr. Califf was a professor of 
medicine and vice chancellor for clinical and translational 
research at Duke University in Durham, NC. During his time at 
Duke, Dr. Califf held a number of positions, including the 
director of Translational Medicine Institute, the director of 
the Clinical Research Institute. He worked to move the 
promising field of translational science forward as the 
director of Clinical Trials Transformation Initiative.
    Dr. Califf is distinguished as a researcher and an author 
with over 1,200 peer-reviewed publications in biomedical 
science. He's a graduate of Duke University School of Medicine. 
He received his residency training in primary care at the 
University of California San Francisco and completed a 
residency in cardiology at Duke University.
    Dr. Califf is a great father, a great husband, a great 
granddad, and is a great doctor. I'll say to my colleagues he's 
a great man, and that stands out the most in his 
qualifications.
    How well the FDA fulfills its mission touches the lives of 
Americans each and every day, from the lifesaving treatments 
patients receive to the safety of the food we feed our 
families. The challenges facing the next Commissioner are 
great, but also the opportunities are as well.
    Dr. Califf, congratulations on your nomination to serve as 
Commissioner of the Food and Drug Administration.
    I urge my colleagues to thoroughly get your questions 
answered and expeditiously move this nomination so a permanent 
Commissioner of the FDA can get to work on some very serious 
problems within our system.
    I thank the Chair. I welcome Dr. Califf.
    The Chairman. Thank you, Senator Burr.
    Senator Scott has a point of clarification.

                       Statement of Senator Scott

    Senator Scott. Thank you, Chairman Alexander. Senator Burr 
referred to Dr. Califf as if he were from North Carolina. The 
fact of the matter, sir, is that while he could not get into 
the Medical University of South Carolina, he had to go to Duke. 
He's actually from South Carolina.
    [Laughter.]
    Understanding the generational responsibilities of 
southerners, you realize that his parents were also from South 
Carolina. Therefore, we know he's a southerner.
    He's from South Carolina. The North is a Yankee called 
North Carolina. I just wanted to make sure that that point was 
made clear, that you didn't insult his parents on the front row 
who are from Saint George, SC, which is in the low country.
    Thank you very much.
    Senator Burr. I welcome his parents and congratulate them 
on his ability to outperform the requirements for South 
Carolina education.
    [Laughter.]
    Senator Mikulski. Mr. Chairman.
    The Chairman. OK.
    Senator Mikulski. Mr. Chairman.
    The Chairman. Senator Mikulski.
    Senator Mikulski. While those guys are still doing border 
wars, I want to also just welcome Dr. Califf, because FDA is in 
my State. He'd be eminently qualified and look forward to 
supporting his nomination proceeding.
    I'm glad you're the son of South Carolina who lived in 
North Carolina, but you're our guy, too.
    I ask unanimous consent that my statement be in the record.
    The Chairman. It will be.
    [The prepared statement of Senator Mikulski was not 
available at time of press.]
    The Chairman. Dr. Califf, you can see the interest the 
committee has in the work you're about to do. Virtually every 
member is here. Each will have 5 minutes to have a conversation 
with you. I'll try to give you time to answer the questions. We 
want to stick pretty closely to the 5-minutes so everyone can 
be involved.
    As I mentioned earlier, you've answered a number of 
questions to the committee staff, and if any Senator has 
additional questions, there'll be a few days after the hearing 
that they can ask them, and we hope you'll respond promptly to 
them. We'll begin a round of questions 5 minutes in length.
    Dr. Califf, around the country and here in Congress, people 
are talking about the high cost of pharmaceutical drugs and 
what can be done to make those drugs affordable. Do you--oh, 
excuse me. I got so excited I didn't give you a chance to make 
your comments.
    [Laughter.]
    Dr. Califf. I've been well-instructed, Senator, not to 
interrupt you.
    [Laughter.]
    The Chairman. Dr. Califf, we look forward to your comments.

 STATEMENT OF ROBERT M. CALIFF, M.D., DEPUTY COMMISSIONER FOR 
 MEDICAL PRODUCTS AND TOBACCO, DEPARTMENT OF HEALTH AND HUMAN 
                      SERVICES, DURHAM, NC

    Dr. Califf. Mr. Chairman and Ranking Member Murray and also 
Senator Burr and Senator Mikulski, thank you for your kind 
comments. I want to thank you and the members of the committee 
for inviting me here today to discuss my nomination to be 
Commissioner of the Food and Drug Administration.
    I'm honored to be accompanied by my family today, as you've 
noted. Sitting behind me are my dad, a World War II veteran--
and we're going to visit the monument later this afternoon--my 
mom, an activist-teacher and a 7-year survivor of multiple 
myeloma; and my wife of 42 years and high school sweetheart, 
Lydia. My three children and my granddaughter, Brooke, are also 
here with us. The support of my family and their feedback have 
been essential to my career success and sustaining my moral 
compass.
    I'm honored to have been nominated by President Obama to 
lead the FDA. Thank you for all of your willingness to share 
with me your perspectives on ways the agency can better serve 
the American people. My primary goals, if confirmed, will be to 
work with you to build on the excellent workforce, relentlessly 
focus on the completion of priority projects, and continue to 
develop the science base that we need to give consumers 
confidence that their food and medical products are safe and 
give patients and clinicians an accurate understanding of the 
benefits and risks of medical products.
    Amid ongoing revolutions in biological science and 
information technology, we must continue to strengthen the 
FDA's vital work, protecting Americans while encouraging 
innovations that hold promise. If confirmed, it would be an 
honor to lead this outstanding workforce in this remarkable 
time.
    I've dedicated my career to advancing the public health as 
a physician, leader, teacher, and researcher. Like each of you, 
my understanding of our health system was shaped by more than 
just my professional life. Our daughter was born with serious 
congenital heart disease, requiring open heart surgery as an 
infant.
    I still vividly remember the inspirational work of her 
doctors, nurses, and healthcare team and the uncertainties of 
that experience, including the discovery that one of our 
daughter's cardiologists had faked his medical credentials. We 
experienced firsthand as a family how important it is to find a 
critical balance between innovation and safeguarding patients.
    When I started in cardiology, heart attack was the leading 
cause of death in America, and our understanding of it was 
limited. It was agonizing that one of six patients that I saw 
in our intensive care unit with a heart attack died during the 
first hospitalization. The intensely personal experience 
dealing with catastrophic illness and personally witnessing the 
death of many people drove us to relentlessly invent and 
develop effective treatments.
    I had the privilege to serve as a leader of global networks 
of doctors and nurses, researchers, computer scientists, and 
statisticians who joined forces to develop and evaluate clot-
busting drugs and lifesaving technologies, including stents and 
defibrillators, that have helped millions of Americans. These 
efforts have cut the risk of death from heart disease by more 
than half and highlight for me the importance of bringing these 
advances to patients as fast as safely possible.
    Indeed, it's not enough to develop new treatments. We must 
prove they are safe and effective and deploy them in a 
systematic way that reaches all Americans and eventually the 
global population. Our initial quality registries for bypass 
surgery, angioplasty, and heart attack have become global 
standards, including adoption by CMS as quality measures, to 
improve the public health by advancing evidence-based therapies 
and reducing medical errors.
    A successful FDA is a critical factor for better public 
health in this changing world. The FDA must be prepared to set 
policies that channel innovative technologies for safe and 
effective use. Also, I firmly believe that the best way to make 
this progress is for different sectors in today's healthcare 
ecosystem to collaborate.
    I've led efforts to help academic researchers collaborate 
with industry in a documented and transparent manner that 
retain their independence and primary role in caring for 
patients. More recently, I've had the pleasure of jointly 
leading a number of projects with patients, consumers, and 
community leaders, I believe, to the great benefit of research 
and public health.
    My first priority as Commissioner would be to strengthen 
and better support FDA's talented and dedicated workforce. 
While FDA scientists make decisions every single day about 
hundreds of products, as technology advances, these decisions 
are becoming more complex. It's essential that we keep pace.
    My next priority as Commissioner is working with you to 
fulfill the ambitious agenda that we set together. The Food 
Safety Modernization Act, for example, will help assure 
Americans their food is safe. The Deeming Rule for tobacco 
products will help us continue to reduce tobacco-related 
deaths. And, of course, the user fee programs are entering a 
period of renegotiation.
    My third and final priority among the leading ones as 
Commissioner would be to further develop the science base that 
informs FDA's decisionmaking--my real professional love. By 
taking advantage of extraordinary advances in biomedicine and 
information sciences, we can build the right infrastructure 
that will unlock greater amounts of useful evidence about food, 
tobacco, and medical products at a dramatically lower cost.
    Finally, we can't forget that health and disease fail to 
recognize national boundaries. In concert with our global 
colleagues, we must continue to develop sophisticated systems 
for monitoring the safety and quality of products produced 
outside our borders.
    The FDA is poised to leverage the acceleration in 
biomedical knowledge to a new era of enhanced safety and 
effective treatments. If confirmed, I would be honored to lead 
the agency in this exciting time.
    Thank you for allowing me to testify before you today, and 
I'm happy to take your questions.
    [The prepared statement of Dr. Califf follows:]
              Prepared Statement of Robert M. Califf, M.D.
                              introduction
    Mr. Chairman and Ranking Member Murray, I want to thank you and 
members of the committee for inviting me here today to discuss my 
nomination to be Commissioner of Food and Drugs in the office of the 
Food and Drug Administration (FDA). I'm honored to be accompanied by 
family today. Sitting behind me are my dad, a WWII Veteran, my mom, a 
7-year survivor of multiple myeloma and my wife of 42 years and high 
school sweetheart, Lydia. My three children and my granddaughter Brooke 
are also with us. The support of my family and their feedback have been 
essential to my career success and moral compass.
    I am honored to have been nominated by President Obama to lead the 
FDA. Thank you all for your willingness to share with me your 
perspectives on ways the FDA can better serve the American people. My 
primary goals, if confirmed, would be to work with you to build on the 
excellent workforce, relentlessly focus on the completion of priority 
projects, and continue to develop the science base needed to give 
consumers and patients even more confidence that their food is safe and 
their medical products are safe and effective. I also believe that we 
need to continue to improve our efforts to give patients and clinicians 
an accurate understanding of the benefits and risks of medical 
products.
    My service as Deputy Commissioner for Medical Products and Tobacco 
has underscored for me both the opportunity and the gravity of this 
undertaking. Amid ongoing revolutions in biological science and 
information technology, we must continue to strengthen the FDA's vital 
work in protecting the American people while encouraging innovations 
that hold promise to improve their health. If confirmed, it would be an 
honor to lead this outstanding workforce in this remarkable time.
                               background
    My career has been dedicated to advancing the public health as a 
physician, leader, and researcher. But, like each of you, my 
understanding of our health system was shaped by more than just my 
professional life. Our first daughter was born with a serious 
congenital heart defect requiring open heart surgery as an infant. I 
still vividly remember the inspirational work of her doctors and the 
uncertainties of that experience--including the shocking discovery that 
one of our daughter's cardiologists was an imposter with faked medical 
credentials. My family has experienced firsthand how important it is to 
find a critical balance between innovative treatments and appropriate 
safeguards for patients. The American people need access to cutting 
edge treatments, but also must be able to trust the information they 
are given about that treatment.
    As a medical student, I worked with one of the first computerized 
medical databases and witnessed the potential for computer technology 
to inform decisions about health and healthcare. When I started in 
cardiology, heart attack was the leading cause of death in the United 
States and our understanding of the cause of this leading cause of 
death in America was limited. It was agonizing that one of six patients 
with a heart attack died during their first hospitalization. This 
intensely personal experience of dealing with a catastrophic illness 
and its consequences on victims of the disease and their families drove 
us to be relentless about inventing and developing effective 
treatments. Together with a global network of doctors and nurses, and 
with an extraordinary team of researchers, computer scientists, and 
statisticians, I had the privilege to serve as a leader on efforts to 
develop ``clot busting'' drugs that restore blood flow to the heart, 
improve the recovery of the heart muscle and help prevent future heart 
attacks. We also worked together to develop and evaluate life-saving 
technologies, including balloon angioplasty, cardiovascular stents, and 
implantable defibrillators, that have helped millions of Americans. 
These efforts have decreased the risk of death from heart disease by 
more than half. This condition that was once a death sentence is now 
treatable thanks to drugs and medical products, highlighting for me the 
importance of bringing these advances to patients as fast as safely 
possible. Much of my work has been at the intersection of public health 
and research, including large-scale efforts to improve our national 
clinical trial research infrastructure and innovative community-based 
projects undertaken in close collaboration with underserved patients 
and their communities.
    Indeed, it is not enough to develop new treatments. We must prove 
they are safe and effective, and deploy them in a systematic way that 
reaches all Americans, and eventually the global population. Our 
initial quality registries for bypass surgery, angioplasty and heart 
attack have become global standards, including adoption of derivatives 
of our quality measures by CMS, to improve the public health by 
advancing evidence-based therapies and reducing medical errors.
                            leading the fda
    A successful FDA is a critical factor for better public health in 
this changing world. We are currently witnessing a revolution in 
biomedical science and information technology that empowers consumers 
to make choices about their health and health care. Today our food 
safety system is undergoing the most comprehensive update since it was 
established and we are working to ensure that medications prescribed to 
animals do not reduce their effectiveness in humans. Against this 
backdrop of revolutionary change, the FDA must be prepared to set 
policies that channel these innovative technologies for safe and 
effective use--protecting the public while approving products with 
clear benefit.
    I firmly believe that the best way to make this progress is for 
different sectors in today's health care ecosystem to collaborate. I 
led efforts at Duke University Medical Center to help academic 
researchers collaborate with industry in a documented and transparent 
manner that retained their independence and primary role in caring for 
patients. Similarly, the United States, and indeed the entire world, 
depends on a strong, unbiased FDA that can work with industry to 
advance critical technologies while still making independent 
determinations to ensure that scientific potential is translated into 
safe and effective products. To advance, we must find common ground 
with industry and academia on the science without compromising this 
fundamental role of the FDA.
    More recently, I have had the pleasure of jointly leading multiple 
projects along with patients, consumers and community leaders, to the 
great benefit of research and public health. The emergence of consumers 
and patients as active participants in the process of developing 
therapies and devising protocols for evaluation is an important theme 
to improve the relevance of our work to the people we serve.
The Importance of the Workforce and Infrastructure
    My first priority as Commissioner would be to strengthen and better 
support FDA's talented and dedicated workforce. However, the products 
we evaluate are increasingly complex. Sustaining the quality of FDA's 
scientific workforce may be more important than any particular policy 
because it is our day-to-day decisionmaking that protects the public 
without impeding technological progress. FDA scientists are making 
decisions every single day about hundreds of products--but as 
technology advances these decisions become more complex. Americans must 
be able to depend on a strong FDA workforce that keeps up with the 
rapidly changing world.
Completion of Critical Priorities
    My next priority as Commissioner would be to carry our critical 
priorities over the finish line. With your guidance, the FDA has 
embarked on an ambitious agenda to keep pace with our changing society. 
The Food Safety Modernization Act will enhance our ability to assure 
Americans of the safety of the food supply. The Deeming Rule for 
tobacco products will be the basis for continuing our success in 
reducing tobacco-related deaths. Several high priority initiatives are 
underway, including the Combating Antibiotic Resistant Bacteria (CARB) 
initiative, medical counter measurement development, and the Precision 
Medicine Initiative to name a few. And, of course, the user fee 
programs that have been so successful in providing resources for review 
of medical products are entering a period of renegotiation.
Focusing on the Science Base
    My third priority as Commissioner would be to further develop the 
science base that informs FDA's decisionmaking across drugs, devices, 
food safety, and more. If we build the right infrastructure, FDA can 
realize the potential of revolutionary advances in biological and 
information sciences that will unlock greater amounts of useful 
evidence about food, tobacco and medical products at dramatically lower 
cost.
    We must also take advantage of the astounding opportunity afforded 
by the fact that the majority of Americans have an electronic health 
record and smart phones. The groundbreaking Sentinel system 
demonstrates the power of evidence to inform FDA's decisionmaking and 
act quickly on safety issues and we have a similar plan for medical 
device surveillance. I am committed to the development of a national 
system for surveillance and evidence generation that will improve 
patient safety and provide a much more efficient way to understand the 
benefits and risks of medical products when used in practice.
    In addition, the proliferation of the Internet allows many 
patients, advocates, and caregivers to be reached directly, both to 
impart information and to solicit their perspectives and experiences. I 
am greatly encouraged to see that FDA expects industry to involve 
patients directly in the process of technology development and 
assessment, but recognize that we are just beginning to understand the 
science of consumer engagement. Further, as ever-growing amounts of 
information become available to consumers about the benefits and risks 
of medical products, we must ensure that it is high-quality 
information.
    Finally, we cannot forget that while the FDA has the well-being of 
Americans as its mission, we are operating in a global environment. 
Because health and disease do not recognize national boundaries, the 
FDA must be in constant communication with the global scientific and 
regulatory communities. We should continue to develop sophisticated and 
robust information systems for monitoring the safety and quality of 
medical products and food produced outside of our borders in concert 
with our global colleagues.
                                summary
    The FDA is poised to leverage the acceleration in biomedical 
knowledge to lead to a new era of enhanced safety and effective 
therapies, and, if confirmed, I would be honored to lead the Agency in 
this exciting time. Thank you for allowing me to testify before you 
today and I am happy to take your questions.

    The Chairman. Thank you, Dr. Califf. We'll now begin a 5-
minute round.
    Dr. Califf, around the country and in Congress, there's 
lots of talk about the high cost of pharmaceutical drugs. Do 
you believe, in terms of drugs, that it's accurate to say that 
the FDA's statutory mission is to promptly and efficiently make 
sure that drugs are safe and effective?
    Dr. Califf. Senator Alexander, that is our primary mission. 
We also can have an impact on the cost of drugs by performing 
that function effectively.
    The Chairman. Let me talk about that just a little bit. Do 
you agree that it's not your job to set the price of drugs?
    Dr. Califf. It is not our job to set the price of drugs.
    The Chairman. Let's talk about generic treatments. If 
generic treatments can move more rapidly through the FDA 
process in a safe and effective way, that would be one way to 
create more competition and presumably lower the cost of drugs. 
Despite getting about a billion dollars in new funds over the 
last 3 years, generic manufacturers estimate that the FDA's 
median approval time for generic drugs has gone from 30 months 
in 2011 to 48 months in 2014.
    Is that accurate, based on your knowledge? Or can you 
explain how the FDA, with the availability of a billion new 
dollars, could have actually presided over a situation where 
the approval of generic drugs has gone from 30 months in 2011 
to 48 months in 2014, especially since a more rapid approval, 
if safe and effective, might have had some effect of lowering 
drug prices?
    Dr. Califf. Senator Alexander, bear with me. I appreciate 
the question. Bear with me for just a second while I explain 
this. First of all, as you point out, 88 percent of American 
prescriptions now are generic. We have made tremendous 
progress. But we can do even better.
    You also know that we're well ahead of the generic drug 
User Fee Act goals that were set. We can still do better, and 
I'm all in favor of that.
    Explaining the backlog is really important, and here's the 
way to think about it. We started with a huge backlog, 
thousands of applications that were waiting until the user fees 
came in. The easy ones, the ones that were good, were well-
written, went through quickly. The new ones, the ones that are 
pertinent to getting the first generic on the market are put in 
what we call a fast lane, and they're going through quickly.
    We have this backlog of applications that are requiring 
back-and-forth, because we want generic drugs to be just as 
safe and effective as the innovator drugs. When the 
applications are not complete, or there are questions about 
manufacturing, those get held up. I'm confident you'll see over 
the next several years as that backlog is cleared that new 
applications are going through very quickly.
    The Chairman. Thank you, Dr. Califf. This question will 
require just a short answer. Will you take a look, if you're 
confirmed, at the FDA's policy of issuing non-guidance 
documents instead of rulemaking?
    I've talked with Shaun Donovan, Director of the Budget, and 
the administration OMB had some pretty strong policies and firm 
views on the difference between rulemaking, which involves 
consultation and is legally binding, and guidances, which are 
not legally binding. Will you take a look at that? Because 
there is a bipartisan concern that agencies of the Federal 
Government, including FDA, are issuing guidances as if they 
were legally binding.
    Dr. Califf. Senator, I will commit to working with you on 
that and taking a careful look at it.
    The Chairman. I'd like, in my remaining time, to ask you to 
comment on a management issue at FDA. We hear that even when 
products are similar, experiences of applicants varies quite a 
bit. Regulated parties ought to be treated in consistent and 
predictable ways. Why do you think that even with similar 
products, the experience of some applicants is so different, 
and what could you do to make sure that regulated parties are 
treated in consistent and predictable ways?
    Dr. Califf. Senator Alexander, I appreciate the question. 
Having spent several decades on the other side of the fence, 
working on new therapies, I can appreciate people's concerns. 
The primary reason is really that each individual medical 
product is different. The clinical trials that need to be done, 
even if they're similar, can have nuances that are critical.
    Still, we are committed at the FDA, and Dr. Woodcock, who 
you know well--I'm working very closely with her, and we're 
going to do everything we can to produce a more even template 
across the FDA so that the standards are the same. I wouldn't 
want anyone to come away thinking you can take a cookie cutter 
and develop a drug or a device. You've got to treat each one 
differently.
    The Chairman. Thank you, Dr. Califf.
    Senator Murray.
    Senator Murray. Thank you, Mr. Chairman.
    Dr. Califf, in contrast to some of our previous FDA 
nominees who have come from the public health sector, you are a 
physician and a researcher with a specialty in large clinical 
trials. As a result, throughout your career, you have partnered 
extensively with pharmaceutical and other industry companies, 
and I want to just ask you some questions about that.
    During your past clinical trial and consulting work you've 
done, how have you ensured industry views have not biased your 
work, and what do you plan to do to ensure you are able to lead 
the FDA without any undue influence?
    Dr. Califf. Thank you, Senator Murray. It's important to 
really divide this into two parts. The clinical trials we do--
that were done at Duke during my tenure and are still being 
done there--if funded by industry--remembering that many of our 
clinical trials are funded by foundations, and we're one of the 
largest NIH grantees, also--but when funded by industry, we 
have an ironclad contract, which I believe your staff has a 
copy of, that guarantees the independent right to publish, 
guarantees access to the database, and in the majority of 
cases, we actually have the database. We are running the trial, 
and we publish the papers with input from the companies, but 
they have absolutely no right to change what we say. We have 
the final right of publication.
    These trials are also done, usually, with international 
steering committees representing many countries, providing an 
independent voice that's really needed. So, yes, industry funds 
the trial, so they need to have their products evaluated. We 
have an independent voice, guaranteed by contract. I believe 
you'll find that 100 percent of the studies that I've been 
involved in have been published so that they're in the public 
record for people to view.
    Senator Murray. What do you see as the appropriate role of 
industry in working with the agency on key challenges like 
trials and the surveillance?
    Dr. Califf. It's critical here to separate the role of 
industry for individual applications versus what we call the 
precompetitive space. That is, what are the right methods--how 
do we understand, for example, how to streamline the clinical 
trial process? How do we share information as medical products 
are rolled out to the public to make sure we understand the 
risks that may only be seen in the post-market phase.
    In the individual applications, there is no role for 
industry other than to present its case, that it has a product 
that meets the criteria for safety and effectiveness, and it's 
the FDA's role to independently judge that application. The 
American public completely depends on having confidence that 
the FDA is independent in those reviews and judgments about 
individual products.
    In that precompetitive space, we've got to work together. 
Industry funds 70 percent of clinical research, for example, 
globally. NIH is a minority funder. I'm pleased to say we're 
working closely with the NIH right now, and we'll bring 
industry in into what will be a dramatically lower cost but 
much more effective clinical research system.
    Senator Murray. I very much appreciate that. I do want to 
turn to an issue that I've raised a number of times this year. 
We know that patients across the country, including in my home 
State in Seattle, got serious antibiotic-resistant infections 
from duodenoscopes. As I have investigated this issue further, 
it seems to me that we need to make significant improvements in 
how FDA monitors medical devices on the market to identify 
safety issues more quickly and prevent the tragedies that we 
have seen with this.
    What steps would you take to improve the post-market 
surveillance system for devices and better protect patients?
    Dr. Califf. Thank you for bringing that up. First, let me 
just say as a cardiologist and someone with administrative 
responsibilities at Duke Hospital, when ERCP, the procedure 
you're referring to, was first developed, it was in the United 
Kingdom, and those doctors came over to Duke and we were one of 
the first places to do it. I have firsthand experience on the 
importance of that procedure, typically in people who are 
critically ill.
    We need to really work on our post-market surveillance in 
devices, and I really hope that you'll help us with this. The 
Sentinel system that you all have helped with--industry has, 
too--but really developed by the FDA by Janet Woodcock, with 
Jeff Shuren's help, by the way, from devices--is a model in 
drugs. We have 170 million Americans' claims data, so that when 
there's a problem with a drug, we can look almost in real time.
    We need the same system on the device side. We have plans 
to do that. We're going to have to work together with you to 
figure out how to fund it and how to fold it in with that 
Sentinel system. Imagine these duodenoscopes--if there had been 
such a system, we would have seen the problem very early. 
Industry could contribute to that, but we could see it 
independently of industry and act on it much more rapidly.
    Senator Murray. I very much appreciate that. This is 
something I'm very concerned about as we move forward, so I 
appreciate your response and look forward to talking with you 
more about that.
    Thank you, Mr. Chairman.
    Dr. Califf. Thank you.
    The Chairman. Thank you, Senator Murray.
    The next four Senators are Burr, Whitehouse, Isakson, and 
Warren.
    Senator Burr.
    Senator Burr. Thank you, Mr. Chairman.
    Dr. Califf, the animal rule was finalized on October 27 of 
this year after a significant and, in my opinion, inexcusable 
delay, given the importance of the rule. I'm pleased that the 
rule has been finalized, as it will provide more certainty for 
those working to develop medical countermeasures to protect 
American people in the event of a public health emergency, 
whether it's natural or the result of a man-made attack on our 
country.
    If confirmed, how would medical countermeasures be 
prioritized within the agency, and how would you ensure that 
the FDA is advancing the development and review of these 
products toward the goal of a timely approval?
    Dr. Califf. Senator Burr, thank you for that question, and 
I'm amazed at the attention and intensity you all have today, 
given the fact that we're all worried about the issue that 
you're bringing up. It can be either man-made or something 
that's totally unanticipated, for example, with an infection.
    We're committed to working on this. I was pleased to be 
able to get the guidance out for the animal rule, which you had 
requested. It's going to take a concerted effort, not just by 
the FDA. As happened with the Ebola crisis, which we've all 
just witnessed, when the Federal agencies work together, a lot 
can be done to quell a crisis and deal with things.
    I do want to refer to the really brilliant work that's been 
done in the outside community, academia, industry, but also 
within the FDA. For those not thinking about it, the animal 
rule basically says in cases where we can't do human studies, 
but there's an emergency, what's a way in which we can 
extrapolate from animal studies to the benefit of humans in 
these catastrophic situations? We're committed. We're going to 
be there 24 by 7 if needed.
    Senator Burr. Thank you for getting that rule out. There 
have been reports that the Tobacco Deeming Rule did not change 
the grandfather date for newly regulated tobacco products. This 
means that many non-combustible tobacco products, which may 
have a public health benefit compared to the more traditional 
forms of tobacco, would not be available to consumers for at 
least some period of time, despite their potential benefits 
compared to a more traditional tobacco product.
    As Commissioner, how would you improve the performance of 
the FDA's Center for Tobacco Products with respect to the 
timely and predictable review of tobacco products?
    Dr. Califf. Senator Burr, this was a new creation just a 
few years ago, and it started with zero employees. It's now up 
in the multi-hundreds. There were no rules by which the tobacco 
applications could come in, so those have had to be developed.
    First of all, let me just say that you bring up a general 
issue of weighing the overall health risk of tobacco products, 
where they're graded from most serious to less serious. There 
is a pathway for doing that. We're committed to reviewing them 
in the timeframes that have been agreed to, and we have funding 
to carry out that activity. We're committed to get it done.
    Senator Burr. I thank you for that commitment. I often hear 
from constituents in North Carolina about the importance of 
laboratory-developed tests. For researchers, it means the next 
step in creating precise therapies. For providers, LDTs help to 
determine accurate diagnosis and the means for more targeted 
treatments and therapies on behalf of patients.
    As someone who has been on the front lines of research and 
treating patients, under your leadership, how would the agency 
collaborate with labs, other existing government structures 
such as CLIA, and the full range of stakeholders in this space 
to ensure that regulation of laboratory-developed tests is 
carried out in a workable way that moves these promising tests 
forward without inappropriate regulatory burdens or delays for 
patients and their practitioners?
    Dr. Califf. As an academician for over 30 years, I'm well 
aware of the importance of laboratory-developed tests. It's 
sort of the place where homebrews are made to make the tests 
better iteratively over time. It's an important activity. On 
the other hand, this has become a big industry with major 
implications for patients, especially with precision medicine, 
where you have a test, and it tells you what therapy to give. 
That can be either really good or really bad, depending on 
whether it's right.
    We're committed to work with the whole ecosystem, which is 
quite complicated, so that there is a standard for tests, so 
they'll have analytical validity and also clinical validity. As 
you may know, there's a hearing going on in the House right now 
about this issue that involves Jeff Shuren from FDA and also 
Pat Conway from CMS. There'll be a lot more to say soon about 
this.
    Senator Burr. Thank you.
    Mr. Chairman, I do have additional questions and would ask 
unanimous consent that those questions be allowed to be sent in 
writing to Dr. Califf.
    I would conclude by saying this--not a question. The FDA 
has over 150 outstanding guidance documents in limbo at the 
agency. Some of these guidances remain in draft form, and 
others have yet to be issued. My hope is that you will take 
that very seriously, because without guidance, I don't know how 
the downstream effects are ever going to be felt of investment 
and development if, in fact, they don't have the guidance as to 
how to move forward.
    I thank the Chair.
    The Chairman. Thank you, Senator Burr.
    Senator Whitehouse.

                    Statement of Senator Whitehouse

    Senator Whitehouse. Dr. Califf, good morning. Welcome.
    Dr. Califf. Good morning.
    Senator Whitehouse. There are increasingly products 
emerging on the market that combine a pharmaceutical component, 
a drug, and a delivery component, a device. The FDA is 
basically broken into one path for pharmaceuticals, the drug 
path, and another path for devices.
    I've spoken to the people who lead both the drug side and 
the device side about this question of the drug-device combined 
products, and both have said the same thing, which is that ``My 
pathway is not suitable for that. If we're going to do that, we 
need to create a new pathway for that drug-device 
combination.'' Could you let me know what your thoughts are 
about that pathway for the drug-device combination products, 
and what you think a reasonable timeframe would be for FDA to 
have such a proposal ready for us to consider?
    Dr. Califf. As a cardiologist, I sort of live and breathe 
this kind of work, because often we give lifesaving drugs 
systemically in acute situations. It would stand to reason in 
many cases if you could deliver them through a catheter, you 
could give them a much lower dose and do better. Maybe that's 
the best example to think about here.
    When you have a drug that's given in full dose 
systemically, and you can give it at a lower dose, you don't 
want to go through the whole thing as if it were a totally new 
dose. You can't assume that you know the risks and benefits of 
the lower dose. There's a strong view at the FDA that we need 
another pathway that will give the FDA the flexibility to 
require the data that's needed to assure the public that the 
proposed treatment is safe and effective.
    Senator Whitehouse. Do you agree that we need that other 
pathway? You said that was the opinion at the FDA. Is that your 
opinion as well?
    Dr. Califf. Yes, but----
    Senator Whitehouse. What is the timeframe for designing 
that pathway and giving us something to look at here in 
Congress?
    Dr. Califf. I feel like within the next year, the FDA's 
opinion can be adjudicated back and forth with you, and we're 
really happy to work with you. We have opinions on this now, so 
we're happy to engage and discuss with you.
    Senator Whitehouse. Great, because there is probably going 
to be legislative action that's going to be required to do 
this. Both of your sides of the house think that it can't be 
done under the existing regulatory authority, that it would 
require Congress to act. Do you agree with that?
    Dr. Califf. We need some help to get the right balance 
here.
    Senator Whitehouse. Great. The last thing that I'll mention 
is I hope that as you go forward with your responsibilities in 
the space of apps and communications technology that are 
adapted to measuring health effects that you'll recognize that, 
in many respects, this is a very valuable and robust industry 
that could well be over-regulated if the FDA's authority over 
those sorts of devices extended too far. What do you see as the 
boundary between informational apps that the FDA should and 
should not regulate?
    Dr. Califf. I had the privilege of going back to my old 
home, an American Heart Association meeting, just last week, 
and we had a whole session on this issue. I won't show the 
brand, but I'm wearing my own device here that has a number of 
apps on it that's like a whole different world than what 
existed 6 months ago.
    There's a good statement, the trilateral statement just 
last year that came out from FDA, the FCC, and the Office of 
the National Coordinator that states the full intention to 
regulate based on risk. Exactly where to draw that boundary is 
a matter that we need to keep talking and thinking about.
    For example, clearly stated in that document, a health-
related app--we're monitoring my heart rate, and I'm healthy 
and I want to exercise more. That's not something that we want 
to be bothering with. If this was attached to my internal 
defibrillator--don't worry, I don't have one--but if I did have 
one, that would be something we would need to regulate, because 
misfiring the defibrillator could kill you.
    We've got to be able to deal with that spectrum and find 
that middle ground, where there will be adjudication as we 
learn how these things work.
    Senator Whitehouse. You'd be looking along the lines of 
regulating technologies that could actually have a direct 
physical effect on the human body, as opposed to just getting 
information that causes you to think that, ``Oh, gosh, my 
heart's better, so I'm not going to run as much.'' You need to 
regulate that because the individual is making a different 
decision based on the information.
    Dr. Califf. That's correct. Also, I would just like to add 
that we're going to learn as we go through this, because there 
may be cases where, for example, heart failure patients using 
the same app may be making more life and death decisions. What 
we don't want to do is suppress innovation.
    Senator Whitehouse. My time has expired, and I don't want 
to take--there's so many of us, and I don't want to trespass on 
other people's time. I thank the doctor, and my appreciation to 
the Chairman.
    The Chairman. Thank you. That's very courteous, Senator 
Whitehouse.
    Senator Isakson.

                      Statement of Senator Isakson

    Senator Isakson. Dr. Califf, following up on Senator 
Alexander's first statement regarding guidance letters, FDA has 
two opportunities. One is to issue guidance letters. The other 
is to do rulemaking. While there are similarities, there are 
substantial differences. Under rulemaking, you have to do a 
cost-benefit analysis. Rulemaking has the force and effect of 
law, and guidance letters do not.
    Yet FDA continues over and over again to try and implement 
policy through guidance letters. For example, and most 
recently, through a guidance letter, you're going to talk about 
regulating laboratories and bring them under the FDA. Guidance 
letters, again, don't have the rulemaking period or the comment 
period to be open. FDA continues to try and regulate parties 
more often through guidance letters than through rulemaking, 
which shuts out the open comment period and has confusing 
effects.
    I have really two questions to ask. No. 1, why has FDA 
grown so reliant on non-binding guidance documents for 
rulemaking? No. 2, Do you think that's a problem?
    Dr. Califf. Senator Isakson, I appreciate your concern with 
this, and one thing that's been really evident to me in my time 
at the FDA so far is that everybody wants to know what the FDA 
is thinking. There's a tremendous value in guidance documents 
to let people know what the FDA is thinking, and the demand for 
these is actually quite high.
    There are other situations where you need the full force of 
rulemaking. I understand there is a difference. I will have to 
work with you--and I look forward to doing it--when things come 
up where you're concerned so that we can discuss it and work 
through it.
    Senator Isakson. Specifically, to that offer, let me ask 
you the following question. Will you commit to require FDA 
staff to go through rulemaking when it intends to legally bind 
regulated parties or change their behavior in a burdensome way?
    Dr. Califf. Senator, I believe the statement about guidance 
documents says they're not legally binding. They're a statement 
about FDA's thinking, and, of course, people would be wise when 
they see a guidance to consider that thinking. Personally, in 
developing drugs with companies, I've often taken a different 
path from the FDA. I'm certainly committed to work with you to 
try to deal with this tension that you're feeling.
    Senator Isakson. Thinking is a subjective thing. Rulemaking 
is a objective thing. When you talk about the cost of 
compliance with things, you ought to have the rulemaking 
procedure, in my judgment, rather than just a guidance letter 
which could affect some and not others.
    Second, on sunscreen, November 26 is the first anniversary 
of the Sunscreen Innovation Act that this committee passed and 
President Obama signed, which was designed to expedite the 
approval of ingredients in sunscreen. As you probably know, 
there are sunscreens that have been available in Europe for 
years and, in some cases, decades that are still not available 
in the United States because FDA has refused to make decisions 
on some of those ingredients. It's been a year since we passed 
the expedited rule and, still, FDA hasn't done it.
    Will you commit to work with us to try and bring those 
ingredients forward and do the proper due diligence to get 
those products to the market?
    Dr. Califf. Senator Isakson, I really do look forward to 
working with you on this. As we discussed earlier, I have a 
family history of melanoma myself and a number of moles that 
probably should be looked at more frequently than they are. 
With Lydia sitting behind me, she would remind me of that.
    Let me also say that part of what we need to work on is 
actually developing the evidence. We've asked the companies 
involved for specific information, which I believe they can 
develop, and we're very open to moving as quickly as we can if 
we have the right evidence.
    I would just point to what's happened with people who have 
melanoma with these amazing new therapies, several of which 
have just come on the market, because the patients with 
melanoma have worked closely with the companies to get the 
clinical trials done so the effective treatments get expedited 
and the ineffective ones don't get out there.
    Preventing melanoma is in the same category. We've got to 
do better. It's a rapidly growing cause of death, and I really 
do want to work with you personally on this issue.
    Senator Isakson. At certain stages, a diagnosis is a death 
sentence for which there is no cure, and I think you know that. 
I've had melanoma myself and survived two of them, fortunately. 
Next March or April is spring break, and the kids are going to 
hit the beaches of America and, hopefully, a lot of Georgia's 
beaches, getting a lot of sun and having a lot of fun. I hope 
they'll also have the best sunscreen ingredients available to 
try and prevent melanoma from being developed.
    My last comment--I'll make it quickly because it's a long 
question, and I know my time will be up. The FDA has sent mixed 
signals to pregnant women with regard to seafood. I know you 
all were in the process of using some determination on seafood 
to make recommendations as to what was good to be eaten and not 
eaten, and you were using results from what was called your Net 
Effects Report. That seems to be abandoned now.
    If you would, when you take over and are confirmed, will 
you expedite the decisionmaking process on seafood for pregnant 
women and the recommendations the FDA makes?
    Dr. Califf. Yes, sir. I look forward to working on that.
    Senator Isakson. Thank you, Mr. Chairman.
    The Chairman. Thank you, Senator Isakson.
    Senator Warren.

                      Statement of Senator Warren

    Senator Warren. Thank you, Mr. Chairman.
    Dr. Califf, it's no secret that during your time at Duke 
University, you received significant financial support from the 
pharmaceutical industry, both for you, personally, and for your 
research. I know this is common practice for principal 
investigators of clinical trials, but it naturally raises 
questions about your relationship with the drug industry. One 
particular concern with industry funding of academic work is 
that drug companies may be able to exert influence over the 
conduct of those studies.
    Let me ask: For the clinical trials you conducted or 
oversaw while at Duke, can you detail for us exactly what input 
pharmaceutical sponsors had, did and did not have, in the 
design of the trials, the analysis of the data, and the 
publication of the results?
    Dr. Califf. I'm glad to do so. When industry funds a 
clinical trial, whether it's devices or drugs, done through our 
institute, the design of the trial is something that's done 
jointly and done very publicly, because, typically, it's done 
to try to get an indication from the FDA.
    It actually involves industry, academia, now patients 
involved in the design of the trial, and the FDA. It's a very 
public process. The protocol is developed, and it has to be 
submitted both to IRBs but also to the FDA before the trial 
starts. The design is something that is done jointly. The final 
say comes from the steering committee, of course, which is the 
academic leadership.
    The database is really the critical factor here, and all of 
our contracts require that we either have access to the 
database or we actually have the database onsite. That's been 
ironclad. I would say 70 percent of the studies I wanted to do, 
we couldn't do, because the company was unwilling to grant that 
right. We had to walk away, if that was not done.
    That leads to publications. Publications are in the purview 
of the steering committee and the authors from the steering 
committee. Industry has a right to make suggestions, but no 
right to censor and no right to change any of the writing 
that's done unless it's agreed to by the authors.
    The same holds for our public presentations, which, in the 
fields that I work in, are very important because evidence 
moves very quickly and it has a large input. Keeping that 
academic independence, we think, is a critical part of the 
effort.
    Senator Warren. Good. If I can, I just want to underline 
this because it is so important. I want to make sure I got this 
right from your question. I hear you to be saying there is no 
instance during your career or any instance involving Duke 
researchers at the Duke Clinical Research Institute during the 
time that you were supervising in which a pharmaceutical 
company provided any input into the analysis or the publication 
of the clinical trial that they paid to conduct. Is that right?
    Dr. Califf. Let me clarify one more time. By input, they 
could make suggestions. That's perfectly allowable in our 
contract----
    Senator Warren. On the analysis and on the publication?
    Dr. Califf. On the publication. On the analysis, this is 
another--I'm sorry to get into details here.
    Senator Warren. That's all right.
    Dr. Califf. The way we do our analyses--because the company 
has to submit the data to the FDA--is, typically, we'll have an 
analysis done by the company, an analysis done by our 
statisticians. Then we compare the results to see if they match 
up and resolve any discrepancies. In no case did we allow the 
company to do the analysis, and we just were recipients of what 
they said the answer was.
    Senator Warren. All right. I'll tell you what I'll do on 
this, just because I know we're pressed on time. I'll followup 
with questions for the record on this so that we can get a 
detailed written account of any such instances.
    I've also requested copies of the contracts that the 
pharmaceutical industry sponsors signed with the Duke Clinical 
Research Institute in order to get a better understanding of 
what's happening here. I look forward to reviewing them before 
this committee moves forward with your nomination.
    These agreements typically spell out in detail the 
relationship between the researchers and the funders. It will 
help us better understand what's happening here.
    In the little bit of time I have left, can I just make one 
other point? That is your financial relationship with the 
industry also raises questions about what your priorities will 
be if you're confirmed for this job. Many in the pharmaceutical 
and device industry spend a lot of time and money arguing that 
the FDA is just too tough, that we should lower the FDA 
standards on safety and effectiveness, and, unfortunately, they 
have a lot of friends in Congress.
    Dr. Califf, do you agree with these arguments and recent 
efforts by some lawmakers to lower the standards for FDA 
approval of drugs and devices?
    Dr. Califf. If you look at my record, you'll find I've 
never been a proponent of lowering standards. If anything, I've 
argued for raising standards with better studies that show the 
full gamut of risk and benefit for the time that a treatment 
might be used. That doesn't mean we couldn't potentially be 
quicker or something else, but in no case would we argue to 
lower the standards.
    Americans depend on safe drugs and devices that are also 
effective. A device or a drug that's safe and is not effective 
actually can harm someone because then they don't use what is 
effective. I've been staunch in that regard.
    Senator Warren. Thank you, Dr. Califf. We could abolish the 
FDA tomorrow and we'd see a lot of new products on the market. 
If they're not safe and effective, then no one is any better 
off.
    Thank you, Mr. Chairman.
    [The prepared statement of Senator Warren follows.]

                  Prepared Statement of Senator Warren

    The position of FDA Commissioner is critical for the 
protection of the public's health and safety and for the 
advancement of science and innovation. Since Dr. Califf 's 
nomination for this position, I have carefully reviewed a 
significant volume of information, including many of his 
published articles and work published under his direction, as 
well as confidential contracts between the Duke Clinical 
Research Institute and pharmaceutical companies governing the 
conduct of major clinical trials in which Dr. Califf has 
participated. In addition, I asked Dr. Califf detailed 
questions about his work, both in person at his HELP Committee 
nomination hearing and through subsequent written questions for 
the record. I have also had multiple meetings with Dr. Califf 
to discuss his background, his qualifications, and his plans 
for the agency should he be confirmed by the Senate, and I've 
had extensive conversations with him about concerns that have 
been raised about his professional relationship with the drug 
and medical device industries. Finally, I have consulted with 
several outside experts in these matters to better understand 
the materials I have been provided by Dr. Califf. All of this 
investigation was aimed at better understanding the focus and 
relative independence of his past work as it gives clues to his 
willingness, if he is confirmed as head of the FDA, to put the 
interests of the public first.
    After carefully examining Dr. Califf 's record and looking 
closely at his representations both to me and to the committee 
generally, I am satisfied that he has conducted himself with 
integrity as an academic researcher. For example, the language 
in the confidential contracts I have reviewed is consistent 
with what independent experts described to me as best practices 
designed to limit the influence of industry sponsors over 
academic investigators. Dr. Califf also indicated to me that 
there are no major trials in which he has participated that 
were not published, and he noted that he has repeatedly 
published negative trial results about products under 
development by the corporate sponsors that funded those trials. 
Dr. Califf also submitted a comprehensive list of the trials in 
which he played a major role. This list details the 
intervention under investigation in each trial and whether the 
trial resulted in the sponsor's preferred outcome. My staff 
conducted an independent analysis of the trials presented in 
this list, and in some instances disagreed with Dr. Califf 's 
conclusions about whether trial results clearly strengthened or 
undermined the position of a corporate sponsor. Even so, after 
re-classifying some of the studies, the totality of the data 
indicate that Dr. Califf has consistently published the results 
of his research, regardless of whether it ultimately bolstered 
the interests of that work's sponsor.
    My examination of the Califf nomination has raised serious 
questions about our current clinical trials system. I am 
particularly concerned with a lack of overall transparency, 
numerous opportunities for conflicts of interest, and a marked 
shortage of trials that are designed to determine which 
products to treat a given condition are the most effective--as 
well as cost-effective--for various patient populations. My 
examination has also raised concerns about the FDA's 
willingness to stand up to industry preferences in the design 
and conduct of clinical trials. Dr. Califf has indicated his 
clear and unequivocal commitment to work hard to address these 
policy issues as Commissioner.
    Dr. Califf and I have also discussed in some detail his 
views regarding other important policies at the FDA, including 
efforts to move the FDA's blood donation deferral policies to 
risk-based policies for all blood donors. We have also 
discussed the importance of reducing antibiotic use in animal 
agriculture to protect public health, including the development 
of meaningful metrics to evaluate the effectiveness of FDA's 
current policies to curb use and the need for strong 
enforcement of current laws and regulations. In addition, some 
Senators have raised concerns about the degree to which the FDA 
is using its current authorities to address the ongoing opioid 
crisis--and as a Senator from a region that has been hard-hit 
by this crisis, I expect Dr. Califf and the other relevant 
agencies to provide full and complete responses to these 
inquiries if this nomination is to move forward.
    The FDA needs a Commissioner who cares more about public 
health than industry profits or Washington politics. Given that 
the majority of major clinical trials are sponsored by private 
industry, it is fair to ask whether anyone with an extensive 
background in clinical research can be trusted to make 
decisions that are independent of the industry. On the other 
hand, there are substantial advantages to having a leader of 
the FDA who is a serious, front-line researcher who understands 
the importance of advancing cutting-edge work that will advance 
the health of millions of Americans--and who is sensitive to 
the conflicts of interest that can arise in industry-funded 
research. Based on the information I have reviewed and Dr. 
Califf 's representations, I am satisfied that he can be a 
strong leader for the FDA, placing the interests of patients 
and the American public above all others. Should he be 
confirmed, I plan to stay closely engaged with Dr. Califf to 
ensure that he advances the integrity and high standards of the 
FDA--and I fully intend to hold him accountable for his actions 
and decisions as the FDA Commissioner.

    The Chairman. Thank you, Senator Warren.
    The next four Senators are Senator Roberts, Senator 
Baldwin, Senator Cassidy, and Senator Mikulski.
    Senator Roberts.

                      Statement of Senator Roberts

    Senator Roberts. Thank you, Mr. Chairman.
    In the first place, thank you for coming by my office. We 
had a very nice visit. My wife is from South Carolina. I 
learned a long time ago you can take the girl out of the South, 
but not the South out of the girl.
    One of your responsibilities is to make sure the FDA is 
committing its resources to doing the most important work. For 
example, the FDA has been, in some cases, a little hesitant to 
implement key food safety goals while putting resources toward 
proposals for regulating sugar, salt, and caffeine. I would 
refer you to the new dietary guidelines that indicate now that 
an increase in salt intake is OK, and caffeine is six cups of 
coffee. This is my third one, so I've got three to go. Sugar, 
however, no.
    The FDA has proposed to expand its jurisdiction by 
regulating laboratory-developed tests in e-cigarettes and 
cigars for the first time. I just want to make sure that the 
FDA's use of resources is to make sure the agency stays focused 
on accomplishing its core objectives as directed by Congress. 
That's just a comment. You don't have to respond.
    Food Safety Modernization Act. The acronym for that is 
FSMA. That's a wonderful acronym. I wear two hats here. I'm 
chairman of the Ag Committee and a member of this distinguished 
committee. I'm concerned about potential overlap with these new 
FSMA regulations and the requirements with which farmers and 
ranchers already have to comply.
    We need to make sure the FDA is working with the Department 
of Agriculture to ensure these new regs and requirements are 
being harmonized with those already on the books. Will you 
commit to working toward that end, if confirmed?
    Dr. Califf. Yes, be glad to work with you on that.
    Senator Roberts. Thank you, sir. I want to followup on 
Senator Isakson's very concise comments with regards to draft 
guidances. I'm particularly apprehensive of the use of the 
guidances as they lack transparency and can escape the 
important cost-benefit analysis and other scrutiny.
    What are your thoughts about setting a maximum period for 
which draft guidance can be left outstanding without being 
finalized or substantially revised? And, second, when 
commenters have expressed concerns, shouldn't the agency be 
required to publicly respond to those concerns or, at least, 
how the concern has been addressed when a guidance is finalized 
or if the agency has rejected the concern?
    Dr. Califf. Senator Roberts, I'm kind of a big advocate of 
transparency, so I do appreciate what you're bringing up. It's 
been noticeable to me, the issues that you raise. It's also 
noticeable, as I mentioned earlier, that every time we give 
people an opportunity to interact with the FDA, they seem to 
want to do it more, in our user fee situations, for example. 
The number of meetings requested always greatly exceeds the 
number that we have.
    The critical thing to me is getting whatever the correct 
format is moved along as quickly as we possibly can through the 
process so that people understand what the FDA is really 
thinking, and in the case where there really needs to be a 
rule, they understand what the rule is and how to implement it. 
To get to the details here, I'd need to come by and spend some 
more time with you to completely understand how you see it, but 
I would be glad to do so.
    Senator Roberts. I appreciate that. My final question: 
Where is Duke ranked right now with regards to the basketball 
situation?
    [Laughter.]
    Dr. Califf. I'm just glad you didn't ask about football. 
Duke is somewhere around No. 4 or No. 5.
    Senator Roberts. I think they're No. 5. Would you be 
interested in knowing who's No. 4?
    [Laughter.]
    Dr. Califf. That might be that school in the Midwest that 
we often beat up on when it comes to tournament time.
    Senator Roberts. It is the University of Kansas. I just 
want to point that out. I might add that South Carolina is No. 
1, but we'll take care of that.
    Dr. Califf. Oh, you mean North Carolina is No. 1.
    Senator Roberts. Yes, that's correct.
    Dr. Califf. UNC. I would rather have Kansas No. 1, 
actually, than UNC, but that's a different story.
    [Laughter.]
    Senator Roberts. I have no further questions, Mr. Chairman.
    The Chairman. Thank you, Senator Roberts, for your 
illuminating inquiry there.
    Senator Baldwin.

                      Statement of Senator Baldwin

    Senator Baldwin. Thank you, Mr. Chairman and Ranking 
Member.
    I'm pleased to have you here today and was pleased to have 
an opportunity to meet with you prior to this. We all agree 
that it's critical for the products that are approved by the 
FDA to be of the highest safety and efficacy standards, and 
that the public must also have meaningful access to accurate 
information about treatments so that they can make the best 
healthcare decisions.
    I share some of my colleagues' concerns with the ever-
increasing drug prices. There's been a little bit of dialog 
about that already, and we can do more and should do more to 
improve drug accessibility, affordability, and transparency. I 
want to start with transparency.
    Dr. Califf, the public still lacks comprehensive access to 
information about medical products. For example, companies do 
not consistently report clinical trial outcomes for drugs in 
the public databases, as a number of recent studies have noted. 
Generics are not yet able to initiate a change in their patient 
labeling if they learn of new safety information because the 
FDA has not yet finalized the generic labeling rule.
    In your new role, when you receive confirmation, how would 
you improve access to accurate information on drugs for 
patients, for doctors, for researchers? How would you ensure 
that the FDA maintains patient safety once these medicines 
actually reach patients?
    Dr. Califf. I'll try to be as quick as I can with this, 
because that's a very important question that you're asking. 
First, I'll just point out again that every study that I was 
involved in has been published, and I think that's a mandate. 
When you ask someone to participate in a human experiment, the 
informed consent actually says you're doing it to create 
generalizable knowledge. We have an obligation. Even if we 
don't like the study, the result was lousy, or whatever, we 
need to publish it.
    Second, just before I left Duke, I was the co-author of a 
New England Journal paper pointing out the track record of 
clinicaltrials.gov reporting. One interesting side issue there 
is that industry is actually doing better than NIH-funded 
investigators, so we have work to do there. I'm pleased to say, 
working with the NIH, they now have a policy that you won't get 
your next grant unless you put your result in 
clinicaltrials.gov. It's been very good working with Kathy 
Hudson and Francis Collins on making this happen.
    The third element, the surveillance system that we talked 
about, Sentinel, and the equivalent on the device side--this is 
really needed. We're now dealing with generic drugs that have 
been on the market for up to 40 years, and we're still learning 
about them. We can't have a system where it depends on the 
innovator company to figure all this out and somehow make it 
public.
    I give Jeff Shuren and Janet Woodcock a lot of credit. We 
have an approach--and we just had a meeting 2 weeks ago with 
other Federal agencies, and there's general agreement that we 
need to have a national evaluation system, which is really a 
public good, and if the companies can develop the best 
products, that's fine. We need to work toward this.
    Senator Baldwin. I want to switch gears, given the role of 
the FDA in food labeling. You and I had a chance to speak about 
one of Wisconsin's products. We're the No. 1 grower of 
cranberries. I know that a couple of other members of the HELP 
Committee represent States that have a robust cranberry 
industry, also.
    I'm concerned that recent FDA proposals to update food 
nutrition labels, specifically with added sugar information, 
may cause some confusion for customers and others by 
categorizing cranberry products, which are clearly highly 
nutrient dense fruits that need added sugar for palatability, 
as somehow comparable to foods that they shouldn't necessarily 
be compared with. For example, should you be comparing 
cranberry juice to other fruit juices or to soda pop? Should 
you be comparing dried cranberries, craisins, to raisins or 
candy?
    As Commissioner, how would you ensure that these and other 
FDA food policies appropriately account for the unique health 
benefits of food like cranberries and ensure that consumers are 
going to have the type of information, comprehensive and 
accurate, that will allow them to make healthy and nutritious 
decisions?
    Dr. Califf. Senator Baldwin, I appreciate that, and I've 
noticed cranberry juice has frequently been in our refrigerator 
at home. It may have something to do with some health benefits 
that are attributed to it. It's a good example of the balancing 
act the FDA has to do. We've got this terrible epidemic of 
obesity and diabetes, so huge amounts of sugar are clearly not 
good for you. I don't think there's any disagreement about 
that. We've also got to preserve nutritious foods that do need 
a little sugar to make it better.
    I talked with Senator Warren and with you a little bit 
about the fact that we need to really work on the cognitive 
psychology of labeling so that when we do take actions and put 
information out there, it's interpretable and actually helps 
people make good decisions. Ultimately, it's up to people to 
make their own decisions, but if we don't present it in a way 
that's clear to them, it could lead to the wrong decision.
    The Chairman. Thank you, Senator Baldwin.
    The next Senators are Senators Cassidy, Franken, Kirk, and 
Bennet.
    Senator Cassidy.

                      Statement of Senator Cassidy

    Senator Cassidy. I enjoyed our meeting. Thank you for 
coming by. I have several questions. First, going back to the 
drug pricing, clearly, we've seen companies like Turing and 
Valeant kind of abuse the social contract, which gives you a 
reasonable rate of return for drug marketing, and they've gone 
way beyond reasonable.
    I've been told in the case of Turing that an approval of a 
generic would take several years because clinical trials would 
be required to prove that the generic competitor was the 
equivalent to that which Turing now has as a sole source 
provider. We know this is a 60-year-old drug.
    It comes to mind because I'm reading now, on-premise, on a 
compounding component that would make the same drug available. 
Of course, compounding--a doc has to write the prescription. In 
a sense, compounding is doing what generic can't do.
    I guess my question is if we know, or I presume we know, 
that the compounded drug being sold for $1 a pill, as opposed 
to $750 from Turing--take that as an advertisement for anybody 
who wants a reasonably priced drug--if it is $1, why can we do 
this in the compounding space but not in the generic space? Why 
does it take so long to work this through the generic when we 
get--do you see what I'm saying? This is cognitive dissidence.
    Dr. Califf. I know you're a doc and you have an 
understanding of all this. Let me just point out, as I 
mentioned earlier, every drug is a little bit different, and 
the whole goal with generics, in most cases, is not to have to 
do major clinical trials. It's really just showing that you 
actually have something that's equivalent. I believe you spent 
a lot of time with Dr. Woodcock on this recently.
    Senator Cassidy. Yes.
    Dr. Califf. There's a lot we can tell about the molecular 
structure in some very simple pharmacodynamics type studies. 
We're not dependent on these large clinical trials that we have 
to do for the innovator drugs. When it comes to compounding, as 
you well know, we're working hard on the standards for 
compounding, because we had some disasters with compounding 
that have required FDA action.
    Senator Cassidy. The disasters were more related to 
infection control, fungi entering an injectable. This, 
obviously, is an oral drug, and I presume--knowing that there 
is liability involved, on-premise would not be selling it were 
it not bioequivalent.
    Dr. Califf. I'll have to get back with you on that because 
I don't know the details on that particular drug. I'll be glad 
to do that.
    Senator Cassidy. Just because I see now that these folks 
have established--the business model works. Again, I have 
something from Valeant--a fellow who was paying $566 a 
prescription. It's now $5,500 a prescription. A total 
exploitation of the system that has been a pretty good social 
contract and now is breaking down because of these folks--
frankly, greed.
    If we're going to somehow circumvent that, we've got to 
come up with a more efficient way to do the generics. Again, 
just to make the editorial comment, it so clearly is working 
with compounding that it seems almost like it should work as 
well with generic.
    Dr. Califf. Again, I'll have to get back with you on the 
specifics. I did have a pharmacy compounding operation at Duke 
Hospital that was required for some of our intensive care unit 
medicines, and I'm very aware of the complexity of compounding. 
It's not as simple as it may sound. I'd have to really look at 
the specifics of this and get back with you.
    Senator Cassidy. That's fair. Second, which is related, 
going to the drugs which are manufactured in India and China, I 
gather that the FDA recently sent out a warning that said 
investigators went, looked, observed holes in the walls and 
roof which allowed pigeons access near production equipment in 
multiple manufacturing areas. There's evidence, or at least 
suspicion, that somebody was hiding audit trails, et cetera.
    I'll just say, again, cognitive dissidence. On the one 
hand, we're continuing to allow folks to import, even when good 
manufacturing procedures are obviously not being followed. Yet 
it seems like we're putting roadblocks up for those who are 
producing domestically, who could give us some relief from the 
exploitative pricing practices. Knowing that you're the new man 
on the job, I don't expect you to comment on that beyond just 
to make the observation.
    Dr. Califf. Yes, I understand what you're saying, and I did 
have the privilege as an academic to do a lot of work in India 
and China over the last decade, and it is going to be a focus 
that we'll have to pay a lot of attention to. A large part of 
our food and our drugs and device supplies are coming from 
India and China. We certainly don't want to disadvantage 
Americans in that regard, either.
    Senator Cassidy. If we found those GMP were not being 
followed, would we shut down those supply--those components of 
the supply chain?
    Dr. Califf. We can't shut down something in India or China, 
but we can shut down importation.
    Senator Cassidy. The ability for that to be used----
    Dr. Califf. Yes, and we do that.
    Senator Cassidy. I got you. I yield back. Thank you.
    The Chairman. Thank you, Senator Cassidy.
    Senator Franken.

                      Statement of Senator Franken

    Senator Franken. Thank you, Mr. Chairman, and I note that 
you, Senator Baldwin and Senator Cassidy have all talked about 
what we're hearing when we go back to our States about 
pharmaceutical costs, and that's something we really have to 
deal with, and the exploitation of positions that companies 
have gotten.
    Dr. Califf, I want to talk about probably the basic 
question that you will face, which is the delicate balance that 
the FDA plays in making sure that products get to people who 
need them quickly, but at the same time making sure that 
they're safe. That's what you deal with every day. I've tried 
to promote this balance in legislation I have introduced with 
Senator Burr, the FDA Device Accountability Act of 2015.
    Given your experience as an outside advisor and now as an 
internal leader at FDA, how can FDA use the tools at its 
disposal to strike this balance?
    Dr. Califf. When it comes to cost, we do have some tools we 
can use to help out. The first, we've already discussed, which 
is doing everything we can to do a good job with the generic 
drug situation. We're at 88 percent now, and that's a good 
thing.
    We now also have biologics, which--biosimilars are now 
coming up, and we've got over 50 applications in the works. 
We're going to need to do a good job with that, too, because 
that's a big expense and we want to make sure that people have 
access when it's appropriate and safe and effective. The 
criteria are stringent there.
    One other that is very important to me, which people 
wouldn't normally think about that much but it's going to come 
up more and more, is that if we really fix our evidence 
generation system, that is, streamline clinical trials, get the 
data that we need, people wouldn't spend money on expensive 
drugs when they're not needed. We need to have better 
information for people, and several Senators have brought that 
up today, and we can do that in a fairly dramatic way.
    And finally, we do keep track of shortages. We prevented 
over 100 shortages a year in each of the last 4 years. One 
year, it was all the way up over 200. There's a constant 
surveillance that goes on. There's a requirement that people 
notify us when there's going to be a shortage problem.
    The new area that we've got to work on is when someone gets 
a monopoly, which is what several of you have referred to, 
understanding who the competitors are and making sure that 
they're doing the right things to be able to compete and get 
their products on the market.
    Those are the things that we've gone through that we can 
clearly do fully within the FDA.
    Senator Franken. Quickly, I want to turn to a different 
issue, which is making sure that products continue to be safe 
once they've hit the market, once they've been approved for the 
market. You mentioned post-market surveillance. Does the FDA 
have adequate authorities here that you need to do this 
adequately, or do you need additional ones from Congress?
    Dr. Califf. I'd have to get back to you on the specifics of 
what you might be thinking. The thing we clearly need is a 
better system for post-marketing. Sentinel on the drug side is 
revolutionary and fantastic, and on the device side, we're 
doing better and better. We have a plan that I hope we can 
really enact, because I believe when we find a problem, for the 
most part, we can deal with it. We've got to have good data and 
quickly in order to identify the problems.
    Senator Franken. I want to talk about generic drug labeling 
and the generic drug labeling rule. This has to do with the 
rulemaking that you are doing on generic drug manufacturers and 
requiring them to update their warning labels and provide new 
safety information. This came out of the Supreme Court 
decision.
    What is the current plan for finalizing the FDA's generic 
drug labeling rule?
    Dr. Califf. Thank you for asking. That's a very important 
issue. As I said, we need to make sure that if there are 
problems with generic drugs that come up later--and they do--
with better surveillance systems that there's a way of making 
sure the labels are up to date and consistent across similar 
products. We got a lot of comments on the proposed rule. 
They're under consideration. I can't talk about decisionmaking. 
We're in the middle of it. It's a very high priority to get 
this finished.
    Senator Franken. Thank you.
    Thank you, Mr. Chairman.
    The Chairman. Thank you, Senator Franken.
    The next Senators are Senator Hatch, Senator Bennet, 
Senator Scott if he returns, and then Senator Sanders.
    Senator Hatch.

                       Statement of Senator Hatch

    Senator Hatch. Thank you, Mr. Chairman.
    I'm very pleased to be able to support your nomination. I'm 
very impressed with what you've been able to do, not only with 
your life, but all the work that you've done down there at Duke 
and elsewhere. To be honest with you, you deserve a lot of 
credit, and you're going to add a great deal to the FDA.
    Let me just say this. I'm very concerned about data 
exclusivity. When we did Hatch-Waxman, we made sure there was 
enough data exclusivity time so that they could recoup the 
cost, because the average cost, according to what I've been 
told, for a pharmaceutical drug is about a billion dollars and 
up to 15 years or more because of the pace at FDA, and for a 
biological drug, about the same. The average cost is $2 billion 
to come up with a biological therapy that is approved by FDA.
    I'm very concerned about it, because if we reduce that data 
exclusivity time, especially with regard to bio, you're talking 
about having to charge a lot more, and you're talking about our 
industries subsidizing other countries all over the world and 
paying, really, so they can have these biotherapies really at 
our expense, and at the same time, in order to recoup the 
amount of money it cost to go through FDA, the cost of these 
therapies is continually rising.
    I just want to know if you feel that we can move ahead 
quicker on these matters and make it so that these companies 
have a chance to recoup their monies that they've invested.
    Dr. Califf. Senator Hatch, I do understand your concern 
that we want to make sure that if someone invests in the 
development of a drug, there's a return on investment. 
Otherwise, people won't invest in our kind of society.
    Senator Hatch. You also understand that the more it costs, 
the more difficult it is to recoup the funds, and the longer 
length it takes to recoup them as well without charging even 
more than we do now.
    Dr. Califf. The FDA doesn't set the length of data 
exclusivity.
    Senator Hatch. I know.
    Dr. Califf. What we can do that you bring up is the cost of 
development is largely driven these days now by the cost of 
clinical trials. We think we can do trials that are actually 
bigger and include more patients and are more representative 
for a much lower cost. I hope you'll work with us on that.
    Senator Hatch. I'm going to work with you on it, but that's 
an important issue, and it even becomes a major issue with 
regard to our trade promotion authority bill and also the Trans 
Pacific Partnership.
    Dr. Califf. I appreciate that.
    Senator Hatch. If we don't allow enough data exclusivity 
time, we're not going to develop these therapies, especially in 
bio, because bio is one of four or five places, four or five 
techniques, where we can actually find treatments and cures. If 
we find the cures, that, over time, will save us trillions of 
dollars. I'm very concerned about this system working very 
well.
    Dr. Califf. I've been fortunate to be a leader in the 
development of several biological therapies that have made a 
difference. So I appreciate what you're saying.
    Senator Hatch. Also, Hatch-Waxman has made a real 
difference as far as getting--I remember when we did Hatch-
Waxman, it was like 18 years to get a generic through. Today, 
it's--and it was very, very difficult. It's kind of automatic 
because----
    Dr. Califf. We're doing better, and 88 percent of 
prescriptions are generic. It's been a tremendous success.
    Senator Hatch. One issue that significantly affects many 
entities in my home State is the FDA's October 2014 proposed 
guidance on the regulation of LDTs, laboratory-developed tests. 
There has been a robust conversation on this proposed guidance 
between stakeholders, Members of Congress, and the FDA ever 
since the announcement.
    Does the FDA intend to issue final guidance, or does the 
agency plan to allow for further comments and feedback on the 
next steps proposed?
    Dr. Califf. As you may know, this is an ecosystem issue 
where we want to have universities continue to innovate, but we 
also want to assure patients that they're getting accurate test 
results for analytical and clinical validity. We're collecting 
a lot of information, ongoing feedback.
    We just had 2 days at the FDA of all the stakeholders 
talking about next generation sequencing, which is an advanced 
form of this testing, so we're still collecting feedback. We 
want to find something that stimulates innovation but also 
assures patients.
    Senator Hatch. Mr. Chairman, may I ask just one other 
question that would just requires a yes or no answer?
    The Chairman. Sure.
    Senator Hatch. Thank you.
    Do you believe, as prior commissioners have--every one has 
told me this--that the Dietary Supplement Health and Education 
Act, DSHEA, provides adequate authority to regulate the dietary 
supplement industry and protect consumers from unsafe products?
    Dr. Califf. We're fully aware of our authorities, and 
you're going to see a lot of action where the authorities are 
pertinent in the near future.
    Senator Hatch. Do you agree you have enough authority?
    Dr. Califf. We're very well aware of our authorities and 
plan to use them as Congress has directed.
    Senator Hatch. All right. Thank you.
    The Chairman. Thank you, Senator Hatch.
    Senator Bennet.

                      Statement of Senator Bennet

    Senator Bennet. Thank you, Mr. Chairman.
    Thank you, Dr. Califf, for your willingness to serve. We're 
delighted that you're here today.
    In my view, the FDA has been extremely successful 
implementing the breakthrough therapy pathway, which has led to 
the approval of 32 lifesaving drugs and over 100 more in the 
pipeline. When I was first working on this bill with Senator 
Hatch and Senator Burr, Colorado startups were saying to me 
that all of the venture capital in this country was moving to 
Asia and moving to Europe because of the regulatory uncertainty 
at the FDA.
    All of us want to keep jobs here, and we want to give 
patients safe and effective drugs as soon as possible. It looks 
to me like this breakthrough pathway may be achieving both, and 
I wonder whether you could talk about it a little bit. What 
have we learned about regulation, and can this kind of approach 
be modeled in other places at the FDA, including at the device 
center?
    Dr. Califf. Thanks for your comment, and my two sons from 
Colorado are listening carefully, I'm sure, to your thoughts on 
this. Breakthrough is----
    Senator Bennet. Barbara Mikulski is not here, so let me say 
we would gladly move the FDA to Colorado if that would make the 
family closer together.
    [Laughter.]
    The concept of breakthrough is where things look really 
promising early on, that it's going to make a dramatic 
difference, and there's an unmet need for a life-threatening 
condition. The FDA works closely with the industry to move 
things along as quickly as possible. There have been a whole 
series of cancer issues, in particular, that have just 
delighted the cancer community and people who otherwise would 
die.
    My mom back here has multiple myeloma. She's now on her 
third or fourth chemotherapy treatment. It's been a tremendous 
success to have the community working with the FDA and with 
industry and with academia in a concerted effort. We don't need 
this for chronic common problems where there's already 
effective treatment. We want to make sure we don't rush things 
to the market that aren't safe. The real key is having the 
criteria to identify where this kind of activity is needed.
    Senator Bennet. I want to say that, at least from my 
perspective, it's fashionable to criticize the agency. This is 
a place where the FDA has really gotten it right.
    How about on the medical device side of the equation?
    Dr. Califf. There have been issues with medical devices 
moving to other parts of the world. They're beginning to come 
back, and one of the reasons is the early device research 
program that's been developed by CDRH together with the 
community that is working with the big centers that can do the 
early device work, bringing those things back.
    There's also an issue with devices that you know a lot 
about, which is, often, a device is useful in a very unusual 
disease, and it's a very niche activity where there's not an 
adequate market. We do have a program for that. It's 
successful. It's a topic that we need to think about and 
discuss more to define ongoing criteria.
    Senator Bennet. I should also say that the cancer community 
was vitally important in getting that piece of legislation 
passed to begin with. It's nice to see that some of the early 
drugs have been drugs that fight cancer.
    Switching gears, I wonder whether you would take a few 
minutes to discuss with the committee how we should think about 
investment in life science innovation, not just as a domestic 
priority, but as a global economic priority to keep us 
competitive with other nations. This is a time when we're 
seeing diminishing resources in this country applied to basic 
science, and I wonder if you could help us understand why 
that's important or whether it is.
    Dr. Califf. It's just the case that almost everyone is 
concerned about, living longer and being more functional in 
their lives, and the way we do that is through public health 
and also through medical products, and in the case of tobacco, 
reducing it, hopefully. As we go about that, the development of 
new medical products does require investment, because it's 
appropriate that there's a law that says you've got to show 
you're safe and effective before you come on the market.
    This requires time to do the development, and it requires 
that you really show that you're not producing an inferior 
product before you come on the market. It's really a critical 
issue. We've got to invest.
    On this note, in our work with the NIH, we're very focused 
on the use of biomarkers, surrogate inpoints, but also on not 
using them inappropriately when they're not going to work. This 
is really hard work to set the conditions that would excite 
investors to put money into biomedical science.
    Ultimately, the United States is saving the world through 
investment in the NIH, and I want to put in a plug for 
continuing with the NIH investment. If not for the scientists 
being funded through NIH, we wouldn't have the basic science to 
translate into effective medical products.
    Senator Bennet. Thank you. Thank you for your testimony.
    Thank you, Mr. Chairman.
    The Chairman. Thank you, Senator Bennet.
    I want to thank Senator Murkowski, who has left the 
hearing, and Senator Casey for allowing Senator Sanders to go 
next. He has been waiting patiently and he has extracurricular 
activities which he's attending to.
    Senator Sanders.

                      Statement of Senator Sanders

    Senator Sanders. Thank you, Mr. Chairman, and thank you, 
Senator Casey.
    Dr. Califf, thanks very much for being with us. You and I 
chatted a while back, and I told you that I would not support 
your nomination, because I believed you were not strong enough 
on the most important issue that the American people are 
concerned about with regard to prescription drugs. That is, in 
our country, we pay, by far, the highest prices in the world 
for prescription drugs. As I understand it, about one out of 
five Americans cannot afford to fill the prescriptions that 
their doctors are writing for them.
    Mr. Chairman, with your permission, I would put into the 
record a comparison of drug prices in the United States and 
Canada, which show that on major and important drugs, the 
prices in Canada are far, far less expensive than they are in 
the United States, and that's true all over the world.
    [The information referred to may be found in Additional 
Material]
    My concern, Mr. Chairman, is that while last year, the top 
four drug companies in this country--Pfizer, Johnson and 
Johnson, Novartis, and Hoffmann-La Roche--made $57 billion in 
profit in 1 year, I heard concern that drug companies are not 
doing well. They're doing quite well, and yet you have millions 
of Americans who cannot afford the high cost of prescription 
drugs.
    While all of us agree that, clearly, we want great new 
products out on the market to save lives, for millions of 
people, it doesn't matter what the products are. They just 
cannot afford them. We need, in my view, an FDA Commissioner 
who is going to be aggressive and understands that very simple 
principle, and I'm not clear, and what I heard today confirms 
that I don't think you get that.
    Here are some of the questions I'd like to ask to make out 
the point. It is not a coincidence that last year, the 
pharmaceutical industry spent $250 million on lobbying and 
campaign contributions and employ some 1,400 lobbyists. Do you 
think, Dr. Califf, that that type of expenditure has any impact 
on the fact that we pay, by far, the highest prices in the 
world for prescription drugs?
    Dr. Califf. Senator Sanders, the ideal situation would be 
if the money went into R&D to develop an adequate picture of 
the risks and benefits of treatment and that was made available 
to people.
    Senator Sanders. Why do we pay the highest prices in the 
world, by far, for prescription drugs?
    Dr. Califf. I'm not an expert on the price of drugs, 
Senator Sanders, but I'm certainly sensitive to the fact that 
in a field like cardiovascular medicine, my specialty, we need 
to have drugs available, because they save lives and----
    Senator Sanders. Doctors and oncologists have written to us 
that it doesn't matter what drugs are available because their 
patients can't afford them. Let me ask you this, a very simple 
question. As head of the FDA, you will oversee the importation 
of food products, vegetables, fish from all over the world. We 
can import lettuce and tomatoes--vegetables from farms all over 
the world. Somehow we cannot reimport from Canada brand name 
prescription drugs manufactured by the largest drug companies 
in the world.
    Can you explain to me, and do you support, the 
reimportation of brand name prescription drugs from major 
companies from Canada and from other major industrialized 
countries? Yes? No?
    Dr. Califf. Senator, as you're aware from our previous 
discussion, we have major concerns about reimportation. The 
system it would take to make sure that the drugs are adequate 
and safe for Americans----
    Senator Sanders. In other words, you think we can bring in 
fish products and vegetables from farms all over the world, but 
we cannot bring from across the Canadian border brand name 
drugs. You don't think we have the capability of doing that?
    Dr. Califf. We have the capability. It would add additional 
cost, and systems would have to be put in place to make it 
work.
    Senator Sanders. This is why, precisely, the American 
people are paying, by far, the highest prices in the world for 
prescription drugs. It is beyond my comprehension that you're 
sitting here saying we can bring in vegetables and fish from 
all over the world, but we cannot bring in brand name drugs 
manufactured by the largest pharmaceutical companies in the 
world from a country like Canada. I just do not accept that.
    Let me ask you another question. One of the reasons we pay 
the highest prices in the world is--today, I can walk into a 
drugstore and they can tell me the medicine I use--the price 
has doubled because we have no regulations. Do you believe, and 
will you support, the right of Medicare to negotiate drug 
prices, which is now currently not allowed by law? Shouldn't 
Medicare sit down and negotiate drug prices so we can lower the 
prices of medicine?
    Dr. Califf. You're aware, I believe, it is the 
administration's position that in certain circumstances that 
have been spelled out in the President's budget, negotiation on 
Medicare prices should be done. It's not the FDA's remit to set 
the prices, as we've already discussed. It is the 
Administration's----
    Senator Sanders. I know. But the issue of affordability is 
within your jurisdiction.
    Let me just conclude, Mr. Chairman, and let me thank, 
again, Senator Casey for jumping over him here.
    We all want great medicine to come onto the market, and I 
respect the work that you have done. At the end of the day, 
people are dying, people are not buying the food they need 
because they have to pay outrageous prices for medicine because 
we have been extraordinarily weak in taking on the 
pharmaceutical industry that is ripping off the American 
people.
    I believe that we need a Commissioner--and I know that's 
not the only responsibility of the FDA--but I believe we need a 
Commissioner who is going to stand up to the pharmaceutical 
industry and protect American consumers. I'm going to have to 
say to you, with regret, that I think you are not that person.
    Thank you very much.
    The Chairman. Thank you, Senator Sanders. Senator Murkowski 
also stepped aside as well as Senator Casey.
    Senator Murkowski, thank you for being here.

                     Statement of Senator Murkowski

    Senator Murkowski. Thank you, Senator Alexander.
    Dr. Califf, welcome. Senator Sanders has just broached very 
briefly the issue of fish. He says we can bring in fish from 
all around the world. I want to suggest to you that perhaps 
bringing in fish from all around when it is mislabeled and 
misnamed is not something that we want to do.
    I would ask you again to look at the issue that we have 
raised repeatedly before the FDA regarding the Pollock 
nomenclature. This is something where we contend that you do 
have the regulatory authority to change the acceptable market 
name from Alaska Pollock to Pollock so that we can put some 
limitation and parameters on what we're seeing from the large 
volume of Russian harvested Pollock that is sold to U.S. 
consumers as Alaska Pollock.
    I have repeatedly raised this and would ask that you would 
work to expedite this change and remove the blockade that has 
been created within the FDA's bureaucracy regarding this 
Pollock nomenclature.
    Dr. Califf. Senator Murkowski, I enjoyed my visit with you 
and I heard clearly what you said then. We are still open for 
comments and thinking about this. I will work with you to come 
to a resolution on this issue.
    Senator Murkowski. I do want to work with you. Again, this 
is something that can easily be resolved, and that's what we're 
looking to do here, to address it through the regulatory route 
as opposed to the legislative, which we will do if we have to. 
This is one that we can fix working together.
    The last question that I have for you also relates to 
seafood, and this is regarding some concerns that we're hearing 
that the forthcoming FDA seafood advice to pregnant women on 
seafood consumption may not be entirely based on science. This 
is something, of course, that is gravely concerning.
    Back in 2014, there was a statement that was released on 
the draft seafood advice that spells out pretty clearly that 
science now tells us that limiting or avoiding fish during 
pregnancy and early childhood can mean missing out on important 
nutrients that can have a positive impact on growth and 
development as well as your general health. The concern is that 
the FDA has revised that advice in a way that ignores this Net 
Effects Report.
    The question to you this morning is: What is the status of 
the FDA's seafood advice for pregnant women? I guess what I'd 
like to hear from you, specifically, is whether or not, when 
that advice is released, that final seafood advice for pregnant 
women and nursing mothers will be based in science, namely, 
using the Net Effects Report.
    Dr. Califf. I can assure you it will be based on science, 
and the recommendation will be something that will be very good 
for American people and----
    Senator Murkowski. Why would it not be based on the Net 
Effects Report?
    Dr. Califf. We're having to balance a lot of input and 
considerations here.
    Senator Murkowski. Wouldn't that input and consideration be 
based on the science that went into that report?
    Dr. Califf. We base it on all the scientific facts that can 
be brought to bear that accumulate over time. These will all be 
considered. You'll be happy with the recommendation when it 
comes out.
    Senator Murkowski. I appreciate that assurance. It doesn't 
necessarily get me to where I would like to be, which is a 
recognition that you will utilize that Net Effects Report, the 
report that very clearly outlines why it is important for the 
nutritional needs of not only the mother, but developing 
children as well.
    Dr. Califf. I'm very familiar with the concept, but the 
detail I'm going to have to come back to you on to make sure 
that----
    Senator Murkowski. Can you tell me when we might anticipate 
this report then?
    Dr. Califf. I can't give exact dates or timelines. This is 
a fairly straightforward issue, and it's a high priority, and 
we've had discussions about it recently. So it's going to move 
along.
    Senator Murkowski. I would agree that it is high priority. 
It is important, and it is overdue. Certainly, the science is 
overwhelming in its support for the recommendations, good sound 
recommendations based in science that pregnant and nursing 
women be given good advice when it comes to seafood in their 
diets.
    Thank you, Mr. Chairman.
    The Chairman. Thank you, Senator Murkowski, and thank you 
for your courtesy to Senator Sanders, even though you were 
chairing a hearing, and thanks also to Senator Casey.
    Dr. Califf, after I call on Senator Casey, I'm going to 
leave for another appointment and turn over the hearing to 
Senator Scott, who will ask his questions, and then if there 
are no other Senators, he will conclude the hearing. Thank you 
for being here.
    Senator Casey, thank you for your courtesy to Senator 
Sanders.

                       Statement of Senator Casey

    Senator Casey. Mr. Chairman, thank you. Thanks for the 
hearing.
    Doctor, we're grateful you're here, and we appreciate your 
commitment to public service and that of your family. I know, 
and we all know, that when an individual makes a commitment to 
service, it involves a sacrifice and a contribution in a 
substantial way by your family, so we're grateful for that.
    I wanted to try to cover maybe three topics, one or two of 
which I may have to do by way of written questions. The first 
is children, and that's what I'll spend most of my time on, and 
the second is food safety, and the third is this issue that's 
been raised about independence and ensuring that's the case 
going forward.
    First, with regard to kids, we're told that today is World 
Prematurity Day, so we're talking about premature babies born. 
I guess 1 in 10 born in the United States today is born 
prematurely. We've had legislation over time, obviously, that 
speaks to this. One is the recent FDA Safety and Improvement 
Act, which required, among other things, that FDA hire a 
neonatologist in the Office of Pediatric Therapeutics to work 
on implementation of the provisions of the act for neonates. 
That happened, and that hiring was done. We're grateful that 
that happened.
    One of the areas I'll be looking at more broadly as you do 
your work is to focus on the implementation of changes by the 
FDA that come as a result of both the Best Pharmaceuticals for 
Children Act and the Pediatric Research Equity Act, and we can 
amplify those later. Just with regard to treating premature 
infants, we know that more must be done to accelerate the 
development of both therapies and devices to treat infants in 
so-called NICUs, neonatal intensive care units.
    If confirmed, I guess my first question would be: How might 
you use FDA's existing authority, the regulatory authority, to 
promote the development of cutting-edge treatments for 
premature babies?
    Dr. Califf. Thanks for asking that question, Senator Casey. 
You may not be aware of this, but when the Children's Act first 
came into existence, I was one of the instigators with the 
phrase, children should not be therapeutic orphans, that is, 
doctors were forced to give treatments to children with no 
evidence about the right way to give the treatment.
    We ended up at Duke being the coordinating center for the 
NIH part of this, to take drugs that were already off patent 
and figure out the right dose. We have a neonatal intensive 
care unit network from my old institute which is focused on 
this. I've written about 20 papers on this topic. We need to 
keep moving along, and we need to move on to pregnancy, which 
is another very high priority issue where the right doses of 
drugs are just not known for the most part.
    Senator Casey. The second question--and I appreciate the 
background of what you've been doing. The second question might 
take more reflection, because it's kind of a broad-based 
question. You can certainly amplify or add to what you say here 
by way of a written response. Is there anything you would hope 
that Congress would do to increase FDA authority in this area?
    Dr. Califf. The food safety?
    Senator Casey. No, I'm sorry. On----
    Dr. Califf. On children?
    Senator Casey. Yes.
    Dr. Califf. We're in pretty good shape where we are in 
terms of authority. If you have good ideas, let me know. The 
studies could be better and could be broader. We can make that 
happen working with the community.
    Senator Casey. I'll move to one other question as it 
relates to children, so-called neonatal abstinence syndrome.
    Dr. Califf. Yes.
    Senator Casey. We're told now among other statistics that 
one baby is born every 25 minutes with opioid withdrawals, 
meaning the equivalent of neonatal abstinence syndrome. It's 
increased some fivefold in the last 12 or so years.
    The majority leader, Senator McConnell, and I just got a 
bill through both the Senate and just, I guess, yesterday, the 
House, which we hope will be signed into law to focus on this 
problem. Anything that you can tell us about either your 
previous work or work you can do leading the FDA on this 
specific issue as it relates to neonates?
    Dr. Califf. This is a terrible problem, the concept that an 
unborn child would be exposed to opiates and essentially 
addicted at birth. We had a public meeting on this recently. 
Like the opioid problem all together, this is a community 
effort. We've all got to work on it, including the FDA.
    We have a whole series of measures that we're implementing, 
including a major effort on physician education, which is 
critical. Tens of thousands of docs have now taken the required 
courses through the REMS program, the post-marketing. This is a 
huge problem. We've got a lot of work to do on this, and I look 
forward to working with you on it.
    Senator Casey. I appreciate that.
    Mr. Chairman, could I have one more minute?
    Senator Scott [presiding]. Certainly.
    Senator Casey. Thank you very much, and I know you're 
waiting.
    Part of this we can develop more in a written question. On 
food safety, one of my constituents just recently was severely 
sickened with listeria in 2012, and I guess as a result of 
ingesting ricotta salata cheese from Italy, among many other 
stories I know that constituents have with regard to food 
safety.
    I know this is a resource issue or, I should say, lack of 
resource issue as well. Can you tell us a little bit about what 
you hope to be able to do even within the confines of limited 
resources?
    Dr. Califf. It's been a real privilege getting to know Mike 
Taylor, who heads up FSMA and heads up this part of the FDA. 
He's been doing this for years. A dream of his was to get FSMA 
put together, and we're now moving to the implementation phase.
    The real key--because this is such a massive food--it's 
just a lot of things. High-quality analytics, like every other 
industry is using now, really is what we're implementing so we 
can target the inspections to where the highest risk is. We're 
even using genomics for bacteria to figure out exactly where 
they come from by doing complete genotyping, just like we do 
with people. It's really moving the science along and then 
realigning the workforce so that it's allocated to preempt and 
prevent these problems before they occur rather than just 
reacting.
    Senator Casey. I'll submit for the record a question about 
the issue that was raised about independence, and I appreciate 
what you said in your testimony about the Duke contract as well 
as your own steps you've taken since being at the FDA on 
recusal. I'll develop a broader question to send to you.
    Dr. Califf. I appreciate it, and I'm glad to respond. I 
just wanted to note in light of Senator Warren's questions that 
Duke University has graciously agreed to make the contracts 
available, and they're either in the staff 's hands or on the 
way. It'll be good for you to look at those.
    Also, just a note that the consulting money abided by these 
principles, but I also made a personal decision to donate that 
money to not-for-profit charities. It's really just a sign that 
the work is something I thought was important, not the money, 
in this case.
    Senator Casey. Thanks, Doctor.
    Thank you, Mr. Chairman, for the extra time.
    Senator Scott. Thank you, Senator Casey.
    Dr. Califf, thank you for your willingness to serve and 
thank you for allowing me to clear up the fact that you're a 
South Carolinian and not from North Carolina. That was 
important to me and----
    Dr. Califf. It's great to be here with a fellow South 
Carolinian.
    Senator Scott. Thank you, sir, especially since Senator 
Burr is now gone. We'll continue.
    [Laughter.]
    Dr. Califf, I am the co-founder of the Sickle Cell Caucus. 
We focus a lot of attention on trying to make sure that people 
understand and appreciate the devastating impact that sickle 
cell has throughout the Nation and specifically within African-
American communities.
    Sickle cell, while rare, is devastating to communities and 
families. It is also one of the most expensive diseases to 
treat, given the high incidence of hospital re-admission. Yet 
we haven't had any new treatments introduced in the market, 
some say for 20 or 30 years. How can we address this and create 
an environment that incentivizes investment in research and 
development for diseases that affect smaller segments of the 
population?
    Dr. Califf. Thank you for asking that question. One of the 
regrets that I have about the wonderful opportunity at the 
FDA--I was glad to do it, but I left behind some things I was 
working on. One of those is the issue of diseases that affect 
minorities, particularly poor minority people, differentially.
    We had a big project going on in North Carolina, West 
Virginia, and Mississippi looking at the population base using 
electronic health records. One thing that pops right out at you 
is that sickle cell disease, while people are children, is 
pretty well covered by the Medicaid system.
    Senator Scott. Yes.
    Dr. Califf. With first-rate care, and then when people 
become adults, they're on their own. They frequently live in 
rural places. They can't get to the big centers, and this has 
created a disincentive to therapeutic development.
    The good news is NHLBI, with Gary Gibbons as the head--he's 
a good friend. I was working with him, and I think there's a 
comprehensive plan, including some of the designations for 
moving therapeutics through more quickly. I'm aware of some of 
the new things that are in development, and they look really 
good. If I wasn't here, I'd be working with those new things.
    Senator Scott. Excellent. Thank you. Two diseases that 
affect my State at a rate higher than the national average are 
heart disease and diabetes. In 2013, heart disease was the 
leading cause of death in South Carolina and accounted for $3.1 
billion in hospitalization costs. In 2013 as well, 11.3 percent 
of South Carolinians had diabetes.
    We are in desperate need for cures for these two chronic 
conditions. However, the high risk and cost of trials, 
particularly Phase 3 trials, actually seems to create an 
incentive for researchers and investors to avoid working on 
medications that could help the many Americans and South 
Carolinians suffering with these chronic diseases.
    What ideas do you have for reforming the clinical trial 
process to incentivize researchers and investors to delve into 
the high-risk but high-reward areas of medicine?
    Dr. Califf. I'm tempted to ask how many hours you have, but 
I'll keep this brief. First of all, let me just make a note 
that in the population base studies we were doing with a CMMI 
innovation grant in North Carolina--unfortunately, not South 
Carolina--West Virginia, and Mississippi, it's really a 
devastating--this was focused on diabetes. We need to get it 
under control.
    In addition to the cures that you mentioned, we also need 
to just deliver good healthcare to people close to where they 
live, and that was what our project was doing, using electronic 
health records to set up systems in neighborhoods so people got 
the care that they needed to deal with chronic disease.
    On the clinical trials front, it's a problem that's related 
to something we discussed earlier, which is that for a disease 
like heart disease, where we have a lot of effective treatments 
already, we don't want to let something on the market that's 
not going to be safe and effective. We have to do adequate 
clinical trials.
    Here's the good news. We're committed, as are all the 
Federal agencies, to work with industry and academia to develop 
a national system that delivers better clinical trial results 
with larger, more representative populations at a lower cost, 
and I would say a dramatically lower cost. The key here is 
using electronic health records that we already have. Almost 
every American has one.
    We've got to overcome the interoperability hurdles and some 
terminology. We can do this, and that would enable people to 
develop new therapies at a much lower cost, but with better 
information about safety and efficacy.
    Senator Scott. My final question. Back in September, I had 
an opportunity to ask Dr. Woodcock of the FDA about labeling of 
biosimilars. She stated that there were tradeoffs in various 
labeling decisions but did not provide any clarity as to what 
industry, physicians, and patients can expect and when they can 
expect it, which was a primary part of my question--the when.
    I continue to feel as if there's a serious risk in not 
providing notice that a product is a biosimilar, considering 
that there can be small differences between biosimilars and 
their branded counterparts, unlike with generics. Can you 
provide any update on where things stand with the labeling of 
biosimilars?
    Dr. Califf. What I can say, Senator Scott, is that we're 
working really hard on it, and it is a very tough, complicated 
issue. As I've already said, much of my career in cardiology 
was developing biological products that were highly effective. 
These molecules are complicated and difficult to work with. You 
really have to understand them.
    Dr. Woodcock is actually one of the world's authorities, so 
I have a lot of confidence in the approaches that she's taking. 
The labels ultimately have to both encourage the use of 
biosimilars where they're as good and enable providers and 
patients to understand when there are differences. We're really 
working hard to come up with--and also have to fit in with 
global standards about nomenclature that exist so that as these 
are on the market, they can be tracked. If there's a safety 
problem, we can keep up with it.
    Those are all the factors. I can't tell you exactly when 
we'll be done. Everybody is interested in this, and it's a very 
high priority.
    Senator Scott. Thank you for your time today.
    The hearing record will remain open for statements for 10 
days. I ask that Senators submit any written questions by 5 
p.m. on November 24th. Thank you for being here today.
    The next HELP Committee hearing will be on mental health on 
Wednesday, December 2d. The committee will stand adjourned.
    [Additional Material follows.]

                          ADDITIONAL MATERIAL

 Response by Robert Califf to Questions of Senator Alexander, Senator 
    Enzi, Senator Burr, Senator Isakson, Senator Murkowski, Senator 
   Collins, Senator Hatch, Senator Roberts, Senator Cassidy, Senator 
    Murray, Senator Sanders, Senator Casey, Senator Bennet, Senator 
               Baldwin, Senator Murphy and Senator Warren
                           senator alexander
    Question 1a. The Food and Drug Administration (FDA) has been 
criticized for how it restricts what drug and medical device 
manufacturers can tell doctors and insurers about lawful uses of their 
products. In particular, current regulations are unclear and heavily 
restrict manufacturers' ability to provide truthful and non-misleading 
information to doctors and insurers, unless the information appears in 
the product's FDA-approved labeling. Often, however, this information 
relates to medically accepted treatments that doctors can--and 
frequently do--prescribe for their patients, and that the Federal 
Government will even reimburse. In some instances, such ``off-label'' 
uses may even be the standard of care.
    In an era when information about medical products abounds on the 
Internet--some of it reputable, some of it not--do you think it is 
appropriate for FDA to maintain decades-old policies that block 
manufacturers from sharing factual, non-misleading information about 
lawful treatments with doctors and insurers?
    Answer 1a. It's important to remember the fundamental public health 
interests underlying the Agency's current statutory and regulatory 
framework, including the requirements related to premarket review of 
medical products before they are distributed for new uses. This 
framework was developed over time in response to public health 
tragedies, which Congress addressed by requiring independent review of 
scientific evidence of the products' safety and efficacy. The Agency is 
currently examining its rules and policies, with the goal of 
harmonizing the important public health and safety interests served by 
FDA's premarket review of new uses of medical products, with the value 
that sharing relevant scientific information regarding unapproved uses 
can have in certain contexts, and with First and Fifth Amendment 
considerations.
    I believe it is appropriate for FDA to continue examination of its 
rules and policies and to refine them as appropriate, in light of the 
important public health issues, free speech, and due process principles 
at stake.

    Question 1b. Several courts, including the U.S. Court of Appeals 
for the Second Circuit and the U.S. District Court for the southern 
district of New York, have indicated that FDA's restrictions on 
manufacturers' speech may violate the First Amendment. These decisions 
raise the possibility that many of FDA's regulations governing the 
promotion of medical products could be struck down by the courts unless 
they are substantially revised. What proactive steps will you take, if 
confirmed, to avoid that situation?
    Answer 1b. If I am confirmed, I will support FDA's efforts to 
comprehensively review its regulations and guidance documents and will 
make it a priority for the Agency to work on revising these documents 
as appropriate, in an effort to harmonize the goal of protecting the 
public health with First-Amendment interests.

    Question 2a. Before you began your current position at FDA, you 
advocated publicly for changes to certain regulations. For example, you 
gave a presentation in 2014 in which you called regulation a ``barrier 
to disruptive innovation,'' and, in 2013, you wrote in the New England 
Journal of Medicine about inefficiencies in the requirements for 
clinical trials and safety monitoring for approved drugs.
    What are the three biggest ways in which FDA poses a barrier to 
innovation? If confirmed, how would you address these problems?
    Answer 2a. I think you are referring to a slide I have used in 
multiple lectures that characterizes regulation as a barrier to 
disruptive innovation.
    This issue is a very important one for people proposing to develop 
new medical therapies. Throughout my career, I have benefited from a 
close relationship with the Fuqua School of Business at Duke and the 
many contacts it brings in the field of health economics and health 
management. Among the many brilliant people I have met is Clayton 
Christensen (``The Innovators Dilemma''), who developed the concept of 
``disruptive innovation.''
    This concept is derived from the study of the transformation of 
industries with the base case being the conversion of radios from the 
vacuum tube to the transistor. The concept is that the new product or 
method initially is inferior but lower priced so there is a market for 
it. This enables innovators to iteratively improve their product until 
it becomes better and supplants the old product or method. My purpose 
in showing this slide in multiple lectures is to explain to audiences 
that often include students, trainees in fellowship and scientists who 
are not involved in development of medical products, why the risk and 
investment in biotechnology is higher than most other industries, i.e., 
because it is a highly regulated industry, which is in fact a necessary 
barrier to protect public health, as discussed below. The amount of 
capital needed is lower and the time to return on investment is shorter 
in many other industries.
    I have never stated, implied, or argued that the barrier should be 
lowered or removed. In fact, I do not believe that we should be putting 
inferior medical products on the market, nor do the American people 
want inferior products to be used in medical practice. The belief that 
we should have evidence of benefits and risks before marketing in 
health care has been a driving force in my career and a motivation to 
develop more effective, efficient and unbiased ways of conducting 
generalizable clinical trials and implementing quality systems for 
learning in health care as a focus of my academic and practical work.
    In summary, the purpose of the slide is to point out an issue that 
is motivational for people who want to develop medical products that 
prevent death and reduce disability: there is a requirement to 
demonstrate that your product is safe and effective before you market 
it and that it does not put people at risk, compared to the clinical 
care that is currently accessible. This is a good thing and forms the 
basis for the benefit of a strong FDA to make these determinations, and 
it places a special responsibility on innovators to develop the 
evidence base that can ensure the FDA (on behalf of the American 
public) that the product is safe and effective.
    With these requirements (i.e., appropriate barriers) in place, it 
is reasonable to ask the question, what can FDA do to enable innovators 
to develop new approaches and technologies, maintaining the same 
standards, but reducing the cost and time so that Americans can get 
access to new technologies that are safe and effective and so that 
investors continue to invest in this enterprise, which is essential to 
our health and vital to our economy? Among a longer list, my top three 
responses would be:

     Reform the clinical trials system, using the principle of 
Quality by Design, so that a combination of small, focused trials for 
precision medicine and very large trials using electronic health 
records for inclusion of important populations can be conducted at a 
dramatically lower cost per unit of knowledge. The small precision 
medicine trials are lower cost because of lower sample size and the 
very large, inclusive trials will be lower cost because they will take 
advantage of data already collected and the novel methods of community-
based research. FDA's Sentinel project is an excellent building block 
with claims data on over 170 million Americans available to evaluate 
the safety of drugs and biologics, but the same system with 
modifications could be used to dramatically reduce the cost of data 
collection in clinical trials. Direct involvement of patients will also 
enable us to streamline, because a more involved public, together with 
more trials relevant to the needs of patients will lead to faster 
enrollment.
     A second key approach is to continue to improve the 
communication between FDA and the scientific community. In every case 
where FDA has offered more meetings with sponsors, the opportunity has 
been over-subscribed. In addition, public-private partnerships have 
been highly successful in promoting multi-sector dialog and developing 
a common view of key issues in medical product development, including 
the Medical Device Innovation Consortium and the Clinical Trials 
Transformation Initiative.
     Finally, effective interactions between FDA and its 
Federal partners can be an important factor in maintaining the 
appropriate standard while reducing the cost of medical product 
development. The FDA-National Institutes of Health (NIH) Leadership 
Council is a successful collaboration between FDA and NIH, focused on 
clarifying the biomarker-surrogate-clinical outcome continuum and 
streamlining clinical trials.

    There are many other measures to achieve the goal of optimizing the 
efficiency of the effort to produce useful, safe, and effective medical 
products based on high-quality evidence.

    Question 2b. In your academic work, you have argued for expanding 
the size of certain clinical trials. What impact would larger clinical 
trials have on the cost and speed at which innovative new treatments 
come to market? Are there specific policies you would promote that 
would affect the size of future trials, and would those policies be 
tailored to particular types of trials?
    Answer 2b. As discussed above, the principle of Quality by Design, 
an initiative that FDA is already undertaking, will lead to some trials 
that are ``targeted,'' when the therapy is expected to have a large 
effect in a small subpopulation, and others that will need to be much 
larger to ensure that the treatment is safe and effective across the 
spectrum of patients likely to be treated. The targeted trials are made 
possible by the dramatic advances in molecular biology and precision 
medicine methods, and the larger trials are made possible by the 
ubiquity of electronic health records and social media. Quality by 
Design is a risk-based approach to pharmaceutical development and 
manufacturing that has been described in numerous FDA guidance 
documents. In recent years, this approach has been increasingly 
recognized as having significant applicability to the development of 
clinical trial protocols and is now included in an FDA guidance 
document on risk-based monitoring.
    Another consideration is that rare diseases will continue to need 
special trial considerations, especially when there is no effective 
treatment. As information and communication technologies advance, 
however, we can also develop new methods to improve enrollment in these 
trials.

    Question 3. Will you commit to requiring FDA staff to act through 
rulemaking, rather than through the guidance process, when (a) it 
intends to legally bind regulated parties or (b) it expects regulated 
parties to change their behavior in burdensome or costly ways?
    Answer 3. The Federal Food, Drug, and Cosmetic Act (FD&C Act), and 
FDA's own regulations, set forth clear criteria for determining whether 
guidance is appropriate and provide for ample opportunity for public 
consideration of, and comment on, FDA guidances. I commit to working to 
ensure that the Agency continues to follow the requirements set forth 
in these authorities and issue guidance only where appropriate.\1\
---------------------------------------------------------------------------
    \1\ In addition, the Administrative Procedure Act (APA) (5 U.S.C. 
551-59) prescribes procedures for an agency issuing a ``rule,'' which 
is defined as ``an agency statement of general or particular 
applicability and future effect designed to implement, interpret, or 
prescribe law or policy or describing the organization, procedure, or 
practice requirements of an agency'' (5 USC 551(4)). For legislative 
and substantive rules that create a new law, rights or duties, the APA 
requires that agencies, among other things, provide the public with 
adequate notice of a proposed rule followed by a meaningful opportunity 
to comment on the rule's content.
---------------------------------------------------------------------------
    When issuing guidance, FDA complies with the requirements set forth 
in the FD&C Act as well as its own good guidance practices (GGPs). 
Section 701(h)(1)(A) of the FD&C Act outlines the procedures that FDA 
must adopt when issuing guidance relating to its initial 
interpretations of a statute or regulation, changes in interpretation 
or policy, and existing practices or minor changes in policy. The FD&C 
Act requires that the Secretary develop guidance documents with public 
participation and makes clear that guidance documents ``shall not 
create or confer any rights for or on any person.''
    FDA's GGP regulation provides greater detail regarding the 
circumstances when guidance is appropriate and the procedures that must 
be employed when the Agency issues guidance. The GGP regulation 
explains that guidance documents are intended to describe the Agency's 
interpretation of policy on a regulatory issue, but are not intended to 
be binding documents or establish legally enforceable rights or 
responsibilities that bind the public or FDA (21 CFR 10.115). Guidance 
documents contain a statement of this non-binding effect.\2\
---------------------------------------------------------------------------
    \2\ That said, in certain instances, FDA is expressly authorized by 
statute to promulgate guidances with binding effect. In such cases FDA 
clearly explains the extent to which such guidance is binding, based on 
the requirements in the statute, in the guidance document itself. See, 
e.g., Guidance for Industry: Necessity of the Use of Food Product 
Categories in Food Facility Registrations and Updates to Food Product 
Categories (October 2012), available at http://www.fda.gov/
RegulatoryInformation/Guidances/ucm324778.htm.
---------------------------------------------------------------------------
    FDA's guidance documents are a valued resource for many external 
stakeholders, including industry and patient advocacy groups, because 
they can serve as a means of conveying FDA's current thinking on 
important issues, such as the most current scientific practices related 
to product development. Often the Agency's guidance documents are 
issued in response to stakeholder requests. Guidance is a helpful tool 
that allows the Agency to inform stakeholders about its views on 
scientific and technical policy issues. Small businesses are often 
particularly interested in and reliant upon Agency guidances on such 
topics.

    Question 4a. Food and medical products regulated by FDA 
increasingly are imported from other countries into the United States. 
Currently, FDA is not able to clear many time-critical and often 
temperature-sensitive shipments quickly enough for them to arrive at 
their destinations intact and when they are needed.
    How do you think FDA can improve its ability to process time-
sensitive shipments by commercial express carriers in a timely manner 
to minimize the expense and disruption that even short delays can 
cause?
    Answer 4a. FDA continues work on streamlining, improving, 
standardizing, and clarifying import processes and has initiated a 
number of efforts designed to process imported shipments more 
efficiently. FDA is a Participating Government Agency (PGA) involved in 
the ACE/ITDS (Automated Commercial Environment/International Trade Data 
System) project, which is designed to provide the import community with 
a single window for importing into the United States, commonly referred 
to as ``One U.S. Government at the Border,'' to streamline the entry 
process and provide improved messaging to the trade community.
    FDA is currently running a Secure Supply Chain Pilot Program 
(SSCPP) for pharmaceuticals. The SSCPP is allowing FDA to assess the 
various entities and processes involved in a repetitive-type import 
chain; and if found acceptable and if all information is accurately 
submitted at the time of entry, it would allow for more and quicker 
system-based releases of shipments (as opposed to having to manually 
verify required information). If successful, the expansion of this 
program will help expedite the admissibility process for 
pharmaceuticals originating from known sources, destined for known U.S. 
entities.
    In addition, FDA is participating with U.S. Customs and Border 
Protection (CBP) in a trusted Trader Program designed to facilitate the 
importation process for selected firms. CBP issued a Federal Register 
Notice announcing a test program on June 16, 2014. FDA has been 
involved in the review of applications. The pilot will begin after the 
applicant awardees have been notified and CBP receives confirmation of 
the intent to participate.
    FDA is in the process of implementing the Voluntary Qualified 
Importer Program (VQIP) for human and animal food to help facilitate 
the import entry of products from importers who demonstrate a high 
level of control over the safety and security of their supply chains. 
VQIP importers must offer FDA various assurances of compliance, 
including facility certifications of their foreign suppliers of VQIP 
products, in exchange for the expedited release of entries of those 
products imported into the United States. FDA continues to work on the 
operational design of VQIP; currently, IT requirements are being 
addressed and importer user fees are under development.
    To improve transparency, FDA developed and deployed the Import 
Trade Auxiliary Communication System (ITACS), which facilitates two-way 
communication with the import trade community. ITACS allows users to 
check the status of FDA-regulated entries and lines, to submit entry 
documentation, and to submit the location of goods availability for 
those lines targeted for FDA exam. The system is currently undergoing 
enhancements to allow for FDA notifications to be sent directly to 
regulated industry via electronic means, which will allow for more 
timely and efficient communications.
    FDA has conducted a centralized entry review pilot for courier 
operations. The results of this pilot are currently under review as a 
possible model for centralized entry review and staffing for all 
couriers that could expand Agency operations and better mirror the 
courier business model.
    FDA is evaluating a dashboard intended to allow real-time 
monitoring of all aspects of the import process to determine if 
backlogs are forming and if delays are occurring, so that resources can 
be allocated before an issue arises.
    In addition, FDA has proposed a request for new authority to assess 
user fees on international express courier facilities (or ``couriers'') 
that import FDA-regulated products into the United States. These fees 
would support part of the cost of certain inspection-related activities 
at courier facilities, including processing, examining, sampling, and 
analysis of FDA-regulated products by FDA to improve timeliness of 
processing. The fees will be charged in accordance with U.S. 
obligations under applicable international agreements (i.e., General 
Agreement on Tariffs and Trade (GATT), North American Free Trade 
Agreement (NAFTA), etc.).

    Question 4b. What will you do to improve FDA's ability to use its 
electronic import review system--the PREDICT system--in a risk-based 
manner that minimizes the burdens on compliant, non-harmful shipments 
so that resources are allocated efficiently to the shipments carrying 
the highest risk?
    Answer 4b. Since December 2011, FDA has been utilizing the 
Predictive Risk-based Evaluation for Dynamic Import Compliance 
Targeting (PREDICT) screening tool to provide a more dynamic and risk-
based assessment of imported shipments. PREDICT is designed to 
calculate a customized risk score based on a wider variety of factors, 
including, but not limited to, inherent risk of the product, data 
anomalies, data quality, and the compliance history of firms (e.g., 
manufacturer, shipper, and consignee) and the product.
    FDA is continuing to improve the capabilities of PREDICT to 
minimize the impact on imported shipments. For example, many shipments 
consist of multiple commodities. Line release is a recently implemented 
enhancement to PREDICT that will allow FDA to evaluate a higher-risk 
commodity in a shipment, independent of other products that may be 
included in the same shipment but do not have the same level of risk.
    FDA has modified the PREDICT risk evaluation process from a pool of 
all FDA-regulated products to a commodity-based approach in order to 
compare products with similar risk factors. This will improve targeting 
for medium- and higher-severity products and improve the ``May 
Proceed'' rate for lower-risk commodities. As of November 2015, this 
improvement has been implemented for medical devices and diagnostics, 
biologics, human foods, pharmaceuticals, radiation-emitting products, 
and animal foods and feeds. FDA continues to work on developing the 
same approach for a number of other commodities, including vitamins and 
supplements, cosmetics, food and color additives, infant foods, house 
wares, veterinary drugs, medicated feed, and tobacco products.

    Question 5a. In recent months, FDA has sent warning letters to 
overseas drug manufacturing facilities, particularly in India and 
China, that detailed alarming violations of current good manufacturing 
practices. These violations include not only sanitary issues--such as 
bird and lizard infestations in processing facilities--but also a 
troubling number of instances in which data were falsified or obscured, 
including an instance in which an employee grabbed a memory stick and 
fled from FDA inspectors. While it is reassuring that FDA identified 
these violations, it also raises questions about the extent to which 
similar violations in other imports are going undetected.
    Section 706 of the Food and Drug Administration Safety and 
Innovation Act, signed into law on July 9, 2012, enables FDA to request 
records in advance or in lieu of an inspection. This authority enables 
FDA to detect many data integrity issues without having to send 
inspectors onsite, thus improving FDA's ability to detect violations 
rapidly and efficiently. It is now more than 3 years since FDA was 
given this authority, but FDA still has not used it to request records 
from a particular manufacturer in advance or in lieu of an inspection. 
Why has FDA not exercised this important authority for improving its 
oversight of drug safety? When can we expect FDA to begin requesting 
records in advance or in lieu of an inspection?
    Answer 5a. FDA recognizes that the authority to request records in 
advance or in lieu of inspection under the Food and Drug Administration 
Safety and Innovation Act (FDASIA) is a potentially powerful tool for 
enhancing FDA's ability to assess drug manufacturers' compliance with 
current good manufacturing practices, and has sought to plan the use of 
this broad authority carefully via the several work streams described 
in greater detail below.
    FDA is actively engaged in projects to implement this authority, 
for example:

     Public Health Incident: Recognizing that FDASIA section 
706 represented a broad statutory authority that could potentially be 
used in many inspection contexts, FDA sought to prioritize 
implementation of the authority based on public health risk. To that 
end, in October 2014, FDA finalized procedures in the Staff Manual 
Guide (SMG) for requesting records in advance or in lieu of inspection 
in the event of a public health incident. Although FDA has not yet 
encountered a situation warranting use of a 706 request under this SMG, 
we continue to monitor appropriate opportunities for doing so.
     Pilot to Optimize On-Site Inspection: FDA is planning to 
pilot the use of the authority in advance of a small number of already-
planned inspections in 2016, and the Agency will use the results of 
that effort to inform its strategy on a broader implementation of the 
authority. FDA believes that use of 706 in advance of an inspection 
could lead to efficiencies by allowing FDA investigators to maximize 
the use of their time while onsite. FDA is seeking to assess the best 
use of this authority by gathering data through this pilot effort to 
evaluate, for example, the appropriate scope and volume of records to 
request, and the burden of producing and reviewing those records.
     Quality Metrics: The continued existence of product 
quality issues may point to increased complexities in the supply chain, 
a lack of innovation in manufacturing, a failure to adopt modern 
manufacturing technologies and robust quality management systems, or 
other factors. In the summer of 2015, FDA announced the availability of 
draft guidance for industry entitled ``Request for Quality Metrics,'' 
and held a public meeting on the Agency's plans associated with a 
quality metrics reporting program. The draft guidance and public 
meeting were intended to gain stakeholders' perspectives on various 
aspects of the development and planned implementation of a quality 
metrics program launched under the new FDASIA authority. FDA expects 
that quality metrics calculated from the data we intend to collect 
through this program will provide objective measures that, when used 
with additional internal data, can provide the Agency with indicators 
of the effectiveness of quality systems associated with pharmaceutical 
manufacturing. These indicators are expected to be a factor in risk-
based inspection coverage, which will enable FDA to focus resources on 
facilities and products that present a greater risk to consumers.

    In addition, FDA has implemented FDASIA section 707 and issued 
guidance related to this section. Section 707 deems adulterated any 
drug that is manufactured in an establishment that delays, limits, 
denies, or refuses to permit entry or inspection. In the FDA final 
guidance issued in October 2014, we specified that under circumstances 
delaying, denying, limiting, or refusing a request for records in 
advance or in lieu of an inspection under section 707 of FDASIA may 
also result in a drug being adulterated under the FD&C Act.\3\ In such 
circumstances FDA may issue an import alert that notifies FDA's field 
staff that the Agency has enough evidence or other information to 
refuse admission of future shipments of that imported product.
---------------------------------------------------------------------------
    \3\ Guidance for Industry: Circumstances that Constitute Delaying, 
Denying, Limiting, or Refusing a Drug Inspection. http://www.fda.gov/
downloads/RegulatoryInformation/Guidances/UCM360484.pdf.

    Question 5b. At your confirmation hearing, you stated that you have 
``major concerns about reimportation'' of drugs from other countries, 
including Canada. Would you please elaborate on these concerns?
    Answer 5b. Drugs that are not FDA-approved nor manufactured in a 
facility inspected by FDA do not have the assurance of safety, 
effectiveness, and quality as do drugs subject to FDA oversight. There 
have been documented incidences of non-FDA-approved imported drugs 
found to be contaminated, counterfeit, containing varying amounts of 
active ingredients or none at all, or containing different ingredients 
than the FDA-approved product. Moreover, FDA would not be able to make 
safety and quality determinations for prescription drugs offered for 
import into the United States that have not gone through the U.S. 
regulatory process. In fact, FDA evaluation of non-FDA-approved 
imported drugs revealed that while nearly half of imported drugs 
claimed to be Canadian or from Canadian pharmacies, 85 percent of such 
drugs were actually from different countries. Typically, these products 
are smuggled into the United States after being transshipped to third-
party countries in an effort to avoid detection and create an 
appearance of coming through countries that consumers may find 
trustworthy. Through FDASIA Title VII and the Drug Supply Chain 
Security Act, Congress has recognized the need to bolster this closed 
drug distribution system. Authorizing importation would compromise the 
closed drug distribution system in the United States and undermine 
these laws, thus making it easier for unapproved drugs, which may 
include counterfeit or other substandard drugs, to reach American 
patients putting their treatment at risk. FDA is concerned that the 
risks of unapproved products from foreign sources outweigh any 
potential cost savings. We are also concerned that adverse events 
flowing from importation of such unapproved products could lead to 
diminished confidence in FDA-approved products.

    Question 6. The Food Safety Modernization Act was signed into law 
in January 2011. It took the agency over 4 years after the law was 
enacted to finalize five of the seven regulations required under the 
law. Congress intended this law to be flexible and risk-based, taking 
into account the very diverse food industry across our country. If 
confirmed, how will you ensure that as FDA implements this law, it 
focuses on and prioritizes high-risk activities in the food supply 
chain consistent with Congress's intent to introduce a risk-based 
framework that targets areas with a history of foodborne illness, is 
flexible, and is not overly burdensome?
    Answer 6. Since the passage of the FDA Food Safety Modernization 
Act (FSMA), the Agency has pursued a transparent process, engaging all 
stakeholders, to allow FDA to craft final regulations that provide 
sufficient flexibility across the broad spectrum of food-producing 
operations. Throughout the rulemaking process, the Agency has been 
committed to developing final regulations that are practical for 
businesses and that help ensure food is safe. An unparalleled outreach 
effort followed the original proposal of the FSMA rules. As you know, 
in September 2014, FDA issued supplemental proposals with a number of 
revisions that would add flexibility and reduce burden in key areas. 
FDA proposed these changes based on extensive outreach and feedback 
received during meetings with the public, industry groups, and consumer 
groups, and in the comments submitted to the Agency on the proposed 
rules.
    In September 2015, FDA finalized preventive controls rules for 
human and animal food, which require modern preventive practices in 
food processing and storage facilities. In November 2015, the Agency 
published additional final rules, which establish enforceable safety 
standards for produce farms and make importers accountable for 
verifying that imported food meets the same food safety standards as 
domestic products. The Agency also issued a rule establishing a program 
for the accreditation of third-party certification bodies, also known 
as auditors, to conduct food safety audits and issue certifications of 
foreign food facilities and their foods. These rules will work together 
to systematically strengthen the food safety system and better protect 
public health.
    The final rules recognize the importance of providing for 
flexibility within the requirements. For example, the final produce 
safety rule enables a State, tribe, or country to request variances if 
it concludes that meeting one or more of the rule's requirements would 
be problematic in light of local growing conditions. The State, tribe, 
or foreign country must demonstrate that the requested variance is 
reasonably likely to ensure that the produce is not adulterated and 
provides the same level of public health protection as the 
corresponding requirement(s) in the rule.
    Through our sustained engagement with stakeholders, the Agency has 
been laying the foundation for effective, efficient, and collaborative 
implementation of the new standards. The Agency intends to provide 
guidance and technical assistance to industry so that they know what is 
expected and are supported in carrying out their responsibilities. For 
example, FDA, in cooperation with the Illinois Institute of 
Technology's Institute for Food Safety and Health, has established the 
Food Safety Preventive Controls Alliance, which is developing training 
courses and materials on preventing hazards for both human and animal 
food during production.\4\ These materials will help industry--
particularly small- and medium-sized companies--comply with the new 
preventive controls rules. Our implementation strategy also calls for 
re-orienting and retraining the FDA inspection and compliance 
workforce, as well as our State food safety partners, so that we can 
provide consistent, high-quality oversight within the more preventive, 
systems-based and technically sophisticated FSMA framework.
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    \4\ http://www.iit.edu/ifsh/alliance/.
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    Going forward, FDA is committed to continuing to ensure that its 
FSMA efforts are risk-based and targeted in order to achieve the 
greatest health benefit, without placing an unnecessary burden on the 
regulated industry.

    Question 7a. In your role as Deputy Commissioner for Medical 
Products and Tobacco, you have overseen activities within the Center 
for Tobacco Products (CTP), including work to finalize a proposed rule 
to deem additional tobacco products subject to regulation. If that 
proposed rule is finalized and applies the same ``grandfather date'' 
that was written into statute for cigarettes, it will force cigars and 
other tobacco products, including most if not all electronic cigarettes 
and e-vapor products, to go through FDA's lengthy premarket tobacco 
application (PMTA) process in order to stay on or enter the market. 
Only recently has FDA acted for the first time to authorize the 
marketing of new tobacco products through the PMTA pathway, which means 
that the agency does not have an established track record of acting 
quickly on PMTAs. As a result, this rule, if finalized, is expected to 
create significant regulatory burdens on small businesses.
    If confirmed, will you commit to ensuring that FDA reviews product 
submissions in a timely manner to prevent a delay of innovative and 
novel tobacco products from entering the market and limiting consumer 
choice, which could cause citizens to lose access to products they have 
been using as less harmful alternatives to traditional smoking? As part 
of this commitment, will you agree to dedicate as much funding as 
necessary from user fees to ensure that (a) FDA acts upon PMTAs within 
the statutory timeframe, and (b) adequate resources to assist 
applicants who previously have not been subject to FDA regulation?
    Answer 7a. FDA is committed to continuing to strengthen the process 
for reviewing tobacco products to determine if they meet the statutory 
standard for marketing, including acting on applications in a timely 
way and working with applicants who have not previously been regulated.
    As you indicated, FDA recently authorized the marketing of eight 
new tobacco products under the PMTA pathway. This action shows that the 
PMTA process is a viable pathway to market for new products, if they 
meet the statutory standard, which includes the requirement that 
permitting the product to be marketed would be ``appropriate for the 
protection of the public health.'' It took FDA 8 months to issue 
decisions on these applications. Currently, the Agency does not have 
any pending PMTAs.
    FDA has made significant progress in reviewing substantial 
equivalence (SE) applications for currently regulated products and this 
momentum will continue. The Agency has increased staffing, taken steps 
to streamline the SE review process, and established performance goals 
that include timeframes for review of regular SE reports\5\ and review 
of exemption from SE requests for currently regulated products. FDA has 
been able to develop these performance goals because of increased 
capacity, efficiency, and knowledge of the scientific evidence needed 
to adequately review SE applications.
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    \5\ SE applications submitted to the Agency are divided into two 
types: ``provisional'' and ``regular.'' Products that are the subject 
of provisional applications were received prior to March 22, 2011, and 
may stay on the market unless FDA issues an order finding them not 
substantially equivalent, or NSE. Products that are the subject of 
regular applications cannot be legally marketed unless FDA issues an 
order that they are substantially equivalent to a valid predicate 
product chosen by the company.
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    As of November 1, nearly 70 percent of full regular SE reports had 
been resolved by a final decision, either because FDA issued an Order 
letter, issued a Refuse-to-Accept letter, or because the submission was 
withdrawn.
    FDA continues to improve the tobacco product review program, 
including hiring and training new staff and addressing the scientific 
policy issues that result from developing a new regulatory review 
program. We will continue to advance our efforts to review and act on 
SE reports while preparing for the PMTAs that may be submitted to FDA 
once the deeming rule is finalized.
    FDA recognizes that manufacturers of newly deemed products will 
need assistance in complying with FDA regulations. The Agency is 
committed to providing this assistance. For example, the Agency intends 
to issue guidance, hold training webinars, meet with companies at their 
request, and increase staffing in the Center for Tobacco Product's 
(CTP) Office of Small Business Assistance.

    Question 7b. If FDA finalizes this rule, it will result in an 
increased workload not only for tobacco-specific offices within CTP, 
but also for other FDA components, such as the Office of Regulatory 
Affairs, which oversees inspections and other enforcement activity, and 
the Office of Chief Counsel. Will you commit to ensuring that the 
increased workload attributable to deeming does not require FDA to 
shift resources away from non-tobacco program areas? What specific 
steps will you take to ensure that such a shift in resources does not 
occur?
    Answer 7b. The workload that will result after the tobacco deeming 
rule is final will not shift resources from non-tobacco program areas. 
The TCA states that tobacco user fees are the only funds available for 
FDA activities related to tobacco regulation. The TCA specifically 
prohibits the use of funds other than tobacco user fees for tobacco 
regulation activities. The TCA user fees are used to hire the necessary 
staff in other parts of the Agency that assist CTP in the 
implementation and enforcement of the law.

    Question 8. FDA's Office of External Affairs engages in a variety 
of patient outreach programs, often through the Office of Health and 
Constituent Affairs. One such program involves a partnership with the 
National Forum for Heart Disease and Stroke Prevention to educate 
patients about heart disease and stroke, and to encourage them to 
follow their doctors' advice about lifestyle changes--such as 
improvements in diet and exercise. Although doctors' advice regarding 
lifestyle changes may be beneficial to the public health, it is not 
clear why FDA--which regulates the safety and effectiveness of medical 
products, but not the practice of medicine--is the right agency to be 
engaging in such efforts.
    Do you believe that FDA's statutory mission includes encouraging 
patients to follow their doctors' advice regarding lifestyle changes, 
such as eating better or exercising more? Or are such efforts better 
left to other public health agencies, such as the Centers for Disease 
Control?
    What do you see as FDA's proper role in the doctor-patient 
relationship?
    Answer 8. FDA believes it is important for the Agency to keep our 
many stakeholders, including health care professionals and patients, 
informed as appropriate, when we approve important products, issue 
safety announcements, and take public health actions. Occasionally 
these communications may touch on lifestyle issues. For example, when 
FDA announced its approval of a medical device to treat obesity, our 
press release pointed out that patients who use the product must follow 
a medically supervised diet and exercise plan to augment their weight 
loss; this information is contained in the product labeling approved by 
FDA. We recognize that while many people learn about FDA's products and 
announcements from their health care providers, others learn through 
FDA's website, the news media, social media, or from family or friends, 
so we make sure that our communications include a recommendation that 
patients and consumers continue to follow their doctor's advice or to 
consult their doctor if they have any questions.
                              senator enzi
    Question. Dr. Califf, labeling of menus for chain restaurants and 
similar retail food establishments will take effect on December 1, 
2016. What steps is the FDA taking to ensure that the new uniform 
labeling standards will not be eroded by additional labeling 
requirements being added across the Nation?
    Answer. Federal law includes an express preemption provision that 
preempts

        ``any requirement for nutrition labeling of food that is not 
        identical to the requirement of section 403(q) [of the FD&C 
        Act] [21 U.S.C. 343(q)],''

except that this provision does not apply

        ``to food that is offered for sale in a restaurant or similar 
        retail food establishment that is not part of a chain with 20 
        or more locations doing business under the same name 
        (regardless of the type of ownership of the locations) and 
        offering for sale substantially the same menu items unless such 
        restaurant or similar retail food establishment complies with 
        the voluntary provision of nutrition information requirements 
        under section 403(q)(5)(H)(ix) [of the FD&C Act].''

    Therefore, State or local governments cannot have nutrition 
labeling requirements for foods sold in establishments covered by the 
final rule, unless such requirements are identical to the Federal 
requirements.
    Under the rule, consumers will have consistent nutrition 
information available to them, whenever they eat out in covered 
establishments. In addition, companies that are covered by the 
requirements won't have to display different nutrition labeling, 
depending on the geographical location.
    Restaurants and similar retail food establishments that are not 
covered under the Federal requirements would remain subject to 
applicable State or local nutrition labeling requirements, unless they 
choose to voluntarily register with FDA to comply with the Federal 
nutrition labeling requirements.
    FDA intends to work with State and local authorities, as 
appropriate, to ensure that the menu labeling requirements are 
uniformly applied.
                              senator burr
    Question 1. The field of cellular therapies continues to show 
promise for a variety of diseases, and is moving at a rapid pace. If 
you are confirmed, how would you ensure that the potential of these 
therapies are fulfilled and that their regulation by the FDA strikes an 
appropriate balance which reflects their unique characteristics in this 
rapidly advancing area of medicine?
    Answer 1. Cellular therapies are rapidly evolving and show great 
promise. Advances in molecular and cellular biology, combined with 
developments in biomedical engineering, have made the concept of in 
vitro production of tissues, and even organs, a reality. An example of 
success in this field is the artificial trachea, which consists of live 
cells layered on a scaffold.
    Due to the breadth of product types, as well as their potentially 
inherent complexity, FDA is working with stakeholders to ensure that 
regulation of these products is appropriate. Appropriate regulation 
should encourage innovation and provide Americans with timely access to 
safe and effective cellular therapies. FDA recently announced a 1-day 
public hearing to obtain input on four recently issued draft guidance 
documents relating to the regulation of HCT/Ps. These draft guidance 
documents were issued by FDA in response to stakeholders' requests for 
guidance on FDA's current views about how manufacturers, 
establishments, and distributors of HCT/Ps and health care 
professionals can meet the criteria under the Agency's regulations that 
apply to HCT/Ps. The comment period for all of these guidances will 
remain open between now and 2 weeks following the public hearing. FDA 
will carefully consider information it obtains from responses submitted 
to the docket and from the public hearing as it works to finalize these 
four guidance documents.

    Question 2. The FDA is in the midst of initial discussions with 
industry and stakeholders for the 2017 User Fee Agreements. The Agency 
is funded by both significant taxpayer dollars through the 
appropriations process as well as the user fees collected by the 
agency. The Agency is always eager for more resources. However, 
additional funding does not always translate into a more predictable 
and timely review process, or a decrease in the total time it takes for 
products to reach patients. Any agreement submitted to Congress will be 
heavily scrutinized.
    The Agency has a responsibility to balance the priorities set forth 
in these agreements as well as those set forth in law by Congress. The 
requirements and priorities that Congress sets forth are not optional. 
The agency needs to satisfy its commitments from the last agreements, 
before making any additional promises. How would you ensure the FDA 
fulfills its current commitments?
    Answer 2. The Agency takes its responsibilities under its user fee 
agreements, as well as those set forth in law by Congress, very 
seriously. We are working toward implementing each commitment, 
including through specific implementation steering committees that have 
been established for each user fee program. FDASIA requires annual 
reports to Congress, which describe the Agency's progress in achieving 
the goals of the agreement. The most recent reports can be found from 
the main User Fee site here: http://www.fda.gov/forindustry/userfees/
default.htm. Please refer to the legend on the left-hand side of the 
website to find reports and plans for program-specific user fees.

    Question 3. You stated during the nomination hearing that you are 
committed to working with the whole ecosystem of regulation for 
Laboratory Developed Tests (LDTs). If confirmed as Commissioner, how 
would you ensure that FDA regulation of LDTs does not cause the 
unintended stifling of innovative test development at research and 
public health labs? Is the FDA working with CMS to ensure that CMS 
policies are updated before any new policy from FDA is effective to 
avoid duplicative regulation? If so, what role does FDA see CMS's CLIA 
office keeping and what sections of CLIA's current regulation does FDA 
intend to overtake?
    Answer 3. FDA is committed to developing a final policy for 
oversight of LDTs that encourages innovation, improves patient 
outcomes, and strengthens patient confidence in the reliability of 
these products. Under the proposed LDT framework, FDA would phase in 
enforcement of premarket review requirements and the quality system 
regulation for some LDTs, with a risk-based approach. We proposed a 
framework that prioritizes attention on those tests that have the 
potential to pose the greatest risk to patients and the public health 
if they do not work as intended.
    FDA's premarket review is necessary to determine if IVDs generally, 
including LDTs, are analytically and clinically valid--that they will 
perform as claimed, and that patients and their physicians can rely 
upon their results to make major medical decisions. When conventional 
IVD manufacturers comply with FDA regulations and labs developing 
similar tests do not, this creates a lack of consistency across the 
diagnostic market. Inconsistent oversight also puts patients at 
considerable risk. Because most LDTs have not undergone premarket 
review for analytical or clinical validity, it is possible that 
patients may receive incorrect results from those LDTs. This could mean 
patients receive incorrect treatment recommendations if their physician 
or hospital is using an LDT. In addition to patient harm, incorrect 
treatment recommendations may increase our health care system costs 
through coverage of unnecessary treatments or more expensive 
treatments.
    This inconsistency also creates a disincentive to develop new and 
innovative tests. Conventional diagnostic manufacturers who have 
invested in the development of an IVD generally obtain premarket 
approval or clearance before packaging their tests into kits for use in 
multiple labs or health care facilities. They also register with FDA, 
list their devices, report adverse events and comply with good 
manufacturing practices. They are concerned that their laboratory 
competitors are currently not doing any of this, yet offer immediate 
competition to their own FDA-authorized tests.
    FDA and CMS have complementary, non-duplicative roles, and FDA does 
not intend to take over any of CMS's current responsibilities. CMS, 
under CLIA, focuses on the labs' overall performance, whereas FDA 
regulates lab tests. CLIA does not require premarket review of tests or 
a showing that a test is clinically valid.
    When FDA finalizes and implements its framework, both FDA and CMS 
will play a role in ensuring that LDTs are high quality--CMS through 
CLIA by continuing to focus on laboratory operations, and FDA by using 
its authority and expertise to ensure the analytical and clinical 
validity of the laboratory tests.
    Although the roles of the agencies are different, FDA and CMS share 
an interest in ensuring effective and efficient oversight of LDTs so 
that laboratories can offer tests to the American public with 
confidence that are accurate and provide clinically meaningful 
information, without unnecessary or duplicative agency oversight.
    To coordinate efforts across the Department, FDA, and CMS 
established an interagency task force this past April that will 
continue and expand on our collaboration related to the oversight of 
LDTs. The task force, comprised of leaders and subject matter experts 
from each agency, will work to address a range of issues, including 
those involving quality requirements for LDTs.

    Question 4. From 2010-14, the FDA spent almost $2 billion on 
external IT contracts. What are the results of these investments? Have 
these investments translated into more timely or faster review periods 
and/or resulted in an increase in the number of FDA-approved products? 
As Commissioner, how would you ensure that investments like these are 
effectively utilizing taxpayer and industry dollars?
    Answer 4. FDA is committed to securing, supporting and enhancing 
its technological capabilities in furtherance of FDA's mission to 
protect the public health, support scientific excellence, and promote 
innovation and collaboration.
    By investing and improving our information technology 
infrastructure, FDA has deployed state-of-the-art IT functionality 
through new systems and upgrades to existing systems to facilitate and 
improve the review of drugs and medical devices. These capabilities 
include electronic submissions processing, advanced search engines, and 
business intelligence capabilities. We are supporting ``media-less,'' 
electronic-only submissions through dedicated client and web portal 
software for premarket and post-market information, enhanced search and 
database functionality with the use of search engines and NoSQL 
databases, and upgraded data mining and reporting for signal detection 
and trend identification.
    As FDA continuously seeks new and innovative technological 
solutions to fulfill its mission, we are working to implement state-of-
the-art technologies and technological improvements that would further 
support and enhance the Agency's initiatives. These innovative 
capabilities include increased automation in the development, 
deployment and maintenance of FDA's information systems, using modern 
technology approaches which will allow for reduced cost and more rapid 
deployments of new systems. In addition we are expanding our data 
network capacity to provide the improved ability to transfer very large 
data files between industry and FDA, as well as internally within HHS. 
The need for expanded network infrastructure is to support and manage 
the very large data sets that enter FDA and allow us to continue to 
expand on our scientific research capabilities.
    Investments such as the FDA Electronic Submissions Gateway (ESG) 
and the Document Archiving, Reporting & Regulatory Tracking System 
(DARRTS) allow FDA to receive and review a significantly increased 
volume of applications. Without these investments, FDA would be unable 
to respond to the increased volume in a timely fashion; for example, 
within the goal timeframes outlined in FDA's user fee performance 
commitments. Additionally, through FDA's Adverse Event Reporting System 
(FAERS) and the Safety Reporting Portal (SRP), FDA is able to more 
efficiently and effectively monitor and report on safety issues in 
accordance with our mission to protect the public health. FDA will 
continue the regular review of the performance of these investments. We 
will review and prioritize funding for IT investments to prevent waste 
and ensure emerging needs are met. Further, we will closely monitor IT 
systems, such as ESG, to safeguard the confidentiality of industry's 
sensitive and protected data.

    Question 5. As you stated during your nomination hearing, the FDA 
is committed to reviewing applications in the Center for Tobacco 
Products according to the agreed upon timelines, which are set forth in 
the Family Smoking Prevention and Tobacco Control Act and require the 
agency to act within 180 days of receiving an application. 
Communication between the agency and the industry it regulates is also 
an important component of a timely review and approval process. As 
Commissioner, how would you ensure that the CTP maintains adequate 
lines of communication with the entities it regulates?
    Answer 5. FDA is committed to communicating with regulated entities 
and reviewing tobacco product applications in a timely manner. The only 
application review timeframe specified in the TCA is for Premarket 
Tobacco Applications. That timeframe is 180 days. We agree that it is 
important for FDA to make tobacco product review decisions in a timely 
manner. It is absolutely critical that these decisions are sound ones, 
grounded in the best-available science, and made in accordance with 
applicable public health standards.
    In 2009, as a new regulatory entity, FDA's CTP needed to establish 
and develop processes for the review of tobacco products that 
manufacturers wanted to bring to market. This had never been done by 
any regulatory body anywhere in the world, and initial review times 
were not as short as we would expect them to be with a more established 
program.
    FDA has made significant progress in reviewing SE applications for 
currently regulated products and this momentum will continue. The 
Agency has increased staffing, taken steps to streamline the SE review 
process, and established performance goals that include timeframes for 
review of regular SE applications and review of exemption from SE 
requests for currently regulated products. FDA has been able to develop 
these performance goals because of increased capacity, efficiency, and 
knowledge of the scientific evidence needed to adequately review SE 
applications.
    The ability to communicate with regulated entities is critical to 
the success of FDA's program to review tobacco product applications. 
FDA has provided many educational materials to help manufacturers 
complete quality product applications that the Agency will be able to 
review in a timely manner. In addition, the Agency assists 
manufacturers on an individual basis at their request. To demonstrate 
FDA's commitment to be responsive to industry and other external 
stakeholders, in October 2014, CTP implemented a performance measure 
for fiscal year 2015 to respond to 80 percent of meeting requests from 
industry and other external stakeholders within 21 calendar days. This 
performance measure increases to 90 percent in fiscal year 2017.\6\
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    \6\ http://www.fda.gov/tobaccoproducts/newsevents/ucm393894.htm.
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    The Agency also communicates with regulated entities by regularly 
attending their conferences and public meetings. Since spring 2014, the 
Director of CTP has spoken at the Tobacco Merchants Association, the 
Global Tobacco Network Forum, the National Association of Tobacco 
Outlets, the Smoke-Free Trade Association, and the National Association 
of Convenience Stores. This is in addition to numerous meetings held 
with industry at their request.
    FDA also looks for opportunities to proactively communicate with 
regulated entities. This will be especially important for manufacturers 
of newly deemed products who will need assistance in complying with FDA 
regulations. The Agency is committed to providing this assistance. For 
example, the Agency intends to issue guidance, hold training webinars, 
meet with companies at their request, and increase staffing in CTP's 
Office of Small Business Assistance.
                            senator isakson
    Question 1. I appreciate all the work that the FDA has done to 
implement the Drug Quality Safety Act (DQSA), and the numerous work 
streams that the Agency has had to initiate to make this important 
legislation work. However, I am concerned that the Agency's 
implementation efforts may cause some unintended consequences outside 
of the parameters that Congress intended be regulated by the law. For 
example, several months ago FDA issued a draft guidance addressing 
repackaging under the authority of the DQSA. I understand that the 
Agency's draft is sweeping in scope, and is very broad in its 
application. More specifically, I understand that the draft guidance, 
if implemented, would fundamentally and negatively change the way in 
which prescription medications are distributed to nursing home 
residents by specialized long-term care pharmacies. As you may be 
aware, long-term care pharmacies that serve nursing home residents are 
obligated by law to dispense individual patient prescriptions in unit-
dose packaging and through emergency kits that can be prepositioned in 
the home in the case of emergencies. Yet, I am told the draft guidance 
may prevent these pharmacies from providing the needed medications to 
residents in unit dose packaging and emergency kits to meet other 
requirements of both Federal and State laws.
    What assurance can you give that the FDA will promptly address and 
correct this seemingly unintended consequence of its draft guidance, 
and how can the Agency improve stakeholder engagement before such 
Guidance is ever issued?
    Answer 1. Title I of the Drug Quality and Security Act (DQSA), the 
Compounding Quality Act, amended the FD&C Act concerning compounded 
human drugs. However, the legislation did not address repackaged drugs, 
which are generally not exempt from any of the provisions of the FD&C 
Act related to the production of drugs. Therefore, on February 13, 
2015, FDA published draft guidance, Repackaging of Certain Human Drug 
Products by Pharmacies and Outsourcing Facilities, to describe the 
conditions under which FDA does not intend to take action regarding 
violations of certain requirements of the FD&C Act, if a State-licensed 
pharmacy, a Federal facility, or an outsourcing facility repackages 
human drug products.
    In June and July 2014, prior to issuance of the draft guidance, FDA 
engaged with approximately 40 stakeholder groups during listening 
sessions regarding compounding and related activities, including 
repackaging. FDA then published the guidance in draft form to seek 
input and feedback from stakeholders regarding its proposed policies. 
The Agency received approximately 625 comments on the draft guidance, 
mostly concerning its implications for long-term care pharmacies and 
the facilities they serve. Since publishing the draft guidance, FDA has 
held listening sessions with members of approximately 60 stakeholder 
groups, including long-term care organizations, to hear their views 
regarding the draft guidance and other issues related to compounding 
and repackaging. FDA is considering all of the issues raised in the 
comments as well as the input we received during the listening 
sessions, before finalizing the draft guidance.

    Question 2a. CBER, or the Center for Biologics Research and 
Evaluation, has issued a series of Untitled Letters related to product 
classification of tissue products. FDA's Regulatory Procedures Manual 
explains that an Untitled Letter

        ``cites violations that do not meet the threshold of regulatory 
        significance for a Warning Letter. Therefore, the format and 
        content of an Untitled Letter should clearly distinguish it 
        from a Warning Letter.''

    Unfortunately, several of these recent CBER Untitled Letters are 
not distinguishable at all from Warning Letters. Because CBER posts 
these documents on its website and they are read exactly like Warning 
letters, these Untitled Letters have caused great disruptions and 
uncertainty for industry including damage to companies.
    Why has FDA begun issuing Untitled Letters rather than trying to 
have a dialog with the company first about the product classification?
    Answer 2a. FDA's Untitled Letters often serve as the initial 
communication with regulated industry concerning regulatory violations. 
But, FDA also uses other means to communicate and resolve questions 
with manufacturers.
    For example, the Center for Biologics Evaluation and Research 
(CBER) formed the Tissue Reference Group (TRG) to assist stakeholders 
on questions regarding human cell tissues and cellular and tissue-based 
products (HCT/Ps). The purpose of the TRG is to provide a single 
reference point for product-specific questions received by FDA 
concerning jurisdiction and applicable regulation of HCT/Ps. FDA has 
publicly posted information on how manufacturers can submit inquiries 
to the TRG and publicly discloses information related to TRG 
recommendations on the CBER website.
    If FDA issued an Untitled Letter subsequent to an establishment 
inspection, the FDA investigator may have already informally discussed 
the situation, though they are not required to do so. In determining 
whether to issue an Untitled Letter, FDA officials generally consider 
whether evidence shows that a firm, product, and/or individual is in 
violation of the law or regulations. Such evidence may have been 
obtained during a routine or directed inspection, or other means of 
surveillance, such as Internet website surveillance.
    Untitled Letters should be clearly distinguishable from Warning 
Letters in their format and content. For example:

     The letter is not titled.
     The letter does not include a statement that FDA will 
advise other Federal agencies of the issuance of the letter so that 
they may take this information into account when considering the awards 
of contracts.
     The letter does not include a warning statement that 
failure to take prompt correction may result in enforcement action.
     The letter does not evoke a mandated district followup.
     The letter requests (rather than requires) a written 
response from the firm within a reasonable amount of time (e.g., 
``Please respond within 30 days''), unless more specific instructions 
are provided in a relevant compliance program.

    Untitled Letters are not limited to potential product 
classification issues, but are generally a mechanism to communicate and 
provide notice of a violation. These letters ordinarily provide the 
factual basis regarding the violation and serve to communicate the 
concern without committing FDA to enforcement action, if the violation 
is not corrected.

    Question 2b. Why is FDA insistent that such letters must be posted 
on their website? FDA has Center-specific policies as to whether to 
post Untitled Letters, except to the extent that it overlaps with FDA's 
approach to proactive posting under the Freedom of Information Act 
(FOIA).
    Answer 2b. FDA's posting approach under FOIA requires the posting 
of any FDA record subject to the FOIA, such as an Untitled Letter if:

    1. FDA has received three or more FOIA requests for a copy of the 
record, or
    2. If the content related to is a matter of significant public 
interest and we expect to receive multiple FOIA requests for it.

    This approach is consistent with Federal law, guidelines from the 
Department of Justice, President Obama's January 21, 2009, FOIA 
Memorandum, and Attorney General Holder's March 19, 2009, Memorandum (5 
U.S.C. Sec. 552(a)(2)(D)).

    Question 2c. In light of the above, are you willing to review your 
process for Untitled Letters, especially as it relates to product 
reclassifications, and examine ways to make issuance of these letters 
fairer, more effective and more consistent?
    What are some procedural protections the agency might consider in 
this space?
    At the hearing, you said that FDA will ``do everything we can to 
produce a more even template across the FDA so that the standards are 
the same.'' Do you believe that it is important to have consistent and 
predictable standards across the FDA governing the use of Untitled 
Letters? What specific steps will you take to improve consistency and 
predictability in this area?
    Answer 2c. We are currently reviewing processes for issuing and 
posting Untitled Letters for FDA and each of our Centers. Specifically, 
we are reviewing ways that Agency and Center policies could be made 
more accessible and transparent.
    FDA believes in transparency and consistency in our procedures. We 
recognize that some stakeholders want greater uniformity in FDA's 
practices related to posting Untitled Letters. We also recognize that 
our product centers need to maintain some specific procedures to 
address the particulars of the products they regulate.

    Question 3a. The American Association of Tissue Banks (AATB) made 
CBER aware on numerous occasions that it was preparing a homologous use 
guidance proposal for FDA's consideration. That AATB proposal was to be 
discussed at the AATB-FDA liaison meeting on October 29, 2015. Given 
the exchange of agendas and meeting materials in the weeks leading up 
to the meeting, the agency was well aware of this scheduled discussion. 
However, around 5 p.m. on October 28, FDA posted its own homologous use 
draft guidance. This had the effect of rendering any substantive 
conversation about the AATB guidance impossible, as the subject matter 
was now part of an open docket which FDA cannot discuss while the 
comment period remains open.
    Why did FDA choose to release this guidance just hours before the 
scheduled discussion with AATB, which limited the ability to have the 
ability to have a meaningful discussion?
    Answer 3a. It was FDA's intention to have this guidance released 
well in advance of this meeting with AATB. The guidance was released as 
soon as the clearance process was completed. Unfortunately, AATB did 
not have enough time to review prior to the meeting. FDA was receptive 
to the comments from AATB regarding their proposed guidance, and looks 
forward to AATB's contributions through written comments on the 
guidance at the upcoming public meeting.

    Question 3b. Will FDA evaluate AATB's proposed guidance document 
during the comment period?
    Answer 3b. FDA will evaluate all comments received regarding this 
guidance, including AATB's proposed guidance, which FDA encouraged AATB 
to submit to the docket.

    Question 3c. In what area is there alignment between the AATB 
proposed guidance and FDA's draft guidance?
    Answer 3c. Both AATB's and FDA's documents share the goal of 
developing better clarity to help facilitate the development of HCT/Ps. 
FDA will carefully review the AATB proposal, as well as other comments 
received. In addition, FDA is having an open public meeting in April 
2016, and this has been announced in the Federal Register.

    Question 4a. The medical device industry continues to strive for 
the best quality and safety record possible, and believes inspections 
are an important part of this. However, there have been a growing 
number of challenges with the lack of consistency, transparency, and 
predictability in the FDA post-market inspection process. I understand 
FDA is engaging a number of efforts to reorganize their inspections 
program, such as Program Alignment.
    Can you provide me with an update on the progress of these 
initiatives?
    Answer 4a. Work continues to advance the transition to a commodity-
based and vertically integrated regulatory program (specialization of 
our inspection and compliance staffs). The Office of Regulatory Affairs 
(ORA) and the Center for Devices and Radiological Health (CDRH) are 
actively working on the action plan for the second year of Program 
Alignment (Fiscal Year 2016). The fiscal year 2016 action plan includes 
development of a medical device and radiological health curriculum to 
ensure that inspection and compliance staffs have the requisite 
knowledge and training for their commodity-specific duties. Fiscal year 
2016 is a transition year for ORA--operating in our current regional 
and district geographic structure, while planning for the 
implementation of program-based operations. Contingent upon appropriate 
approvals, standup is expected early in fiscal year 2017.

    Question 4b. Has FDA included industry's perspective in developing 
these initiatives?
    Answer 4b. The device program has multiple ongoing initiatives, and 
the device industry is engaged in many of these initiatives. The Agency 
has met, and will continue working with, industry to enhance 
communication channels and to assist us with identifying device program 
specialties and overall program enhancements. For example, we plan to 
share the medical device and radiological health curriculum with our 
stakeholders to ensure comprehension and identify current and emerging 
gaps. ORA and CDRH plan to work with our stakeholders to identify and 
leverage state-of-the-art training opportunities. We also welcome 
additional approaches to better engage with industry.

    Question 4c. How best can industry be a partner in addressing these 
challenges?
    Answer 4c. All medical device and radiological health stakeholder 
organizations (e.g., AdvaMed, MITA, MDIC, MDMA, etc.) should engage in 
regular dialog with ORA's program director for medical devices, as well 
as the device management teams in the device divisions.

    Question 4d. What other opportunities do you see for further 
improvements in the FDA post-market inspection process to address these 
challenges?
    Answer 4d. ORA will continue to work with its stakeholders to 
ensure awareness of advances in manufacturing technology and 
development of corresponding training for inspection staff.
    ORA also will continue to communicate with industry stakeholders 
about the inspection process; expectations, engagement opportunities, 
etc. ORA and CDRH, together with our stakeholders, will continue to 
identify opportunities to enhance and optimize the inspection method 
used for medical devices, and we will continue to develop feedback 
opportunities to use in process improvement.
                 senator isakson and senator murkowski
    Question. We believe that pregnant women should have access to the 
latest science-based nutrition advice that empowers them to make 
healthy nutrition decisions during pregnancy. The FDA's draft guidance 
has been pending since June 2014, and at that point, the release was 3 
years past the date of when Secretary Sebelius told us it would be 
issued. In April, we wrote to the current Commissioner along with many 
of our colleagues asking FDA to finalize this guidance in order to 
ensure that women have the best advice that reflecting the latest 
nutrition science about the types of seafood that is healthy and safe 
to eat during pregnancy. In addition to FDA's 2014 draft guidance on 
seafood nutrition advice to pregnant women, the agency also issued a 
comprehensive scientific study of the effects of consuming seafood 
during pregnancy, called the Net Effects Report. It is our 
understanding that FDA may be moving away from the findings of the Net 
Effects Report in order to finalize the advice, yet it is not clear to 
me why the agency would be shifting away from their most recent 
scientific study and contradicting its own scientific findings.
    If the agency is not consulting its own Net Effects Report, what 
new scientific study is FDA using as the basis for finalizing its 
current thinking on seafood advice for pregnant women?
    Furthermore, if FDA is using a different study, can you provide the 
source of funding for this new study or studies?
    If confirmed, will you ensure that pregnant women receive final 
guidance on nutrition advice for what seafood is safe and healthy to 
consume that is consistent, understandable, and based on FDA's latest 
scientific review of the net effects of seafood consumption?
    Answer. FDA shares your interest in ensuring that pregnant women 
have access to sound, science-driven, and clearly understandable 
recommendations that enable them to make informed decisions about their 
diets. The final seafood consumption advice for pregnant women is 
undergoing interagency review. We will continue to take steps to ensure 
that it is reflective of the latest nutrition science.
    In response to our 2014 draft advice, we received many comments on 
science related to the draft advice. FDA has not initiated any 
additional studies on this topic, but we have looked carefully at the 
comments, the scientific literature cited in the comments, and the 
scientific literature that continues to surface relevant to this topic. 
Based on the totality of the scientific evidence, we remain confident 
that pregnant women, breast feeding women, and women considering 
becoming pregnant should eat more fish, particularly fish lower in 
mercury. Completing the updated advice remains a priority for the 
Agency.
                   senator isakson and senator murphy
    Question. Every day over 1 million Americans are treated with 
medical gases. In 2012, this Committee and FDA worked together to enact 
historic reforms that we drafted, governing how this unique class of 
drugs are approved and regulated by FDA. The FDA is considerably behind 
in its rulemaking to implement this law, resulting in unnecessary 
confusion and disruption to the provision of medical gas. In fact, 
there have been recent enforcement actions in Iowa, New Jersey, Ohio 
and Florida trying to apply FDA regulations that the agency has 
acknowledged should not apply to medical gases, such as expiration 
dating. And as communicated by both Houses in the Appropriates Bill 
Report Language, guidance and inspector training alone is not adequate.
    If confirmed, will you commit to updating FDA's regulations to 
address the longstanding enforcement issues as to medical gas?
    Answer. As required in FDASIA, FDA reviewed Federal drug 
regulations that apply to medical gases, and submitted a Report to 
Congress in June 2015. During that process, FDA sought public comments 
through meetings and a public docket.
    As described in that report, FDA has determined that the current 
regulatory framework is adequate and flexible enough to appropriately 
regulate medical gases, with regard to most issues. FDA can work within 
the existing regulatory framework to regulate the production and 
distribution of medical gases without rulemaking, for example, through 
publication of revised guidance to industry and revisions to FDA's 
medical gas inspection program and related inspection training.
    FDA is currently engaged in a number of activities intended to 
reduce any regulatory uncertainty and clarify expectations for industry 
and the public, including additional training of inspectors, issuing an 
updated compliance guide inspection program, and updating the 2003 
draft guidance to industry on CGMPs for medical gases, with input from 
stakeholders, including industry.
    Also, as stated in FDA's Report to Congress on the regulation 
review, FDA has determined that certain regulation changes regarding 
warning label statements and adverse event reporting are or may be 
needed, and FDA will continue to evaluate the need for regulatory 
changes on an ongoing basis. FDA expects to maintain open communication 
with industry, Members of Congress, and other stakeholders as 
appropriate, and will continue to evaluate and address medical gas 
issues as needed.
                            senator collins
    Question 1. I am concerned about the sudden, aggressive price hikes 
in certain off-patent drugs where there is just one supplier. This to 
me represents a market failure that hurts patients and providers and 
increases costs for Federal and State programs too. Do you have any 
initial thoughts of what the FDA could do to bring to market generic or 
safe foreign drugs to compete with these prescriptions drugs to put 
pressure on costs?
    Answer 1. I appreciate the concerns about drug costs. FDA works as 
quickly as possible to get safe and effective generic drugs to the 
market and will continue to evaluate other steps that may be able to be 
taken to address this concern. It is important to note, however, that 
FDA's role is to review drug applications for the statutory approval 
criteria but this authority does not extend to reviewing or approving 
drug costs or pricing, which are set by manufacturers and distributors. 
That said, FDA is concerned that the prices of drugs can interfere with 
patients' access to drugs, including lifesaving therapies. By making 
safe and effective generic drugs available, there is greater price 
competition with innovator drugs, resulting in significant drug cost 
savings to the American people.
    Through GDUFA, the Agency has built up the infrastructure for a 
21st-Century generic drug program. As part of this, FDA has established 
a review prioritization policy for generic drug applications determined 
to be a priority of the Agency.
    Specifically, FDA considers certain types of ANDAs to be public 
health priorities, and expedites their review accordingly. In August 
2014, FDA's Center for Drug Evaluation and Research (CDER) updated its 
Manual of Policies and Procedures (MAPP) entitled Prioritization of the 
Review of Original ANDAs, Amendments, and Supplements. This MAPP, which 
is publicly available, describes how the review of ANDAs, ANDA 
amendments, and ANDA supplements are prioritized.
    For example, FDA considers potential ``first generic'' ANDAs to be 
a public health priority. First generics are the first generic to enter 
the market for a given branded product. Potential first generics are 
about 15 percent of our workload. All of them have been tagged as 
priorities, and their review has been expedited. This is true 
regardless of when the ANDA was submitted. In the past 3 years, we have 
approved hundreds of first generics for more than 200 new drug 
products. FDA also considers shortage-related drugs a priority, and 
expedites their review, as well as other public health priorities.
    It is important to note that regardless of FDA granting approval, 
the sponsor makes the ultimate decision whether to market the approved 
product. There are many instances of FDA granting approval and the 
sponsor, for one reason or another, deciding not to bring the product 
to the market. This has occurred even in the ``first generics'' space.
    Drugs that are not FDA-approved nor manufactured in a facility 
inspected by FDA do not have the assurance of safety, effectiveness, 
and quality as do drugs subject to FDA oversight. There have been 
documented incidences of non-FDA-approved imported drugs found to be 
contaminated, counterfeit, containing varying amounts of active 
ingredients or none at all, or containing different ingredients than 
the FDA-approved product. Moreover, FDA would not be able to make 
safety and quality determinations for prescription drugs offered for 
import into the United States that have not gone through the U.S. 
regulatory process. In fact, FDA evaluation of non-FDA-approved 
imported drugs revealed that while nearly half of imported drugs 
claimed to be Canadian or from Canadian pharmacies, 85 percent of such 
drugs were actually from different countries. Typically, these products 
are smuggled into the United States after being transshipped to third-
party countries in an effort to avoid detection and create an 
appearance of coming through countries that consumers may find 
trustworthy. Through FDASIA Title VII and the Drug Supply Chain 
Security Act, Congress has recognized the need to bolster this closed 
drug distribution system. Authorizing importation would compromise the 
closed drug distribution system in the United States and undermine 
these laws, thus making it easier for unapproved drugs, which may 
include counterfeit or other substandard drugs, to reach American 
patients putting their treatment at risk. FDA is concerned that the 
risks of unapproved products from foreign sources outweigh any 
potential cost savings. We are also concerned that adverse events 
flowing from importation of such unapproved products could lead to 
diminished confidence in FDA-approved products.

    Question 2. Dr. Califf, I would like to relay some ongoing 
frustrations I am hearing from grocery stores regarding the FDA's 
handling of the menu labeling regulations. There are clear differences 
between chain restaurants with pre-printed menus and grocery stores 
with salad bars, yet the menu labeling rule does not reflect this fact 
and is a one-size-fits-all regulation.
    Former Commissioner Margaret Hamburg, just days before she left 
office, told the Senate Agriculture Appropriations Subcommittee, on 
which I serve, that supermarkets had legitimate concerns that required 
additional guidance and flexibility. It then took more than 10-months 
for the agency to provide ``draft'' guidance, which confused the 
situation even more.
    One point that illustrates the need for flexibility is with local 
and seasonal foods. In Maine, you will see salad bar offerings or other 
menu items that are made with local blueberries or seafood. These foods 
may be sold at one or two stores, under the same name as 20 or more 
other stores, but the ingredients or recipe may vary from store-to-
store. Under FDA's rules, these would all be considered ``standard menu 
items,'' and require a store manager to provide a calorie-count for 
each of these locally made foods before selling them to their 
customers. Concerns have been raised that this will cause a store 
manager to move away from offering truly fresh and local items and 
instead outsource them to a central kitchen or standardized, pre-
packaged food offerings. The date for complying with this menu labeling 
rule has been pushed out until December 2016, however, I am concerned 
that the rule is still burdensome for many who will have to follow it.
    Would you be willing to explore ways to provide additional 
flexibility for these grocery store settings before compliance begins?
    Answer 2. The final menu labeling rule applies to standard menu 
items sold at covered establishments. There is flexibility built into 
the final rule. If a food is not routinely included on a menu or menu 
board or routinely offered as a self-service food or food on display at 
a covered establishment, it is not a standard menu item and, therefore, 
is not covered by this rule. Also, if a food's ingredients and recipe 
changes daily based on food available in the store, it is likely that 
the food would not be a standard menu item but rather a daily special, 
and thus exempt from the provisions of this rule. Also, temporary menu 
items or a self-service food and food on display that is offered for 
sale for less than a total of 60 days per calendar year are exempt.
    Further, daily specials that are not listed regularly on the menu 
are also exempt from the provisions of this rule.
    If a covered establishment offers salad bar offerings or other menu 
items prepared using local or seasonal foods, and these menu items are 
standard menu items, they would be covered under the menu labeling 
requirements, even if they are not sold at every location within the 
chain. We note, however, that covered establishments have several means 
that can be used to determine the calorie and other nutrition 
information, including existing databases and cookbooks.
    FDA is committed to working collaboratively with establishments 
covered by the menu labeling final rule, including chain restaurants, 
covered grocery stores serving restaurant-type food, and others, now 
and in the future, to answer questions. In addition, we will be 
providing educational and technical assistance for covered 
establishments and for our State, local, and tribal regulatory partners 
to support consistent compliance nationwide. We will work flexibly and 
cooperatively with individual companies making a good faith effort to 
comply. FDA believes that this cooperative approach helps to improve 
the dialog surrounding the requirements and facilitates successful 
implementation in a practical way.

    Question 3. Dr. Califf, the Department of Health and Human Services 
Inspector General listed the cybersecurity of networked medical devices 
as a new priority for oversight in 2016, writing that they pose a 
growing threat to the security and privacy of personal health 
information. Moreover, the research technology firm Forrester has 
predicted that hackers will release ransomware for medical devices that 
would allow criminals to take control of a medical device and hold the 
power to hold that device's control ransom until the victims meet the 
attacker's demands.
    I understand FDA has started to take steps to address this problem, 
including releasing final guidance last year on its expectation that 
cybersecurity will be baked into the design of future medical devices. 
Many networked medical devices in use today, however, were created 
before cybersecurity was even a consideration. Dr. Califf, what role do 
you see for FDA in helping to address vulnerabilities that exist in 
these legacy medical devices?
    Answer 3. FDA is taking a proactive approach to mitigating any 
medical device cybersecurity vulnerabilities that could pose a threat 
to patient safety. The landscape of medical device cybersecurity is 
complex, and a commitment from multiple stakeholders--including device 
manufacturers, cybersecurity researchers, hospitals, and others--is 
necessary.
    FDA's approach embraces the National Institute of Standards and 
Technology (NIST) framework of ``identify, protect, detect, respond and 
recover'' in assuring the safety and effectiveness of medical devices 
and in facilitating medical device manufacturers and other stakeholders 
in the Health and Public Health Critical Infrastructure Sector to 
engage, assess, and address cybersecurity vulnerabilities before they 
are exploited. To that end, FDA's 2014 guidance addresses the Agency's 
premarket expectations to address cybersecurity vulnerabilities. FDA 
has established a Cybersecurity Working Group within the Center for 
Devices and Radiological Health to focus on Agency activities related 
to device cybersecurity. The Agency also partners with other Federal 
entities, such as the Department of Homeland Security's Industrial 
Control Systems Cyber Emergency Response Team (ICS-CERT) to quickly 
address cybersecurity vulnerabilities when they are identified and to 
facilitate communication among relevant stakeholders.
    FDA is currently working on, and plans to soon publish, draft 
guidance to address post-market concerns regarding the cybersecurity of 
medical devices. This includes ``legacy medical devices,'' some of 
which have been on the market before present-day cybersecurity concerns 
existed. In particular, the draft guidance will State FDA's 
expectations with regard to cybersecurity risk management across the 
total product life cycle. It will emphasize the need for vigilance, 
continuous monitoring and ongoing cybersecurity risk management, not 
just before commercialization or procurement, but for the entire 
lifespan of the product.
    Additionally, in the coming weeks, FDA will announce a medical 
device cybersecurity workshop to be scheduled for January 2016. As a 
followup to the previously held October 2014 workshop, this workshop 
will emphasize the total product life cycle and will bring diverse 
stakeholders together to present progress as well as persistent 
challenges in information-sharing, implementation of voluntary 
frameworks, vulnerability disclosure, and proactive vulnerability 
management.

    Question 4. Dr. Califf, I am pleased with the continued progress 
toward strengthening the role and voice of the patient in the medical 
product development process and the leadership that the FDA has shown. 
The patient voice is critical in understanding what patients value and 
the risk they are willing to accept in exchange for any potential 
benefit from any medical product.
    To ensure that patient-focused drug development tools are of a 
caliber appropriate for FDA reviewers, do you see a role for publicly 
reporting how such tools are being used in product reviews?
    Answer 4. I certainly agree that patient engagement in the drug 
development process is critical, and I look forward to continuing FDA's 
leadership in this area. In the last several years especially, the 
Agency has made significant efforts to publicly involve the patient 
community in product development in a variety of ways. Given that our 
activities have been public, I do not believe that a formal reporting 
mechanism is needed and instead would commit to continuing the Agency's 
transparency activities around these issues. Below are some examples of 
the work FDA has done to date on this important issue.
    The engagement by Parent Project Muscular Dystrophy (PPMD) in 
submitting their proposed guidance is an example of how early input 
from patients and caregivers can contribute to drug development. For 
the first time, the development of FDA guidance was preceded by the 
submission on June 25, 2014, of a proposed draft guidance independently 
prepared by PPMD. FDA values PPMD's effort and input and appreciates 
the insights provided by PPMD. PPMD's proposed draft guidance was 
posted on the web for public comment. Both the proposed guidance and 
public comments submitted to FDA were carefully considered in 
developing FDA's draft guidance. This example of collaboration between 
engaged stakeholders and FDA highlights how input from patients and 
caregivers can contribute to drug development.
    In addition, FDA has conducted a series of disease-specific public 
meetings to systematically gather patients' perspectives on their 
condition and available therapies to treat their condition. These 
meetings have been a rich source of information for the Agency, and we 
hope to continue them in the future. We also anticipate issuing 
guidances in the future to address scientific and methodological issues 
related to incorporating patients' perspectives in medical product 
development and subsequent regulatory review, and look forward to 
receiving public comment on these guidances. In sum, we believe that it 
is especially appropriate for the Agency to be transparent regarding 
its activities related to patient engagement, and we will continue to 
involve the patient community and other interested stakeholders.

    Question 5. Dr. Califf, we spoke last month about the FDA's 
proposed rule on electronic prescribing information and its implication 
for rural pharmacists. I continue to hear concerns that this rule, if 
finalized, would have an adverse effect on patient safety. This would 
be acutely felt by rural Americans who live in areas with limited 
Internet access. It would also affect patients and health care 
providers when electronic technologies are unavailable, including 
during a power outage or in the wake of a natural disaster or terrorist 
attack.
    Given that 96 percent of the public comments were in opposition to 
the proposal, are you willing to carefully evaluate the concerns before 
proceeding any further with this rulemaking?
    Answer 5. We encouraged patients, health care providers, and other 
stakeholders to submit comments to the docket for this proposed rule, 
with information or data supporting their concerns. In addition, in the 
preamble to the proposed rule, FDA specifically requested public 
comments on aspects of the proposal, including whether alternatives to 
request a paper copy of the prescribing information are adequate, and 
on alternative distribution systems in which both paper and electronic 
prescribing information would be available. As you know, FDA granted a 
request to extend the comment period for 60 days, until May 18, 2015. 
The Agency will consider all comments submitted in response to the 
proposal as we work to finalize the rule.

    Question 6. Dr. Califf, I want to switch gears for a minute to an 
issue of growing interest to many Americans, personal care products. 
The average consumer uses 10 personal care products every day, yet the 
laws governing the cosmetics and personal care products industry 
haven't been updated since 1938, and States have been acting on their 
own in the absence of a national standard. I have been working with 
Senator Feinstein on legislation that would modernize cosmetic safety 
laws and provide greater transparency for consumers and regulatory 
certainty for manufacturers.
    Would you agree that it is time to update the laws to better ensure 
the safety of personal care products?
    Answer 6. The Administration believes that the United States needs 
a modern and effective system of safety oversight for cosmetics. The 
President's fiscal year 2016 budget requests authority to require 
cosmetic firms to register their establishments and products with FDA 
and to pay a user fee. The product, ingredient, and facility 
information submitted with registration would expand FDA's information 
about the industry and better enable the Agency to develop necessary 
guidance and safety standards. With additional funding resources, FDA 
would be able to conduct priority activities that meet public health 
and industry goals. This authority would be an important step toward 
improving FDA's capacity to promote greater safety and understanding of 
cosmetic products. We would be pleased to work with you and your 
colleagues on the HELP Committee to achieve these and other meaningful 
enhancements to our cosmetics safety program.
                             senator hatch
    Question 1a. One issue that significantly affects many entities in 
my home State is the FDA's October 2014 proposed guidance on the 
regulation of laboratory-developed tests (LDTs).
    FDA's proposal to regulate LDTs is a significant change that would 
impose considerable new burdens on regulated parties. Why was this 
proposed by guidance, when rulemaking would be more transparent, 
provide clear and binding rules, and include a better cost assessment?
    Answer 1a. The draft guidances describe FDA's proposed new 
enforcement policy for LDTs. Issuing the proposed enforcement policy 
for LDTs via guidance, rather than regulation, is appropriate because 
FDA is communicating a change in its enforcement of applicable 
requirements that already exist in statute and regulations.
    FDA is committed to a transparent and evidence-based process in the 
development of its guidance. In 2007, FDA issued a draft guidance 
proposing to no longer exercise enforcement discretion over a certain 
category of LDTs (in vitro diagnostic multivariate index assays), but 
the lab community urged FDA to address LDTs generally, rather than take 
a piecemeal approach in order to provide for greater predictability. In 
2010, FDA held a public meeting to discuss FDA oversight of LDTs and 
also opened a public docket providing additional opportunity for public 
comment. In developing the draft guidances, FDA considered and 
incorporated many of the suggestions provided by stakeholders. In 
addition, upon issuing the draft guidances, FDA provided an extended 
comment period and provided additional opportunity for comment at a 2-
day public meeting. FDA has received 300 public comments, has met with 
numerous stakeholders, and is working to incorporate suggested changes 
into the final guidances, as appropriate.
    FDA oversight is needed to ensure that LDTs used in making major 
medical decisions are safe and effective. Due to advances in technology 
and business models, LDTs have evolved from being relatively simple 
tests that were generally only available on a limited basis to complex 
tests that have a nationwide reach and have higher risk uses, such as 
predicting breast cancer risk and directing critical treatment 
decisions, similar to those of other IVDs that have undergone FDA 
premarket review. Patients and physicians should be able to rely on the 
results of these tests to make major medical decisions.
    It is also important to note that other entities, including NIH and 
the Department of Energy in the 1990s and two advisory committees to 
the HHS Secretary after the 1990s, have been talking about the need for 
greater FDA oversight of LDTs. More recently, the Institute of Medicine 
(IOM) reinforced this as well.\7\
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    \7\ National Human Genome Research Institute (1997). Promoting Safe 
and Effective Genetic Testing in the United States. See http://
www.genome.gov/10001733.
    Secretary's Advisory Committee on Genetic Testing (2000). Enhancing 
the Oversight of Genetic Tests: Recommendations of SACGT. See http://
www4.od.nih.gov/oba/sacgt/reports/oversight_report.pdf. Accessed 
September 16, 2010.
    Secretary's Advisory Committee on Genetics, Health, and Society 
(SACGHS). U.S. system of oversight of genetic testing: a response to 
the charge of the Secretary of Health and Human Services. Washington, 
DC: Department of Health & Human Services; 2008 Apr. 276 p. Also 
available at http://oba.od.nih.gov/oba/SACGHS/reports/SACGHS.
    Institute of Medicine. Evolution of Translational Omics: Lessons 
Learned and the Path Forward. Washington, DC: The National Academies 
Press, 2012.

    Question 1b. Many stakeholders in my State and around the country 
have shared with me concerns on the impact of this proposed guidance. 
If the FDA finalizes it, how would the agency respond to potential non-
compliance from those impacted, given that FDA guidance documents do 
not have the force of law and are non-binding on FDA and regulated 
parties?
    Answer 1b. FDA is committed to developing a final policy for 
oversight of LDTs that encourages innovation, improves patient 
outcomes, and strengthens patient confidence in the reliability of 
these products. The Agency's premarket review is necessary to determine 
if IVDs generally, including LDTs, are analytically and clinically 
valid--that they will perform as claimed, regardless of where they are 
developed, and that patients and their physicians can rely upon their 
results to make major medical decisions.
    Under the proposed LDT framework, FDA would phase in enforcement of 
premarket review requirements and the quality system regulation for 
some LDTs using a risk-based approach. This approach will allow for a 
clear and transparent process for those clinical laboratories complying 
with premarket review requirements. We appreciate concerns from 
laboratories and others about the FDA oversight proposal, and have 
proposed a framework that prioritizes attention on those tests that 
have the potential to pose the greatest risk to patients and the public 
health, if they do not work as intended.

    Question 2. Many entities are engaging in criminal activity by 
manufacturing and marketing products that masquerade as ``dietary 
supplements'' but contain anabolic steroids, active pharmaceutical 
ingredients (APIs), or analogues of APIs. With the large number of 
legitimate dietary supplement companies who manufacture and market safe 
products to consumers, it is imperative that illegal manufacturers and 
marketers be removed to protect the public health. I was very pleased 
to see the FDA join with the Department of Justice (DOJ) and other 
Federal agencies in announcing a sweep of criminal and civil actions on 
Tuesday, November 17, 2015.
    Should you be confirmed, will you make it a priority for FDA to 
develop a plan, in conjunction with the DOJ, to take more aggressive 
action, including pursuit of both felony and misdemeanor convictions, 
against these bad actors who are threatening the public health of 
American consumers?
    During your hearing before the Senate HELP Committee, I asked 
whether you believe that the Dietary Supplement Health and Education 
Act (DSHEA) provides adequate authority to regulate the dietary 
supplement industry and protect consumers from unsafe products. In 
response, you stated that you are ``fully aware of [your] authorities 
and plan to use them as Congress has directed.'' In light of the 
sweeping enforcement actions announced by the FDA together with the DOJ 
and other agencies later that same day, it seems apparent to me that 
the FDA does have ample authority to take action in this space. Given 
these points, can you elaborate beyond your statement cited above 
whether you believe, as prior FDA commissioners have, that DSHEA 
provides adequate authority to regulate the dietary supplement industry 
and protect consumers from unsafe products?
    Answer 2. FDA is committed to fully enforcing DSHEA as vigorously 
as possible to protect the public health. Using these authorities, FDA 
has been able to take significant steps to protect the public, 
including recent Warning Letter initiatives related to products 
containing BMPEA, DMBA, DMAA and pure powdered caffeine.
    The Agency is continuing to work on better focusing our resources 
to quickly identify and act against unsafe dietary supplements. For 
instance, over the past 5 years, we have emphasized inspections and 
enforcement of our current Good Manufacturing Practice regulations 
across the entire industry, and that is helping to ensure that dietary 
supplements are manufactured safely. Also, we have implemented the 
serious adverse event reporting law for dietary supplements passed in 
2007. As we receive adverse event information under this system, our 
ability to recognize trends and patterns in adverse events is helping 
us target dangerous products or categories of products.
    As you know, DSHEA puts the burden on FDA to develop the evidence 
necessary to take action against unsafe dietary supplements. In 
addition, dietary supplement manufacturers and distributors are not 
required to inform the Agency of most products they sell prior to 
marketing. This creates enforcement challenges for FDA in discovering 
violations within a huge universe of dietary supplements, proving the 
violation, and effectively deterring future bad actors.
    FDA's dietary supplement program office is currently undergoing a 
strategic review of its structure and practices, including a review of 
the underlying statutory and regulatory authority for dietary 
supplements and how the Agency has traditionally used this authority. 
This effort is intended to ensure that we are using our full 
authorities in the most effective way possible.
    FDA works with DOJ on civil and criminal actions, such as 
injunction or seizure. For those firms demonstrating repeated or 
significant non-compliance with dietary supplement regulations, we will 
continue to pursue the most appropriate action to assure public health, 
which may include, but not be limited to, such joint actions with DOJ.

    Question 3. In September of this year, FDA's Division on Dietary 
Supplement Programs provided a Declaration to certain State attorneys 
general in response to concerns on whether a certain substance is a 
legal dietary ingredient under the Federal Food, Drug, and Cosmetic 
Act. This Declaration was then used in State enforcement activities by 
State AGs as primary evidence in cease and desist efforts against 
retailers.
    Can you shed any light on why the FDA chose to engage with State 
enforcement actions and proceed with such a Declaration, and more 
importantly why FDA took this action instead of following the usual 
transparent process, such as issuing a public statement, a warning 
letter, consumer advisory, or requesting a voluntary recall on the 
ingredient?
    I am concerned that FDA's approach of providing a Declaration 
privately to a State law enforcement agency on an issue never raised by 
the agency in a public forum or with industry could set a dangerous 
precedent. Should you be confirmed as Commissioner, will you commit to 
engaging in a more public and transparent process? Do you believe that 
FDA should clarify its position on this issue, if so, how will you 
ensure clarification? Do you believe it is appropriate and good 
regulatory practice to issue warning letters or consumer advisories 
when taking action in the future on such ingredients of concern?
    Answer 3. FDA prioritizes its enforcement actions based on 
available resources and the level of safety concern identified. The 
Agency faces the challenge of having limited resources to monitor the 
ever growing marketplace for potentially harmful dietary supplements 
and dietary ingredients. As a way of leveraging those limited 
resources, we work with outside partners, such as other Federal and 
State agencies, as well as industry stakeholders, to encourage full 
compliance with applicable statutes and regulations.
    In responding to requests from certain State attorneys general, FDA 
recognized the opportunity to work cooperatively in providing an Agency 
determination as to the validity of the purported dietary ingredient. 
This would not only assist these State agencies in exercising their 
jurisdiction over such products, but also help to conserve limited FDA 
resources while protecting the public health. FDA continues to 
investigate the marketing of products containing the ingredient in 
question, and will exercise our authority as warranted.
    FDA is committed to protecting public health through a variety of 
avenues.

    Question 4. In fiscal year 2015, FDA received around $1.9 billion 
in user fees from industry and others, and about $2.5 billion in 
appropriated funds. For the user fees, members of this committee 
receive annual financial and performance reports that are quite 
granular on the reporting of how those dollars are spent. My concern is 
that congressional dollars are not tracked as thoroughly. Programs 
without fees seem to suffer from delayed or ineffective implementation, 
including the over-the-counter drug program and food safety law. Can 
you comment to how you all currently track resources for programs 
outside of the user fee agreements, and commit to tracking taxpayer 
dollars to the same level of detail you track dollars from industry?
    Answer 4. FDA tracks the spending of all of its resources to 
include appropriated budget authority and user fees. FDA has set up its 
financial system of record to enable the Agency to track and report on 
spending by the source of funds (i.e., budget authority or user fee) as 
well as by the organization doing the spending (i.e., Center and 
Office).

    Question 5a. One of the hallmarks of the Hatch-Waxman framework 
governing generic drugs is that each generic version of a brand-name 
drug must have the same labeling as its brand-name equivalent. This 
requirement protects patients by ensuring that they have the same FDA-
approved information no matter which version of a drug is dispensed and 
helps promote the use of lower cost generic drugs by providing public 
assurance that the products are identical. In November 2013, however, 
FDA proposed to require generic manufacturers to change the safety 
information on their drugs' labeling without prior FDA approval. If 
finalized, this proposed rule would lead to situations in which there 
are three or more different versions of the labeling of the same drug, 
with patients receiving different information depending on which 
version of the drug their pharmacists dispense.
    The labeling for a generic drug is required by statute to be ``the 
same as the labeling approved for'' its brand name equivalent. Under 
this longstanding policy, a generic drug's labeling must match the 
brand-name labeling at the time of approval, and the generic drugmaker 
must update its labeling to follow changes made by the brand-name 
manufacturer. FDA's proposal, however, would allow a generic drugmaker 
to change a drug's labeling to be different from the labeling approved 
for its brand-name equivalent. What do you believe the word ``same'' 
means in this context?
    Answer 5a. In the current marketplace, approximately 80 percent of 
drugs dispensed are generic and, as we have learned, brand drug 
manufacturers may discontinue marketing after generic drug entry. The 
proposed rule, if finalized, would provide abbreviated new drug 
application (ANDA) holders with the means to update product labeling to 
reflect data obtained through post-market surveillance, even though 
this may result in temporary labeling differences among products, while 
FDA reviews the proposed labeling change. During its review of a 
generic drug manufacturer's changes being effected (CBE-0) supplement, 
FDA would consider submissions by the brand drug manufacturer and other 
generic drug manufacturers related to the safety issue, and determine 
whether the labeling update is justified and whether modifications are 
needed. FDA would make an approval decision on proposed labeling 
changes for the generic drug and the corresponding brand drug at the 
same time, so that brand and generic drug products have the same FDA-
approved labeling.
    The proposed rule would likely reduce the variation between brand 
and generic drug labeling that currently takes place. Under current 
regulations, only brand drug manufacturers can independently update 
product labeling with certain newly acquired safety information and 
distribute revised labeling, before FDA reviews or approves the 
labeling change, by submitting a CBE-0 supplement. Under the current 
regulation, FDA generally has advised that a generic drug manufacturer 
may use the CBE-0 supplement process only to update its product 
labeling to conform to the FDA-approved labeling for the corresponding 
brand drug or to respond to FDA's specific request to submit a labeling 
change through the CBE-0 process. Accordingly, while FDA reviews a 
brand drug manufacturer's CBE-0 supplement, there currently is a 
difference between the brand drug labeling and generic drug labeling. 
Once FDA approves a change to the brand drug labeling, the generic drug 
manufacturer is required to revise its product labeling to conform to 
the approved labeling of the corresponding brand drug. FDA advises that 
this update should occur at the very earliest time possible; however, 
FDA has determined that there is often a delay, of varying lengths, 
between the date on which revised brand drug labeling is approved and 
the date on which the generic drug manufacturer submits such labeling 
updates. The proposed rule, if finalized, generally would reduce the 
time in which all generic drug manufacturers make safety-related 
labeling changes by requiring generic drug manufacturers to submit 
conforming labeling changes within a 30-day timeframe.

    Question 5b. Will you commit to considering carefully, before 
taking further action on this proposal, what impact it will have on 
public perceptions regarding the sameness of generic and brand-name 
equivalents?
    Answer 5b. The proposed rule is intended to improve the 
communication of important drug safety information to health care 
professionals and patients. FDA has received a great deal of public 
input from stakeholders during the comment period on the proposed rule 
regarding the best way to accomplish this important public health 
objective.
    FDA is carefully considering comments submitted to the public 
docket, established for the proposed rule from a diverse group of 
stakeholders including: consumers and consumer groups, academia 
(including economists), health care associations, drug and pharmacy 
associations, brand and generic drug companies, law firms, State 
governments, and Congress, including comments on how the proposed rule, 
if finalized, may affect public confidence in generic drugs and 
comments proposing alternative approaches to communicating newly 
acquired, safety-related information in a multi-source environment. FDA 
also met with the Generic Pharmaceutical Association (GPhA) on 
September 8, 2014, to listen to their comments and views regarding the 
proposed rule, and a summary of this meeting has been posted to the 
public docket (FDA-2013-N-0500). In addition, FDA held a public meeting 
at which any stakeholder had the opportunity to present or comment on 
the proposed rule, or on any alternative proposals intended to improve 
communication of important, newly acquired drug safety information to 
health care professionals and the public. In the February 18, 2015, 
notice announcing the public meeting, FDA also reopened the docket for 
the proposed rule until April 27, 2015, to allow the submissions of 
written comments concerning proposals advanced during the public 
meeting. FDA will determine next steps based on our analysis of 
comments on the proposed rule and additional information submitted as 
part of the public meeting.

    Question 5c. Under current Supreme Court precedent, FDA's proposal 
could expand generic drugmakers' potential exposure to tort lawsuits 
under State law. To what extent do you believe it is appropriate for 
FDA to consider this potential impact on the proposal's (a) cost 
assessment, and (b) policy merits?
    Answer 5c. It is appropriate for FDA to consider whether the 
proposed rule, if finalized, would result in higher costs to generic 
drug manufacturers, and also to consider information from commenters 
who support an alternative to the regulatory changes proposed by FDA in 
the proposed rule.
                            senator roberts
    Question 1. Congress was clear when it passed the Food Safety 
Modernization Act that FDA was to clearly distinguish in its 
regulations the difference between animal foods and human foods. Can 
you please explain why these rules are so similar and how the agency 
accounted for Congress' intended risk-based approach to regulating the 
supply chain for both human and animal foods? If confirmed, will you 
commit to working with inspectors to ensure the nuances between the 
animal food industry and the human food industry are taken into 
account?
    Answer 1. In the final preventive controls for animal food (PCAF) 
rule, FDA finalized baseline CGMP requirements for producing safe 
animal food. FDA recognizes that the CGMPs have to take into 
consideration the unique aspects of the animal food industry and 
provide flexibility for the wide diversity in types of animal food 
facilities. From our original proposed rule in 2013 to the supplemental 
proposal in 2014, we significantly revised the CGMPs based on feedback 
from the regulated industry. We received a number of comments from 
industry that supported the revised CGMPs in the supplemental proposal, 
but additional modifications were also requested. For the final rule, 
we revised the CGMPs, based on the comments received and existing 
industry standards. These modifications provide clarity, additional 
flexibility, and decreased prescriptiveness, while still maintaining a 
baseline to protect against animal food contamination that would be 
harmful to public health.
    FDA developed the rule with risk-based processes in mind to ensure 
that, where appropriate, the requirements for hazard analysis and risk-
based preventive controls were the same for both the preventive 
controls for human food and the PCAF rules. Consistency in the 
regulations is beneficial for industry, especially those that 
manufacture raw material and other ingredients that may be used in both 
human food and animal food. Although the regulations are similar, the 
flexibility provided allows for the application of the regulations to 
reflect the type of facility and the type of food being processed. We 
expect the application to look different between human food facilities 
and animal food facilities, based on the expected hazards and types of 
food being processed.
    Application of the regulations will also differ across the animal 
food industry, given the great diversity of facilities, ranging from a 
small feed mill to a large pet food facility. We are committed to 
training our workforce and our State, local, and tribal regulatory 
partners to understand the flexibility built into the final rule and 
the nuances of how they may see it being applied in an animal food 
facility. We are working with both State regulatory partners and 
industry in the Food Safety Preventive Controls Alliance (FSPCA) to 
develop training that will be required for all investigators; both 
regulatory personnel and industry will receive the same base training. 
FDA is also working on development of training specific to regulators, 
which will include expectations of what one might expect to see in 
various animal food facilities. We are also working on the development 
of several guidance documents to support the final rule and will be 
engaging with industry during the process to seek their input as the 
documents are intended to help them achieve compliance with the rule. 
FDA is committed to making implementation of the animal food preventive 
control rule a success, and we recognize it will take continued 
collaboration with our State and local regulatory partners and industry 
to achieve that goal.

    Question 2. I understand the FDA is spending much of its food 
safety resources on training and education, in addition to utilizing 
State partnerships. It is also important that inspectors interact with 
those they are inspecting in a consistent manner, while also 
considering the diversity of the food industry. While some changes and 
improvements were made when the rules were finalized, the agency did 
not go nearly far enough in simplifying, ensuring consistency, and 
reducing unnecessary paperwork burdens. Now that five of the seven FSMA 
rules are final, will you commit to ensuring that the implementation 
and enforcement of the rules is consistent and as simple as possible if 
confirmed?
    Answer 2. Yes. FDA is committed to implementing FSMA efficiently 
and effectively, in collaboration with our State and local regulatory 
partners and industry. As part of this effort, we have developed a new 
inspection paradigm and enforcement strategies that reflect the 
flexible, systems-based approach of the new FSMA rules. This new 
paradigm involves a major re-orientation and retraining of more than 
2,000 FDA inspectors, compliance officers, and other staff involved in 
food safety activities, as well as thousands of State, local, and 
tribal inspectors. The training emphasizes that inspections under the 
FSMA regulations must be performed consistently from one region to 
another, and by both Federal and State officials.
    We are also working on the development of several guidance 
documents to support the final rules and will be engaging with industry 
during the process to seek their input as the documents are intended to 
help them achieve compliance with the rule. Through guidance and 
technical assistance, we will continue to work together to ensure that 
firms can tailor their food safety systems to meet their particular 
needs and exercise a myriad of flexible options under the new FSMA 
rules.
    In addition, FDA has funded and is working with three private-
public, university-based alliances, which are responsible for providing 
standardized curricula and establishing mechanisms to train industry 
and regulators on the requirements of the produce safety and preventive 
controls rules.

    Question 3. What are the existing tools the agency has, and if 
confirmed, how do you plan to use these existing hiring authorities to 
fill the 1,800 vacancies within the agency?
    Answer 3. Addressing FDA's hiring needs is one of my top priorities 
during my time at FDA. I have already begun working with FDA's human 
resources staff to help ensure that our internal processes are working 
as efficiently as possible.
    FDA primarily uses title 5 and title 42 hiring authorities to fill 
positions. These authorities include various flexibilities facilitating 
the inclusion of veterans, disabled persons, students, minorities, and 
others, as applicable. To ensure that the 1,800 vacancies are filled in 
the Agency, we are working to implement a corporate recruitment 
strategy to identify and recruit for mission-critical scientific and 
professional positions in an expedited manner. This includes targeted 
outreach to professional and scientific organizations/communities, 
academia, and industry, to further support FDA's goals and objectives. 
Outreach efforts involve announcing vacant positions through various 
sources such as USAJOBS, social media, paid advertisements, 
professional and scientific organizations, among others. In addition, 
FDA is working to utilize all available hiring and compensation 
authorities to assist with recruiting and retaining hard-to-fill 
scientific and medical staff.
    FDA and industry agree on the importance of the Agency having 
highly qualified experts who can efficiently and expeditiously review 
cutting-edge products, and conduct post-market surveillance activities. 
We appreciate that Congress and industry have recognized the necessity 
of having a highly skilled FDA workforce, and I look forward to working 
with you to address the challenges that FDA faces in recruiting and 
retaining the talented individuals the Agency needs.

    Question 4. Over the past 2 years, four studies, including two 
published in the New England Journal of Medicine and one from the 
Institute of Medicine (IOM), have found that diets too low in sodium (< 
2,300 mg/day) result in negative health outcomes. As a cardiologist, 
why do you believe the government continues to push for population wide 
reduction in sodium intake knowing that it might be associated with an 
increase in cardiovascular disease risks? And if confirmed, would you 
continue to support this position?
    Answer 4. U.S. Government efforts focus on reducing the average 
sodium intake in the United States for those aged 2 years and older 
from the current 3,400 mg/day closer to 2,300 mg/day. The 2013 IOM 
report entitled ``Sodium Intake in Populations, an Assessment of the 
Evidence'' reaffirmed that sodium intake levels are too high and should 
be reduced to 2,300 mg/day. This recommendation is also supported by 
the Scientific Report of the 2015 Dietary Guidelines Advisory 
Committee, which thoroughly considered the 2013 IOM Sodium Report and 
other evidence in their review. The 2010 DGAs recommended a reduction 
in sodium intake to less than 2,300 mg/day and a further reduction to 
1,500 mg/day among African Americans, individuals with hypertension, 
diabetes, or chronic kidney disease, and individuals ages 51 years or 
older. Again, the focus of FDA is on the general population 
recommendation with gradual reductions in intake levels for the general 
population toward the 2,300 mg/day mark.
    A large body of evidence indicates that as sodium intake increases, 
so does blood pressure (Aburto, et al., 2013; Sacks, et al., 2001; He, 
et al., 2013; Mozzaffarian, et al., 2014). High blood pressure is a 
leading risk factor for heart disease and stroke (Stamler, et al., 
1993; Kannel, et al., 1996; van den Hoogen, et al., 2000; O'Donnell, et 
al., 1997, Prospective Studies Collaboration, 2002). It is estimated 
that about 41-45 percent of deaths due to heart disease and stroke are 
attributed to high blood pressure (Yang, et al. 2012; Danai, et al, 
2009). Heart disease is the No. 1 killer of men and women in the United 
States and stroke is No. 5 (CDC, 2015). One in three adults in the 
United States have high blood pressure, with only half having it under 
control (Nwankwo, et al., 2013; Egan, et al., 2010). Reducing average 
sodium intake in the U.S. population can reduce blood pressure and is 
projected to save tens of thousands of deaths and billions of health 
care dollars each year (Coxson, et al., 2013; Bibbins and Domingo, 
2010), including among people whose blood pressure is above 120/80 
(Huang, et al., 2014a). Average dietary sodium intake in the U.S. 
population, aged 2 years and older, is about 3,400 mg/day before salt 
is added at the table, compared to a recommended intake of less than 
2,300 mg/day 2015 DGAC Report.) Because about 75 percent of sodium in 
the diet of the U.S. population is estimated to be added during the 
manufacturing of foods and preparation of restaurant foods, it is 
challenging for consumers to reduce their sodium intake (Anderson, et 
al., 2010; Mattes and Donnelly, 1991).
    Some recent observational studies (Stolarz-Skrzypek, et al., 2011; 
O'Donnell, et al., 2011; O'Donnell, et al., 2014; Graudal, et al., 
2014) are inconsistent with a large body of evidence that consistently 
shows a dose-response relationship between sodium intake and blood 
pressure (Aburto, et al., 2013; Sacks, et al., 2001; He, et al., 2013; 
Mozaffarian, et al., 2014; Eckel, et al., 2014). Results of these 
recent observational studies suggest low- and high-sodium intakes are 
associated with cardiovascular disease (CVD) events or deaths, and are 
inconsistent with other observational studies showing lower sodium 
intake is associated with lower risk of CVD (Cook, et al., 2014; 
Poggio, et al., 2015). Expert review of these studies by FDA and CDC 
scientific experts indicate that they do not shift the weight of 
evidence.
    Like other studies reviewed by IOM in 2013 and an American Heart 
Association Scientific Advisory Committee in 2014 (Cobb, et al., 2014), 
these studies have major limitations in the selection of participants 
and/or measurement of sodium intake. For example, a problem with some 
of these studies is the possibility for reverse causation. Reverse 
causation could occur if participants who have a major risk factor for 
CVD, such as chronic kidney disease, have lowered their sodium intake 
because of medical advice or because their illness reduces the amount 
of food consumed. Another major weakness is use of a measure of short-
term sodium intake, like a single 24-hour urine collection or a spot 
urine specimen that does not accurately reflect an individual's long-
term exposure. Many studies show a spot urine specimen can over or 
under-estimate individual daily sodium intake by as much as 3,000 mg or 
more (Mente, et al., 2013 and Cogswell, et al., 2015). This means 
people with high sodium intake are mis-classified as having low-
estimated sodium intake and vice versa. This could result in people 
with low-estimated sodium intake falsely appearing to have an increased 
risk of CVD.

    Question 5. I support encouraging industry to gradually lower 
sodium in the foods that are available to consumers, so that they will 
have more options if they choose to consume less sodium. The 2015 
Dietary Guidelines Advisory Committee (DGAC) recommended that the FDA 
should modify the generally recognized as safe (GRAS) status of salt in 
processed foods to reduce the salt content of the food supply. Given 
the Dietary Guidelines Advisory Committee's stated research gaps, and 
the science that increasing finds adverse health outcomes at low-sodium 
intake levels, would you suspend any action in this regard until 
further research is conducted and a comprehensive review of all related 
science is concluded?
    Answer 5. The Scientific Report of the 2015 Dietary Guidelines 
Advisory Committee referenced the 2010 IOM report on Strategies to 
Reduce Sodium Intake in the United States in their report. It was this 
2010 IOM report that recommended the FDA should set mandatory national 
standards for the sodium content in foods by modifying the generally 
recognized as safe (GRAS) status of salt added to processed foods to 
reduce the salt content of the food supply.
    Americans are consuming excess sodium, and this excess contributes 
to increased risk of hypertension, a primary contributor to stroke and 
heart disease. Encouraging industry to voluntarily reduce sodium in 
products so that consumers have more options does not require bringing 
consumers into an excessively low sodium intake range such as 1,500 mg/
day. In fact, with average sodium intake at 3,400 mg/day there is 
considerable work to do to phase-down intake to the recommended level 
of 2,300 mg of sodium per day, which is consistent with the current 
State of the science.
    We are in support of conducting well-designed research to add to 
the knowledge base on sodium intake in different population groups.

    Question 6a. The 2015 Dietary Guidelines for Americans provides the 
basis of nutritional information for numerous Federal programs, 
including the Food and Drug Administration's Nutrition Facts label. The 
Dietary Guidelines are published jointly by the Department of Health 
and Human Services and the Department of Agriculture and are informed 
in part by an Advisory Committee, but most importantly are a source of 
nutritional and dietary information and guidelines. The 2015 Dietary 
Guidelines have not been finalized, yet the FDA is proposing to 
establish a new percent daily value (DV) for added sugars on the 
Nutrition Facts labels of packaged foods.
    Is it appropriate for FDA to propose a policy change that is based 
on an unofficial Advisory Committee recommendation before the 
Departments of HHS and Agriculture finalize the 2015 Dietary Guidelines 
for Americans? And how will you ensure FDA upholds its use of 
scientific consensus standards when proposing a policy change, such as 
proposing a change to the Daily Recommended Value for added sugars?
    Answer 6a. In July 2015, FDA released a supplemental proposal to 
establish a Daily Reference Value (DRV) of 10 percent of total calorie 
intake from added sugars. The comment period for the proposal closed on 
October 23, 2015. The Agency is reviewing and considering the comments.
    In developing the proposal, FDA did consider the scientific 
evidence underpinning the recommendations provided in the Dietary 
Guidelines Advisory Committee's report to set a DRV for added sugars. 
In considering any final proposal, I can assure you that FDA will 
continue to use the best available science and evidence.

    Question 6b. Will you commit to ensuring that the agency's proposal 
to require the disclosure of added sugars per serving on the Nutrition 
Facts label is adequately understood by consumers and provide 
scientific evidence that supports such consumer comprehension before 
finalizing any new labeling requirement?
    Answer 6b. FDA released the results of its consumer studies on 
added sugars in the Agency's supplemental rulemaking in July 2015. We 
initiated this research to explore consumers' potential interpretations 
of Nutrition Facts labels that include added sugars declarations. The 
Agency is considering and reviewing the comments on this consumer 
research. This research would inform any consumer education if added 
sugars are declared on the label. FDA believes that a multi-component, 
coordinated consumer education campaign should be implemented to make 
any new food label a successful tool in continuing to help consumers 
understand and use the label to assist them in making healthy food and 
beverage choices.
                            senator cassidy
    Question 1. Back in September I chaired a hearing where Dr. 
Woodcock spoke to the committee about implementation of the biosimilars 
pathway. She was, as always, very responsive and detailed in answering 
the many questions about the science and promise of biosimilars. 
However, she was repeatedly questioned about the timing of outstanding 
guidances, including those on labeling and interchangeability of 
biosimilars. She told the committee that those additional guidances are 
expected in 2015. Can you assure the committee that the outstanding 
biosimilars guidances will be published by the end of this year?
    Answer 1. FDA has published the following final guidances related 
to biosimilars: Scientific Considerations in Demonstrating 
Biosimilarity to a Reference Product; Quality Considerations in 
Demonstrating Biosimilarity of a Therapeutic Protein Product to a 
Reference Product; and Biosimilars: Questions and Answers Regarding 
Implementation of the Biologics Price Competition and Innovation Act of 
2009; and Formal Meetings Between the FDA and Biosimilar Biological 
Product Sponsors or Applicants.
    FDA has also published the following draft guidances since 2012: 
Clinical Pharmacology Data to Support a Demonstration of Biosimilarity 
to a Reference Product; Reference Product Exclusivity for Biological 
Products Filed Under Section 351 (a) of the PHS Act; Biosimilars: 
Additional Questions and Answers Regarding Implementation of the BPCI 
Act of 2009; and Nonproprietary Naming for Biological Products.
    The Agency is committed to carefully reviewing the comments 
received as we move forward in finalizing the draft guidances noted 
above. Upcoming guidances are expected to include: Considerations in 
Demonstrating Interchangeability to a Reference Product; Statistical 
Approaches to Evaluation of Analytical Similarity Data to Support a 
Demonstration of Biosimilarity; and Labeling for Biosimilar Biological 
Products.
    FDA is diligently working to issue guidance on issues that have 
been identified by FDA and key stakeholders as key topics of interest. 
While the Agency cannot provide a specific timeline for the release of 
any guidance, we continue to provide information to assist biological 
product developers--sponsors/companies--with bringing biosimilar and 
interchangeable products to market. FDA is continuing to clarify its 
approach to implementation of the BPCI Act to further facilitate 
sponsors' development of biosimilars and interchangeable biological 
products.

    Question 2. Despite FDA reporting a decline in shortages in the 
last few years, we are still hearing that shortages are a substantial 
concern for providers. How do you reconcile the decline in shortages 
FDA is tracking with the continued struggles providers are reporting? 
What do you see as the key things that the agency still needs to do to 
better position itself to address shortages?
    Answer 2. The Drug Shortage Staff in FDA's CDER is tracking numbers 
of new shortages annually, and this has greatly decreased since 2011. 
There were 44 new shortages in both 2014 and 2013 compared to 117 new 
shortages in 2012. These numbers are significantly lower than the 251 
new shortages recorded in 2011.
    FDA is well-positioned to work with manufacturers to find ways to 
prevent or reduce a shortage's impact on patients, provided we are 
aware that there is a potential for a shortage. Early and timely 
notification by manufacturers has been aided importantly by Executive 
Order 13588 and by passage of FDASIA, and has enabled FDA and 
manufacturers to prevent 195 drug shortages in 2011; 282 drug shortages 
in 2012; 170 drug shortages in 2013; and 101 shortages in 2014. FDA has 
also used other tools to prevent or mitigate shortages, including 
expediting the review of shortage-related ANDAs. Since the enactment of 
FDASIA on July 9, 2012, through December 31, 2014, CDER's Office of 
Generic Drugs expedited the review of 298 applications, including 182 
abbreviated new drug applications and 116 supplemental ANDAs, to 
prevent or mitigate drug shortages.
    FDA also continues to improve its system for data tracking and 
analysis for drug shortages, with the Drug Shortage Data System (DSDS), 
which was put into place in 2014 and enhances the efficiency and 
consistency of drug shortage data entry. FDA is continuing to integrate 
DSDS with other CDER data systems to improve its drug shortage tracking 
and reporting capabilities. FDA works to find ways to mitigate drugs 
shortages; however, there are still shortages that persist for longer 
periods of time. There are a number of factors that can cause or 
contribute to drug shortages that are outside of the control of FDA. 
These factors include:

     Production delays at the manufacturer and delays companies 
have experienced receiving raw materials and components from suppliers;
     Discontinuations--for example, older drugs that are 
discontinued by companies in favor of newer, more profitable drugs;
     In the case of older sterile injectable drugs, limited 
production line capacity, which, combined with long lead times and 
complexity of the manufacturing process, results in vulnerability to 
shortage.

    Drug shortages remain a top priority for FDA. Although FDA cannot 
directly affect many of the business and economic decisions that 
contribute to drug shortages, FDA is well-positioned to play a 
significant role as manufacturers work to restore lost production of 
lifesaving medications. While important progress has been made in 
preventing drug shortages from occurring, and decreases have been seen 
in the total numbers of new shortages, FDA continues to work to ensure 
that patients in the United States will have access to the medicines 
they need.

    Question 3. Congress has made every effort to support the 
advancement of science, most notably giving FDA explicit flexibilities 
in FDASIA to review new drug applications under accelerated approval or 
via ``breakthrough'' status. What we intended--and in some cases FDA 
has embraced--is for the Agency to maintain the highest safety 
standards but to think creatively about what data can be provided where 
the traditional large, placebo-controlled clinical trial is simply 
infeasible or unethical due to the rarity and severity of a disease or 
the small patient population. We intended for FDA to re-evaluate the 
risk-benefit model and allow patients a voice in the process, where 
higher risk and greater uncertainty may be ok with them given the 
severity of their disease. For serious and life threatening diseases, 
particularly for children, we intended for some new drugs to move 
through the approval process more quickly, allowing a drug sponsor to 
submit post market data to confirm initial safety and efficacy data. 
And we intended for FDA to take a team approach on drug applications 
where the drug could be a ``game changer,'' by allowing for additional 
communication between the Agency and the sponsor, including access to 
the senior management team.
    Yet, despite our best intentions and FDA's best intentions in 
embracing FDASIA, I continue to hear from patients and innovators that 
there are significant inconsistencies across the review divisions. I 
understand the Oncology Division has a long track record of utilizing 
the accelerated approval pathway and as a result there are fewer death 
sentences from cancer. And I have been told recently the Metabolism and 
Endocrinology division has applied regulatory flexibility by allowing 
natural history data to serve as historical controls in support of at 
least 2 approvals in 2015 of rare disease treatments. Congress 
explicitly expanded the tools adapted in the battle against cancer and 
HIV/AIDS to other diseases and I applaud FDA for these examples of 
using them to the benefit of patients.
    On the other hand, I have also been told that the Neurology 
Division continues to question that flexibility, seemingly resistant to 
approaches that are not traditional, placebo-controlled large scale 
trials that may be both infeasible and unethical for very sick 
patients, including children. This committee questioned Dr. Hamburg at 
a hearing about this very division in March 2014. And yet I am 
compelled to raise the same essential question with you again today.
    This is not about whether you approve or deny drug applications. 
The question is about embracing the science, technology and approval 
pathways that allow new treatments to get to patients under the same 
high safety standards. It is about FDA adapting across the board to 
patient needs by allowing more and consistent regulatory flexibility, 
so all patients can benefit as they have in the case of cancer and HIV.
    If confirmed, could you please share with me your ideas for 
improving the adoption of FDASIA's flexibilities across review 
divisions? How will you make flexibility the rule for rare diseases?
    Answer 3. I share your interest in improving flexibilities across 
review divisions, including for rare diseases, building on FDA's 
efforts to date. We've improved the efficiency and predictability of 
clinical drug development by developing tools such as biomarkers and 
surrogate endpoints--markers of drug effect that do not directly 
represent an improvement in how a patient feels or functions, but are 
reasonably likely to predict a clinical benefit. In the early 1990s, 
only 5 percent of FDA's new drug approvals were for targeted therapies 
using biomarkers and in 2013, 45 percent of FDA's approvals were for 
targeted therapies using biomarkers. FDA has approved hundreds of drugs 
on the basis of validated surrogate endpoints using traditional 
approval. FDA has also frequently relied upon surrogate endpoints for 
accelerated approval. When a biomarker or surrogate endpoint is already 
validated, accelerated approval is not needed, because confirmatory 
post-approval studies generally are not necessary in this context to 
verify and describe the drug's clinical benefit. Whether accelerated 
approval can be utilized rests on the availability of biomarkers and 
surrogate endpoints applicable in a given disease. In some areas, like 
oncology, robust research has focused heavily on development of these, 
but that is not necessarily the case in other disease areas.
    FDA published guidance in 2014 on our various programs to expedite 
the development and review of new drugs to address unmet medical need 
in the treatment of serious or life-threatening conditions. FDA expects 
this guidance to help sponsors consider a range of possible endpoints 
that might support accelerated approval, and we are committed to 
working closely with them to facilitate the use of accelerated approval 
where appropriate to help bring needed drugs to patients. We know this 
cuts across many therapeutic areas and rare diseases offer some of the 
biggest challenges. In fact, CDER and OND have established a Rare 
Diseases Program to facilitate OND's review divisions strategic 
engagement in best utilizing tools like accelerated approval to make 
most efficient use of clinical trials and ensure the most creative 
approaches to product development.
    For example, FDA used the accelerated approval pathway to approve 
Tysabri (natalizumab), a treatment for multiple sclerosis, based on a 
large therapeutic effect on relapse rate through approximately 13 
months of treatment, despite uncertainty about the durability of the 
observed effect. As a condition of its accelerated approval, the 
sponsor was required to continue the existing trials into the post-
marketing period to confirm durability of the observed effect at 2 
years.
    These are exciting times as we experience simultaneous revolutions 
in the biological and information sciences. We expect that the 
astounding increase in knowledge of biological systems enabled by whole 
genome sequencing, cloud computing, social media, and wearable devices 
to monitor physiology will create challenges to traditional thinking. 
And we are confident that this increased knowledge will continue to 
expand the pipeline of new therapies. We are prepared to deal with the 
product of this scientific investment by using regulatory paradigms 
that match the State of the science and by supporting dissemination of 
the latest knowledge applied to drug development.
    In this paradigm that takes advantage of the depth of this new 
biomedical information, it will be critical to continue to support 
ongoing clinical trials and observational studies to ensure sufficient 
knowledge of the benefit-risk profile of therapies as they evolve into 
broad use. Even the best of the current surrogates such as systolic 
blood pressure cannot substitute for the entire cumulative effects of a 
drug on the intended biological target and for off-target effects.
    FDA has in place standard operating procedures and guidance on good 
review practices for management of the review of marketing applications 
that are followed by all CDER review divisions. In addition, reviewers 
undergo rigorous training to ensure consistency in application of 
guidance, regulations, and best practices. However, like drug 
development strategies, review times can differ depending on the 
condition being treated and what is known about an individual product. 
Review times can be shorter for certain conditions, such as some 
cancers, since many cancer drugs qualify for one or more of our 
expedited review programs and may present a very favorable benefit-risk 
profile and a more limited amount of data that must be reviewed prior 
to making an approval decision. It is a misconception that speedy 
reviews only occur in oncology, however. For example, approval of the 
first drug for cystic fibrosis was accomplished well ahead of the PDUFA 
goal date.
    FDA's drug approval process--the final stage of drug development--
is the fastest in the world, which means that Americans typically have 
first access to new drugs when they are demonstrated to be safe and 
effective. But even as our Agency has transformed the approval 
process--approving 51 new molecular entities and biological products 
last year alone, including more new orphan drugs for rare diseases than 
in any previous year--drug discovery and development is not keeping 
pace for many diseases (see 2014 Novel New Drugs Summary (January 
2015), at http://www.fda.gov/downloads/drugs/
developmentapprovalprocess/druginnovation/ucm430299.pdf).
    Speeding the availability of safe and effective drugs that treat 
serious diseases is in everyone's interest, especially when the drugs 
are the first available treatment or if the drug has advantages over 
existing treatments. To encourage innovation, we will continue to work 
with other government agencies and the health care community, including 
members of patient groups, academia, and industry. It will take a 
collaborative effort to improve our Nation's understanding of certain 
diseases and to translate any resulting scientific discoveries into 
cures.
                             senator murray
    Question 1a. As we've discussed, FDA has jurisdiction over critical 
public health issues beyond the regulation of drugs and medical 
devices. The agency is also charged with protecting kids from the 
dangers posed by tobacco, giving Americans the nutrition information 
they need to make decisions about the foods they choose for themselves 
and their families, and ensuring the safety and nutritional soundness 
of our food supply, to name a few.
    I'm particularly eager to see full implementation of two long-
awaited FDA rules--the first to ensure menu labeling in restaurants and 
similar establishments, and the second expanding FDA regulation of 
tobacco products to include e-cigarettes and other products--a rule 
that urgently needs to be finalized.
    Can you tell me more about what your priorities will be when it 
comes to these kinds of public health protections?
    Answer 1a. Finalizing the tobacco deeming rule is of the highest 
priority for the Agency and the Administration. We share your sense of 
urgency on this important matter. We are working diligently to finalize 
the rule as soon as possible. The rule has undergone extensive internal 
review within FDA and HHS and is now under review at the Office of 
Management and Budget.
    Once the proposed rule is finalized, some provisions (e.g., 
establishment registration, product listing, ingredient listing, and 
the adulteration and misbranding provisions of the statute) in the FD&C 
Act would automatically apply to all deemed tobacco products. In 
addition, other provisions of the proposed rule would apply to covered, 
newly deemed tobacco products--if included in the final rule--such as: 
minimum age and identification restrictions to prevent sales to 
underage youth; requirements to include health warnings; and a 
prohibition of vending machine sales, unless in a facility that never 
admits youth.
    When the rule is final, FDA will prioritize implementation, 
including educating industry on how to comply with the requirements in 
the rule. In addition, FDA considers the deeming rule to be a 
foundational regulation, which, once finalized, will allow the Agency 
to take further actions regarding critical public health issues.
    With respect to menu labeling, on September 11, 2015, FDA issued 
the draft guidance document titled ``A Labeling Guide for Restaurants 
and Retail Establishments Selling Away-From-Home Foods--Part II (Menu 
Labeling Requirements in Accordance with 21 CFR 101.11.'' We currently 
anticipate issuing the final guidance in late spring 2016.
    FDA will be focusing the first year of implementation on providing 
educational and technical assistance for persons and covered 
establishments, and for our State, local, and tribal regulatory 
partners to support consistent compliance nationwide. Since publication 
of the final rule, FDA has been very active in attending conferences as 
invited presenters, participating in industry-sponsored webinars and 
conference calls, and meeting with industry representatives to help 
them understand the provisions of the rule and how to implement the 
provisions. We will continue to be available for these types of 
activities. In addition, we have established a special mailbox for 
covered establishments ([email protected]) to contact us with 
their questions.

    Question 1b. Once FDA finally asserts their jurisdiction over 
additional tobacco products, what steps will you take to make sure the 
agency moves swiftly to fully use its new authority and ensure that 
Americans--and especially kids--are protected from the full range of 
tobacco products?
    Answer 1b. FDA has vigorously enforced the youth access and 
marketing restrictions for currently regulated tobacco products. This 
includes conducting more than 522,000 retail compliance checks 
nationwide to ensure retailers are complying with the law, initiating 
enforcement action when violations are observed, and providing 
compliance training and education to retailers so they understand the 
requirements under the law. These efforts will continue for newly 
deemed products, once the proposed rule is finalized.
    As stated above, when the rule is final, FDA will prioritize 
implementation of all aspects of the rule and take further actions, 
when warranted, to protect the public health.

    Question 1c. I know that limiting the amount of the sodium in the 
food supply is something the agency has been thinking about for a long 
time--and I'm guessing, as a cardiologist, as issue of personal 
interest to you. When do you think we might finally see action on this 
issue?
    Answer 1c. I do have a strong interest in this issue and I can 
assure you that FDA is continuing to work diligently in this area, but 
we do not have a specified timeframe for issuing a proposal.

    Question 2. In April 2015, Senator Isakson and I led a letter from 
a bipartisan group of 29 Senators to Acting Commissioner Stephen 
Ostroff stating,

          ``Ensuring that women have the best advice that reflects the 
        latest nutrition science about what to eat during pregnancy, 
        for their health and the health of their children, is of the 
        utmost importance.''

    If confirmed, will you ensure that pregnant women receive final 
nutrition advice that is clearly presented and consistent with the 
latest science?
    Answer 2. FDA shares your interest in ensuring that pregnant women 
have access to sound, science-driven, and clearly understandable 
recommendations that enable them to make informed decisions about their 
diets. The final seafood consumption advice for pregnant women is 
undergoing interagency review. We will continue to take steps to ensure 
that it is reflective of the latest nutrition science. Completing the 
updated advice remains a priority for the Agency.

    Question 3. One of the many responsibilities of the Food and Drug 
Administration is to consider aspects of food and nutrition labeling 
for Americans. As you are aware, the Dietary Guidelines for Americans 
are a set of recommendations that encourage Americans to eat healthy 
foods like fruits, vegetables, whole grains, lean meats, eggs, and 
nuts. Current FDA labeling regulations, however, do not allow some of 
these foods to be labeled as ``healthy.'' Can you explain steps you 
would take to ensure FDA's approach to nutrient content claims--
specifically the use of the term ``healthy'' to make a nutrient content 
claim--reflect current Federal dietary guidance and scientific 
evidence?
    Answer 3. The Dietary Guidelines for Americans provide information 
and advice for choosing a healthy eating pattern. Included in this 
advice are food choices that are emphasized and encouraged to help 
Americans move toward healthful eating patterns. Healthful eating 
patterns can be achieved through a wide variety of foods, not just 
foods that are considered ``healthy'' individually. The recommendations 
include a wide variety of food choices which may not, individually, 
have nutrient profiles consistent with the definition of a ``healthy'' 
claim.
    FDA's regulations provide a set of minimum nutrient content 
standards for individual foods to be considered ``healthy'' and bear a 
``healthy'' claim. A ``healthy'' claim can generally be used if a food 
contains less than 3 grams of fat, 1 gram of saturated fat, 60 mg of 
cholesterol and 420 mg of sodium per reference amount customarily 
consumed.
    It is possible that a food may not meet these minimum standards, 
yet may be able to contribute to an overall healthful eating pattern. 
To illustrate, a food can contribute an essential nutrient, such as 
calcium, to an overall healthful eating pattern, yet also contain 
nutrients that are recommended to be limited in the diet, such as 
saturated fat. This individual food could contribute to an overall 
healthful eating pattern, yet not be considered an overall ``healthy'' 
food by itself.
    While we try to ensure that all regulations related to nutrition 
labeling are consistent with the Dietary Guidelines for Americans, it 
is important to understand that the focus of the Guidelines is 
healthful eating patterns. FDA will continue to monitor and assess the 
most recent science to update our nutrition and nutrition-related 
regulations as needed.
    For example, we are currently working to update our requirements 
for the Nutrition Facts label.

    Question 4. As you know, an increasing amount of manufacturing of 
both active pharmaceutical ingredients and finished pharmaceutical 
products, as well as testing for new drug applications, is occurring in 
foreign countries. How can we better ensure that drugs, devices, food, 
and other products regulated by the FDA--that are developed and made 
outside our borders--meet the quality and safety standards we require 
in this country to protect the public?
    Answer 4. All drugs delivered to patients in the United States are 
subject to the same high standards, regardless of country of origin. 
Registered drug manufacturing facilities in foreign countries are 
subject to FDA inspection, with inspection frequency determined on the 
basis of risk to patients. FDA employs a highly trained global 
inspectorate, which is skilled in evaluating processes and uncovering 
manufacturing problems during inspections. Whenever FDA investigators 
find product quality issues that potentially implicate drug safety and 
efficacy, the Agency takes appropriate action, which could include 
issuing a Warning Letter or import alert, or taking other enforcement 
action. Because of resources made available under the Generic Drug User 
Fee Amendments of 2012 (GDUFA), FDA has been able to significantly 
increase the number of inspections (both surveillance and pre-approval) 
it conducts in foreign countries (e.g., India). Having in-country 
investigators allows FDA to be more responsive to high-priority public 
health and safety issues. FDA utilizes risk-based strategies and local 
intelligence in order to maximize its resources to conduct timely and 
high quality inspections. Such strategies may include the 
establishment's compliance, records, and recalls-related history, as 
well as the inherent risks of the drug produced at the facility.

    Question 5. Please provide a description of the work that you 
performed in creating and leading the Duke Clinical Research Institute 
including what you believe is some of the most significant work you 
conducted or oversaw at DCRI.
    Answer 5. The Duke Clinical Research Institute (DCRI) was 
established in 1996 by Duke University Medical Center (Duke) as an 
institutional resource for Duke faculty members conducting clinical 
research; including clinical trials, health services research and 
health policy research (www.dcri.org). I was appointed as the founding 
director of the DCRI in 1996 and served in this capacity until 2006. 
The DCRI operates as a multidisciplinary research unit within the Duke 
University School of Medicine. The mission of the DCRI is to ``develop 
and share knowledge that improves the care of patients through 
innovative clinical research.''
    As part of their academic endeavors, Duke faculty members pursue 
grants and contracts for research studies based on their individual 
clinical and research interests. DCRI staff provide assistance to the 
faculty in preparing grant applications and proposals for potential 
studies sponsored by government agencies, non-profit organizations, and 
foundations and commercial entities.
    When grants or contracts are awarded, the faculty member serves as 
the principal investigator of a study and a team of DCRI staff members 
and faculty (including statisticians, project managers, data managers, 
regulatory associates, etc.) is assigned to perform operational and 
regulatory activities required for the conduct of the study. Following 
completion of the study, the faculty member is responsible for 
conducting an independent analysis and interpretation of the study 
results, and disseminating the results through the peer-reviewed 
literature and presentations at scientific meetings.
    In my role as director, my responsibilities included the following:

     Providing institutional leadership and a vision for 
directing the faculty toward the future of clinical research while 
meeting societal needs.
     Overseeing the work of faculty members and staff involved 
in research studies awarded to the DCRI.
     Overseeing the clinical, operational and financial 
performance and ensuring regulatory compliance of all research studies 
conducted at the DCRI.
     Ensuring the publication and dissemination of the results 
of studies conducted at the DCRI.
     Ensuring that DCRI operational capabilities are aligned 
with the research interests of the faculty.
     Developing a cadre of faculty members and staff who are 
experts in clinical research methods.
     Educating and training junior faculty, fellows, and 
students in clinical research.
     Ensuring a balanced portfolio of research studies by 
funding source to achieve financial self-sustainability and being a 
prudent steward of institutional resources.

    Significant accomplishments:

     Developed a model for academic coordination of large scale 
research, including direct involvement in national policies on CMS 
reimbursement for clinical trials, conflict of interest reporting, and 
management and policies for sustaining independent voice for academics 
and clinicians in design and interpretation of clinical research.
     Expanded from a cardiology-focused research unit to 
include almost 20 therapeutic areas, ranging from pediatrics to 
obstetrics and gynecology, anesthesiology, infectious diseases, mental 
health, drug abuse prevention and treatment, and others. To date, DCRI 
has conducted studies at 37,000 research sites in 65 countries and 
enrolled over 1.2 million patients.

     Served as a major hub of clinical trial networks, with 
Federal funding from over 15 NIH Centers and Institutes.
     Established a nexus of patient registries in partnership 
with medical professional societies to improve healthcare quality and 
prevent medical errors. The registries in acute cardiac care and 
cardiac surgery have become national models with adoption of 
performance measures by CMS.
     Participated in multiple efforts on transparency of 
results of clinical research including major role in the development of 
ClinicalTrials.gov as a member of the Lister Hill Center (National 
Library of Medicine) Board and a contributor to the development of data 
fields and analytical efforts with the database.
     Developed one of the country's largest training programs 
for clinical research and expanded the program to an international 
reach.
     DCRI published over 800 manuscripts per year in the peer-
reviewed literature.

    Question 6. Please provide a description of the work that you 
performed in creating and leading the Duke Translational Medicine 
Institute including what you believe are some of the most significant 
work you conducted or oversaw at DTMI.

    Answer 6. The Duke Translational Medicine Institute (DTMI) was 
established in 2006 to serve as an academic home for Duke's clinical 
and translational research community. I was appointed as the founding 
director of the DTMI in 2006 and served in this capacity until joining 
the FDA in February 2015. DTMI was created to expand the DCRI model to 
faculty across the entire translational research spectrum in concert 
with Duke's first Clinical and Translational Science Award from the NIH 
(the major translational research grant offered by the NIH at the 
institutional level). The mission of DTMI is to,

        ``improve individual and population health by catalyzing 
        translation across the continuum of scientific discovery, 
        clinical research care delivery, and global health.''

    The DTMI serves as an umbrella organization including the 
Translational Research Institute (bench to bedside research), the 
Clinical Research Institute (described above) and the Duke Center for 
Community and Population Health Improvement. It functions as integrated 
support structure to facilitate the efforts of faculty members to 
accelerate the translation of basic science discoveries into new 
medical therapies to advance patient care and to develop methods of 
improving population health through community engaged research and the 
use of electronic records and analytics to improve access and effective 
implementation of health services. DTMI provides a continuum of 
resources and training, such as statistical expertise, degree-granting 
programs, regulatory affairs, project management, and biobanking.
    In my role as DTMI director, my responsibilities mirrored those of 
my prior role as DCRI director, with the inclusion of a much broader 
scope of research ranging from pre-clinical translation to population 
health and community engaged research.
    Significant accomplishments:

     Established the Duke Center for Community and Population 
Health Improvement to foster collaborations among community partners, 
researchers, and health system leaders with the goal of decreasing 
health inequities in the Southeast and across the country through 
studies designed to intervene at both the individual and community 
levels. This includes a CMS-funded project that uses geospatial mapping 
technology to identify residents in four counties in West Virginia, 
Mississippi, and North Carolina at greatest risk of poor health 
outcomes and implement interventions to achieve the ``triple aim'' of 
improved outcomes, better care and lower cost.
     Launched a major effort to develop innovative approaches 
for conducting pragmatic, patient-centered clinical trials. Served as 
the coordinating center for the NIH-funded Health Care Systems Research 
Collaboratory to increase the efficiency of clinical trials by using 
data from electronic health records; and the PCORI-funded National 
Patient-Centered Clinical Research Network to establish national 
networks of health systems, researchers, health care providers, and 
patients conducting clinical trials that answer ``real-world'' 
questions most important to patients and their families.
     Created a regulatory affairs group to provide academic 
investigators with access to the regulatory expertise typically found 
in industry and assist them in navigating the regulatory process 
required to develop new diagnostic and therapeutic technologies. This 
group improved institutional compliance by creating a central database 
of regulatory submissions by Duke investigators and providing extensive 
training in regulatory requirements. This group is considered a model 
among other academic centers.
     Launched ``The MURDOCK Study,'' a longitudinal health 
study involving the populations of Kannapolis/Cabarrus County, NC. The 
study aims to collect genetic and behavioral health profiles from 
50,000 participants using participatory research methods to involve the 
entire community in the design and interpretation of the study. This 
has been described as a modern Framingham Study (a landmark study 
cardiovascular health). Over 11,000 participants have been enrolled to 
date.
     Developed a mechanism for all Duke investigators to access 
statistical expertise to improve research quality. The increased 
accessibility of these resources helped to facilitate a change in 
institutional culture regarding the value and importance of formal 
quantitative expertise, which is increasingly critical to ensure that 
research results are reproducible.

    Question 7. In your hearing you testified that you were unable to 
undertake as much as 70 percent of the clinical trial work that was 
proposed because industry companies were not willing to agree to DCRI's 
requirements that all data from the trials be housed at DCRI. Why is it 
important that academic research centers maintain control of study data 
and why are some industry companies unwilling to agree to this 
requirement?
    Answer 7. Under my leadership, the DCRI never and would never 
participate in coordinating a multi-site clinical trial without a 
contractual agreement that specifies the right to full access to the 
study data and to conduct its own analysis and interpretation of the 
data.
    The independent role of the academic in the analysis and 
interpretation of the study data is an important element of the 
research enterprise. I have been a strong and consistent advocate for 
transparency through both www.ClinicalTrials.gov and the creation of 
access through independent coordinating centers. As discussed below, 
when industry controls the questions asked by the study, the data 
collection, and the analysis, there is significant bias because of the 
direct financial interest involved. Although academic investigators may 
have other biases, when they are conducting research in the context of 
their role as a faculty member in a university, there is a contract 
between the university and the industry sponsor, which includes the 
independent right to publish. This provides a balancing factor that I 
believe is important to ensure that the questions addressed by clinical 
trials are in the interest of patients, the data collected are not 
biased and the analyses have a perspective independent of the sponsor. 
The important role of patients and their advocates is discussed in the 
response to question 15.
    Unfortunately, the majority of multi-site, industry-sponsored 
clinical trials do not have an academic coordinating center. Individual 
research sites that do not have coordinating center functionality do 
not have copies of the entire database, and if they did, they typically 
do not have the expertise to conduct the analyses. Thus, I believe that 
the role of academically based, not-for-profit coordinating centers is 
important to the clinical trials process.
    While most major academic medical centers have some coordinating 
center function, there are only a limited number who are capable of 
conducting large multinational trials like the DCRI. The majority of 
multi-site, industry-sponsored clinical trials are coordinated in-house 
by the sponsor or outsourced by the sponsor to a for-profit contract 
research organization (CRO). In the early years of the DCRI's 
existence, it was common for industry sponsors to be highly resistant 
or even unwilling to allow full access to the study data because of 
their view that, in the event of a negative trial result, it would not 
be in their financial interest for findings to be made public.
    It is now customary for medical journals to require that the 
authors of a manuscript attest that they had full access to the data 
and ability to analyze the data independent of the industry sponsor. 
The recommendations of the International Committee of Medical Journal 
Editors (ICMJE) now state that,

        ``we will not review or publish articles based on studies that 
        are conducted under conditions that allow the sponsor to have 
        sole control of the data or to withhold publication.'' \8\
---------------------------------------------------------------------------
    \8\ International Committee of Medical Journal Editors. 
Sponsorship, Authorship, and Accountability (2007). Available at http:/
/www.icmje.org/news-and-editorials/update_spon_sep2001
.html.

    I have been a strong and consistent advocate for transparency 
through both\9\ and the creation of access through independent 
coordinating centers.\10\ The composite of all of these efforts has 
changed the landscape, and industry sponsors are now much more willing 
to agree to independent analysis.
---------------------------------------------------------------------------
    \9\ Characteristics of clinical trials registered in 
ClinicalTrials.gov, 2007-10. Califf RM, Zarin DA, Kramer JM, Sherman 
RE, Aberle LH, Tasneem A. JAMA. 2012 May 2;307(17):1838-47. doi: 
10.1001/Jama.2012.3424. PMID:22550198. Compliance with results 
reporting at Clinical
Trials.gov. Anderson ML, Chiswell K, Peterson ED, Tasneem A, Topping J, 
Califf RM. N Engl J Med. 2015 Mar 12; 372(11):1031-9. doi: 10.1056/
NEJMsa1409364. PMID:25760355.
    \10\ Eur Heart J. 2010 Apr;31(8):911-7. doi: 10.1093/eurheartj/
ehp550. Epub 2010 Feb 3. Toward a new order in cardiovascular medicine: 
re-engineering through global collaboration.
    Califf RM, Armstrong PW, Granger CB, Harrington RA, Lee K, Simes 
RJ, Van de Werf F, Wallentin L, White HD; Virtual Coordinating Centre 
for Global Collaborative Cardiovascular Research Organization.

    Question 8. The 2011-14 conflict of interest statements filed by 
you that list the names of all private companies from whom you received 
consulting fees or other funds are publicly available on the Duke 
Clinical Research Institute website. Please explain the policy of DCRI 
regarding submission and posting of these conflict of interest 
disclosures, why that policy exists, and how long it has been in place.
    Answer 8. The DCRI, as part of Duke University, abided by 
University policies. Like most major universities, Duke faculty members 
have the right to participate in private consulting 1 day per work 
week. All consulting must be reported to the University conflict-of-
interest committee, and these consulting engagements are screened for 
the potential of conflict of interest and conflict of commitment by 
relevant committee members and institutional leaders. All of this 
information is kept within an institutional database to ensure 
followup.
    I decided to begin publicly posting my interactions with industry 
to set an example for transparency, and DCRI created the venue for 
posting. Many DCRI faculty followed suit, but it was not a requirement 
of DCRI policy.

    Question 9. Along with a number of other researchers at Duke 
University you receive consulting payments from industry companies 
through Faculty Connection, LLC. Please describe the purpose of Faculty 
Connection and the services that it performs for its consultant 
partners. Please include a description of the administrative fees and 
how excess administrative fees are used.
    Answer 9. Faculty Connection, LLC was established by a group of 
Duke faculty members to provide administrative support for the faculty 
when they participate in consulting activities involving private 
industry. It has expanded over time to include faculty from several 
other institutions with similar needs.
    It is designed to ease and consolidate the administrative burdens 
on individual faculty as they participate in consultation activities 
with industry on personal time and create greater efficiency for their 
work. Among the support it provides is:

     filing administrative paperwork required by the 
University, including summaries to facilitate accurate reporting to 
university conflict-of-interest oversight committees,
     ensuring compliance with legal and ethical requirements,
     negotiating contracts and ensuring that the contracts are 
in compliance with university policy and protect the rights of academic 
faculty to remain independent, and
     billing and accounting.

    Payments for consulting activity are made directly to Faculty 
Connection, which retains 20 percent of the fees for administrative 
overhead (primarily to cover staff salaries), and the faculty member 
receives the remaining 80 percent. Since its inception, Faculty 
Connection has donated the proceeds not consumed by administrative 
costs to Duke University (and Stanford University beginning in 2013) to 
fund research and education activities for trainees.
    In 2014, the following contributions were made by Faculty 
Connection to Duke University and Stanford University:

     $15,000 to the Stanford University Department of Medicine 
Residency Program for house staff research;
     $30,000 to the Duke Clinical Research Institute (DCRI) 
fellowship fund to support current and future fellows including the 
adult cardiology fellows;
     $24,000 to the Duke Department of Medicine for research 
and pilot projects performed by residents and/or house-staff. The main 
purpose of the donation is to help the department encourage and support 
residents as they start their research careers;
     $15,000 to the Duke Department of Pediatrics for research 
and pilot projects performed by residents, house-staff, and trainees to 
support research careers; and
     $4,000 to the Duke Cancer Institute to train and provide 
research opportunities for the residents and or house-staff.

    2013  Contributions to Duke and Stanford Universities totaled 
$115,000.
    2012 Contributions to Duke University totaled $154,000.
    2011 Contributions to Duke University totaled $100,000.
    2010 Contributions to Duke University totaled $ 75,000.

    Question 10. At your hearing you stated that you have a personal 
policy of donating all consulting fees received from industry to 
charitable organizations of your choosing. Is it correct that, not 
including funds paid toward clinical trial work conducted at Duke, all 
consulting fees you have received from industry have been paid to you 
through Faculty Connections and subsequently donated according to your 
long-standing practice?
    Answer 10. Yes, this is correct.

    Question 11. Please list any additional measures that you have 
taken to ensure that the scientific integrity of the clinical trial 
work you have undertaken in your career it is not compromised as a 
result of industry sponsorship and funding.
    Answer 11. In addition to publishing the results of all clinical 
trials I have conducted throughout my career, I have publicly posted my 
Duke conflict-of-interest information since 2006, and donated all 
consulting fees to charity. I have been intimately involved in the 
development of structural and policy changes in the global research 
enterprise to increase transparency and reduce bias in the conduct, 
analysis, and reporting of clinical trials.
    For the past three decades, I have worked with global colleagues 
who are experts in medicine, clinical research methodology, and medical 
ethics to develop new mechanisms to ensure that the data obtained from 
individuals who consent to participate in a human experiment (i.e., a 
clinical trial) are evaluated by parties who do not have a financial 
interest in the success or failure of the treatment under study, and 
who, by virtue of their employment as a faculty member in a university, 
are guaranteed the right to academic freedom. I do not use the term 
``human experiment'' lightly, because asking someone to volunteer for a 
study carries with it a responsibility to do the best job possible to 
ensure that the trial is conducted properly and that the result of the 
trial will contribute to generalizable knowledge to help future 
patients.
    One such mechanism is the establishment of steering committees for 
an individual clinical trial, comprised of academic investigators from 
multiple institutions and countries, to serve as a collective body to 
interact with the industry sponsor in developing the protocol and 
overseeing the operational conduct of the trial. This approach 
minimizes the influence of any given individual, ensures inclusion of a 
wide range of perspectives and opinions, and provides a formal 
structure for decisionmaking. The steering committee does not include 
representation from the sponsor but may have one or two sponsor 
representatives to ensure effective communication.
    Another mechanism is the use of an independent academically based 
analytical center which is responsible for receiving data collected 
during a trial, ensuring the accuracy of the data, and analyzing the 
data following the conclusion of the trial. These are often referred to 
as Data and Statistical Coordinating Centers. This structure allows the 
database to be maintained by a party external to the industry sponsor 
and for the data to be fully analyzed before the results are shared 
with the industry sponsor.
    A third mechanism is the formation of data monitoring committees, 
comprised of independent experts who oversee the conduct of the trial 
and have access to the data to protect the safety and interests of the 
research participants. I have published significant papers with 
colleagues to improve the function and scientific basis for data 
monitoring committees.\11\
---------------------------------------------------------------------------
    \11\ Independent data monitoring committees: preparing a path for 
the future. Hess CN, Roe MT, Gibson CM, Temple RJ, Pencina MJ, Zarin 
DA, Anstrom KJ, Alexander JH, Sherman RE, Fiedorek FT, Mahaffey KW, Lee 
KL, Chow SC, Armstrong PW, Califf RM. Am Heart J. 2014 Aug;168(2):135-
41.e1. doi: 10.1016/j.ahj.2014.05.003.
    Data and safety monitoring boards: academic credit where credit is 
due? Armstrong PW, Califf RM. JAMA. 2013 Oct 16;310(15):1563-4. doi: 
10.1001/jama.2013.280383. No abstract available. PMID: 24129461
    Issues in regulatory guidelines for data monitoring committees. 
DeMets D, Califf R, Dixon D, Ellenberg S, Fleming T, Held P, Julian D, 
Kaplan R, Levine R, Neaton J, Packer M, Pocock S, Rockhold F, Seto B, 
Siegel J, Snapinn S, Stump D, Temple R, Whitley R. Clin Trials. 
2004;1(2):162-9. Review.
    Liability issues for data monitoring committee members. DeMets DL, 
Fleming TR, Rockhold F, Massie B, Merchant T, Meisel A, Mishkin B, 
Wittes J, Stump D, Califf R. Clin Trials. 2004;1(6):525-31. 
PMID:16279293.
    Monitoring and ensuring safety during clinical research. Morse MA, 
Califf RM, Sugarman J. JAMA. 2001 Mar 7;285(9):1201-5. PMID:11231751.
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    Finally, the formation of a publication committee, which is now 
standard practice at the DCRI and other academic coordinating centers, 
serves as another extremely valuable mechanism for ensuring independent 
decisionmaking in the interpretation and publication of trial results. 
As is the case with steering committees, publication committees provide 
a formal organizing structure for decisions regarding both primary and 
secondary manuscripts, as well as a transparent and inclusive process 
for any investigator to propose an idea for a manuscript and to access 
the data in order to perform the proposed analysis. A representative of 
the industry sponsor is allowed to serve as a member of the committee, 
however, the majority of members must be academic investigators and 
decisions require a majority vote.

    Question 12. Earlier this year, after joining the FDA you removed 
your name from three journal articles published in the Journal of 
Clinical trials that discussed pragmatic cluster randomized trials 
(PCRT). You have previously advocated for using more pragmatic cluster 
randomized trials or pragmatic clinical trials in research. Have you 
previously expressed the theme and ideas contained in these articles in 
published articles and speeches?
    Answer 12. The depiction of my actions with regard to these issues 
was inaccurate. The articles in question were part of a major joint 
project between the NIH Health Care Systems Research Collaboratory 
(``the Collaboratory'') and PCORnet, PCORI's large national network for 
clinical research. I was Principal Investigator (PI) of the 
Collaboratory and co-PI of PCORnet. Together with Professor Jeremy 
Sugarman, distinguished Chair of Medical Ethics at Johns Hopkins 
University, we organized 10 writing teams from the two projects, in 
addition to some outside experts to address ethics and regulatory 
issues that need to be better understood as the United States moves 
toward a ``learning health system'' model. Each team was assigned to 
work on a specific manuscript, all 11 of which (plus one capstone 
summary article) were to appear together in a special issue of Clinical 
Trials (published by the Society of Clinical Trials).
    At the time of my transition to FDA in February 2015, the 11 
manuscripts were moving along nicely, but they were not substantially 
complete. For three of the 11, I had done enough work personally to be 
on the author list. However, upon moving to FDA, it was clear that I 
could no longer devote the effort needed to be acknowledged as an 
author. The rules governing criteria for authorship, which include 
substantive participation throughout the process of revision as well as 
final approval of the manuscript prior to submission, are clearly 
delineated in guidelines published by the ICMJE, to which most peer-
reviewed medical journals (including Clinical Trials) conform. (Please 
see http://www.icmje.org/recommendations/browse/roles-and-
responsibilities/defining-the-role-of-authors-and-contributors.html#two 
for details).
    Realizing that I was unable to devote the time needed to represent 
responsibility for the full content of the articles, I worked with the 
co-authors to acknowledge my contribution in writing in each of the 
three articles up until the time I joined FDA--these acknowledgements 
are contained within the respective manuscripts. My commitment to the 
project and the general direction of the body of work is clearly stated 
in the introduction to the series, which I authored along with Dr. 
Sugarman.\12\
---------------------------------------------------------------------------
    \12\ Califf RM, Sugarman J. Exploring the ethical and regulatory 
issues in pragmatic clinical trials. Clin Trials 2015;12(5):436-41.
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    In summary, my contributions to the articles are clearly stated in 
the articles themselves, and I am deeply committed to the development 
of appropriate methods for pragmatic clinical trials and fully support 
the body of work represented by the articles. The details of the final 
recommendations are the work of the authors of the manuscripts, and as 
editor of the series it was not my role to agree or disagree with all 
detailed recommendations.

    Question 13. It has been reported that in 2014 you gave a speech to 
healthcare and pharmaceutical stakeholders in which you characterized 
some regulations as a ``barrier'' to innovation in medicine. Please 
provide additional details regarding the speech and explain what you 
meant by this statement.
    Answer 13. I think you are referring to a slide I have used in 
multiple lectures that characterizes regulation as a barrier to 
disruptive innovation.
    This issue is a very important one for people proposing to develop 
new medical therapies. Throughout my career, I have benefited from a 
close relationship with the Fuqua School of Business at Duke and the 
many contacts it brings in the field of health economics and health 
management. Among the many brilliant people I have met is Clayton 
Christensen (``The Innovators Dilemma''), who developed the concept of 
``disruptive innovation.'' This concept is derived from the study of 
the transformation of industries with the base case being the 
conversion of radios from the vacuum tube to the transistor. The 
concept is that the new product or method initially is inferior but 
lower priced so there is a market for it. This enables innovators to 
iteratively improve their product until it becomes better and supplants 
the old product or method. My purpose in showing this slide in multiple 
lectures is to explain to audiences that often include students, 
trainees in fellowship, and scientists who are not involved in 
development of medical products, why the risk and investment in 
biotechnology is higher than most other industries, i.e., because it is 
a highly regulated industry, which is in fact a necessary barrier to 
protect public health, as discussed below. The amount of capital needed 
is lower and the time to return on investment is shorter in many other 
industries.
    I have never stated, implied, or argued that the barrier should be 
lowered or removed. In fact I do not believe that we should be putting 
inferior medical products on the market, nor do the American people 
want inferior products to be used in medical practice. The belief that 
we should have evidence of benefits and risks before marketing in 
health care has been a driving force in my career and a motivation to 
develop more effective, efficient and unbiased ways of conducting 
generalizable clinical trials and implementing quality systems for 
learning in health care as a focus of my academic and practical work.
    In summary, the purpose of the slide is to point out an issue that 
is motivational for people who want to develop medical products that 
prevent death and reduce disability: there is a requirement to 
demonstrate that your product is safe and effective before you market 
it and that it does not put people at risk compared to the clinical 
care that is currently accessible. This is a good thing and forms the 
basis for the benefit of a strong FDA to make these determinations, and 
it places a special responsibility on innovators to develop the 
evidence base that can ensure the FDA (on behalf of the American 
public) that the product is safe and effective.

    Question 14. Are there particular FDA regulations you believe 
should be modified so that clinical trials can be run more efficiently 
and effectively?
    Answer 14. I do not believe that new FDA regulations are needed, 
but there is a major need for the U.S. system to organize around some 
key principles that can be enunciated through multiple venues, 
including FDA guidances. We are already making substantial progress in 
developing a more efficient and effective approach for the United 
States built on the solid foundation of, among others: FDA's Sentinel 
Initiative and the existing specifications, developed in consultation 
with industry and other stakeholders, for submission of drug and 
biologic applications using common data standards and terminology; 
NIH's HealthCare Systems Research Collaboratory and multiple clinical 
trial networks; the VA's networks and million veteran cohort; DOD's 
commitment to research in its vast health system; and ONC's progress on 
interoperability.
    The Precision Medicine Initiative is playing a key role as a use-
case to develop appropriate approaches to patient volunteers, provider 
participation, data standards, interoperability and ethics. My overall 
views on these issues are described in publications #1204,\13\ 
#1162\14\ and #1133\15\ on my CV. Much of this work is proceeding 
through the work of the NIH-FDA Leadership Council.
---------------------------------------------------------------------------
    \13\ Anderson ML, Califf RM, Sugarman J, participants in the NIH 
Health Care Systems Research Collaboratory Cluster Randomized Trial 
Workshop. Ethical and regulatory issues of pragmatic cluster randomized 
trials in contemporary health systems. Clin Trials. 2015 Jun;12(3):276-
86. PMCID: PMC4498459.
    \14\ Sugarman J, Califf RM. Ethics and regulatory complexities for 
pragmatic clinical trials. JAMA. 2014 Jun 18;311(23):2381-82. PMID: 
24810723.
    \15\ Califf RM, Platt R. Embedding cardiovascular research into 
practice. JAMA. 2013 Nov 20;310(19):2037-38. PMID: 24240926.

    Question 15. What are your ideas about how we can improve the 
design of clinical trials to ensure we understand the effect of new 
drugs and devices on subpopulations of patients, including women, 
children, and racial and ethnic minorities?
    Answer 15. A rational approach to medical product development would 
be to include the relevant populations for whom the product is intended 
to be used. This would include women, children, minorities and 
populations identified by biological, social, or preference 
characteristics.
    Unfortunately, it is well-documented that clinical trial 
populations typically are not representative of the population intended 
to be treated, with particular deficits in the categories mentioned 
above. The solutions include consideration of the following approaches, 
and this issue is a high priority:

     The issue of designing, conducting, and analyzing clinical 
trials to produce results to give patients, caregivers, providers, and 
policymakers adequate information about benefits and risks of 
therapeutic interventions in specific individual patients and 
populations with similar characteristics is a major challenge. 
Improving the situation will require a comprehensive, multifaceted 
approach using a concept known as ``quality by design.'' \16\ The 
general tools consist of small focused trials in people with common 
characteristics using clinical and molecular markers and, on the other 
extreme, very large trials using electronic health records and quality 
registries to provide a low-cost data system. Each circumstance is 
somewhat different and carefully planned trials to most efficiently 
answer the important questions are needed. All of this needs to occur 
in the context of more efficient networks of research sites with 
standard procedures and common data standards and terminology.
---------------------------------------------------------------------------
    \16\ Please see http://www.ctti-clinicaltrials.org/what-we-do/
investigational-plan/qbd-qrm for further details about this approach.
---------------------------------------------------------------------------
     A major new advance is the direct involvement of patients, 
their caregivers, and advocates in every aspect of the clinical trials, 
including prioritization of questions, protocol design, quality 
oversight and analysis and dissemination. FDA is already committed to 
more inclusion of patients in the effort, and as it evolves, it is 
already clear that trials are improving as result. The rapid advance of 
social media is enabling inclusion of patients in a direct and 
interactive manner, which has the potential for enormous improvement in 
generalizable enrollment into studies.
     The use of biomarkers and other patient characteristics 
can enable small, focused trials to evaluate particular populations. 
When viewed in the overall context of product development this approach 
will be a critical tool, and the Precision Medicine Initiative will 
accelerate the potential.
     On the other hand, the use of integrated health systems, 
community clinics, and community engaged research in combination with 
electronic health records and registries built on informed consent and 
developed to improve quality offer the realistic opportunity to do much 
larger trials with more generalizability at a dramatically lower cost. 
Considerable work on this approach is already underway at FDA and it 
will accelerate in the upcoming year. Before joining FDA, I was the PI 
of the NIH-funded Healthcare Systems Research Collaboratory and Co-PI 
of the (PCORnet), both of which are developing the concepts and 
operations for this transformation of the clinical trials system (see 
https://www.nihcollaboratory.org/about-us/Pages/default.aspx).
     In conjunction with industry for drugs and biologics, 
there is an agreement to submit data using common data standard over 
the next several years. This will enable FDA to look at inclusion of 
relevant populations much more effectively. Similar approaches are 
underway for devices.
     Two special populations merit consideration: pregnant 
women and the elderly.

          We know little about the proper dosing of drugs in 
        pregnant women, and the success of the treatment of congenital 
        disorders, serious genetically determined diseases and chronic 
        diseases of childhood has dramatically increased the number of 
        pregnant women who must be treated during pregnancy.
          The elderly are the most rapidly growing segment of 
        our population but little is known about medical products in 
        people over age 80, for example. FDA can help by calling 
        attention to these efforts and working with industry sponsors, 
        investigators and NIH to improve their inclusion in trials.

    Question 16. With respect to pediatric research, what else can be 
done to ensure that providers and parents have the information they 
need to help them better understand how a child will respond to a 
particular treatment? Do you have specific ideas about how new products 
can be developed to meet the unique needs of children?
    Answer 16. The Best Pharmaceuticals for Children Act (BPCA) and the 
Pediatric Research Equity Act (PREA) were passed by Congress to 
encourage the study of drugs and biological products in pediatric 
patients in order to provide adequate pediatric use information in drug 
and biological product labeling. FDASIA made permanent BPCA and PREA.
    Prior to the passage of the laws, almost 80 percent of products 
contained no pediatric-specific information. Since the passage of these 
important laws, FDA has approved almost 600 labeling changes to 
incorporate pediatric information. In addition, under PREA, sponsors 
submit pediatric study plans early enough in development to minimize 
the time from approval of a drug in adults to the addition of pediatric 
information.
    It should be noted that some products intended for treatment of 
rare disorders, including rare disorders in children, can receive 
designation under the Orphan Drug Act, and as such, not be required to 
comply with requirements under PREA. However, the Orphan Drug Act is 
also an important and successful law that provides separate incentives 
for the development of products used to treat rare diseases, including 
rare pediatric cancers.
    Additionally, under BPCA, the Pediatric Subcommittee of the 
Oncologic Drugs Advisory Committee (ODAC) was directed to evaluate, and 
to the extent practicable, prioritize new and emerging therapeutic 
alternatives to treat pediatric cancer. Products under development for 
use in adult cancers are brought forward for discussion by the 
Pediatric Subcommittee of the ODAC after consideration by pediatric 
experts within FDA; advice and recommendation of outside pediatric 
oncology experts; and pediatric oncology advocacy groups.
    If you or your HELP Committee colleagues have particular ideas in 
mind to further advance therapies for pediatric populations, we would 
be happy to discuss them.

    Question 17a. There have been media reports discussing concerns 
with the Rocket-AF trial you led while at Duke and that ultimately 
resulted in FDA approval of the anti-coagulent drug Xarelto in 2011.
    Please describe the design process for the study, and the role of 
the Steering Committee in determining the once-a-day dosage of Xarelto 
for purposes of the Rocket-AF trial.
    Answer 17a. Like other large, international Phase 3 trials in this 
field, the international Steering Committee and Executive Committee 
consisted of dozens of experts in cardiology, thrombosis, 
anticoagulation, and primary care. A large number of studies already 
had been conducted with rivaroxaban (Xarelto) when the design of the 
Phase 3 trial came into focus.

    Question 17b. The Rocket-AF trial sought to determine if Xarelto 
(Rivaroxaban) once a day was non-inferior to Coumadin (Warfarin), a 
drug that has been on the market for many years. When the results of 
the trial are examined on a country-by-country basis is there any 
country where Xarelto was found to be inferior to Coumadin?
    Answer 17b. There was no significant heterogeneity of treatment 
effect for the comparison of rivaroxaban and warfarin across countries 
included in the trial. This is assessed routinely in large 
international trials using standard methods and closely evaluated by 
FDA. The results for regions of the world are displayed in the Appendix 
to the primary publication in the NEJM (please see reference #1039\17\ 
in the enclosed CV; the relevant data can be found in the figures on 
pages 21-23 of the appendix, available at http://www.nejm.org/doi/
suppl/10.1056/NEJMoa1009638/suppl_file/nejmoa1009638_appendix.pdf).
---------------------------------------------------------------------------
    \17\ Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, 
Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, 
Paolini JF, Berkowitz SD, Fox KAA, Califf RM, ROCKET AF Investigators. 
Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl 
J Med. 2011 Sep 8;365(10):883-91. PMID: 21830957.

    Question 17c. Is data from the Rocket-AF trial publicly available?
    Answer 17c. FDA review and sponsor submissions are available, and 
27 publications are already available with another 12 in press or other 
stages of review/development, and several dozen more in the planning 
stage. The trial results are also reported in www.ClinicalTrials.gov 
(NCT # NCT00403767; https://clinicaltrials.gov/ct2/show/
NCT00403767?term=NCT00403767&rank=1). These have extensive tables of 
baseline characteristics, outcomes, and adverse events. Study sponsor 
Johnson & Johnson is working with Yale University through an open-
science project called YODA (http://yoda.yale.edu/) that will make the 
raw data available upon request in the future.

    Question 17d. In the 4-years since Xarelto has been on the market 
have post-market surveillance studies been conducted, and what have 
they shown regarding the safety and efficacy of Xarelto?
    Answer 17d. Over 190 clinical trials are now registered in 
www.ClinicalTrials.gov involving rivaroxaban. In addition, numerous 
registries and observational studies have been undertaken. Finally, FDA 
uses post-marketing surveillance, including its Sentinel Initiative, to 
monitor the safety of marketed drugs, but as noted in the article by 
Dr. Ellis Unger (``Atrial fibrillation, oral anticoagulant drugs, and 
their reversal agents'' http://www.fda.gov/Drugs/NewsEvents/
ucm467203.htm), the safety of rivaroxaban has been a special area of 
interest. No signals have been announced by FDA, and the article offers 
reassurance.
                            senator sanders
    Question 1. I believe that when 35 million Americans are unable to 
afford to fill their prescriptions, as is the case now in this country, 
that constitutes a public health crisis. And FDA is a public health 
agency; as you noted in your testimony, ``a successful FDA is a 
critical factor for better public health.'' In order to address a 
public health crisis of this magnitude, we need to do far more to make 
sure medications are affordable for all Americans. The best drug in the 
world won't save someone if they cannot afford to take it.
    In your testimony you said that the United States does have the 
capability to import prescription drugs but that it would add 
additional costs and systems would have to be put in place to make it 
work. Please elaborate on what you will do, as Commissioner, to work 
with President Obama and Secretary Burwell to implement current law and 
begin importing prescription drugs from Canada. In case you are not 
aware, President Obama said in 2011,

          ``Canada and Mexico are bulk purchasers of--drugs, so they 
        negotiate much cheaper drug prices with the drug companies. We 
        still don't do that, and I actually think it's something we 
        should do--it would save us money.''

    He added, ``It may be that importation is still something we should 
look at in terms of further lowering the price of drugs.''
    If you will not commit to importing prescription drugs from Canada 
at this time, please explain how it is possible that FDA can safely 
oversee the importation of millions of food and cosmetic products 
including vegetables, seafood, and infant formula that Americans ingest 
every day from dozens of countries--and yet FDA cannot take steps to 
import any prescription drugs from Canada.
    Answer 1. FDA oversees the products it regulates including food, 
drugs, and medical devices through the provisions in the FD&C Act, 
which includes a number of more recent congressional authorities, 
including FSMA, FDASIA, and DQSA. These authorities establish differing 
systems of oversight to monitor manufacturers, producers, and growers 
of FDA-regulated goods, depending on the FDA-regulated product. For 
example, prescription pharmaceuticals receive a facility inspection 
prior to marketing to ensure the product was manufactured in compliance 
with FDA's good manufacturing practice standards. Drugs from foreign 
sources that are not FDA-approved nor have such an inspection do not 
have the assurance of safety, effectiveness, and quality as drugs 
subject to FDA oversight.
    Drugs that are not FDA-approved nor manufactured in a facility 
inspected by FDA do not have the assurance of safety, effectiveness, 
and quality as do drugs subject to FDA oversight. There have been 
documented incidences of non-FDA-approved imported drugs found to be 
contaminated, counterfeit, containing varying amounts of active 
ingredients or none at all, or containing different ingredients than 
the FDA-approved product. Moreover, FDA would not be able to make 
safety and quality determinations for prescription drugs offered for 
import into the United States that have not gone through the U.S. 
regulatory process. In fact, FDA evaluation of non-FDA-approved 
imported drugs revealed that while nearly half of imported drugs 
claimed to be Canadian or from Canadian pharmacies, 85 percent of such 
drugs were actually from different countries. Typically, these products 
are smuggled into the United States after being transshipped to third-
party countries in an effort to avoid detection and create an 
appearance of coming through countries that consumers may find 
trustworthy. Through FDASIA Title VII and the Drug Supply Chain 
Security Act, Congress has recognized the need to bolster this closed 
drug distribution system. Authorizing importation would compromise the 
closed drug distribution system in the United States and undermine 
these laws, thus making it easier for unapproved drugs, which may 
include counterfeit or other substandard drugs, to reach American 
patients putting their treatment at risk. FDA is concerned that the 
risks of unapproved products from foreign sources outweigh any 
potential cost savings. We are also concerned that adverse events 
flowing from importation of such unapproved products could lead to 
diminished confidence in FDA-approved products.

    Question 2. According to a 2013 CDC study, about five million 
Americans import medication for personal use in order to reduce their 
drug costs. Will you continue FDA's current personal importation 
policy?
    Answer 2. The policy referred to in the question is not based on 
considerations of whether the importation of drugs for personal use is 
to reduce drug costs. Congress charges FDA with ensuring the safety and 
effectiveness of drugs sold in the United States. The FD&C Act 
prohibits the interstate shipment (which includes importation) of 
unapproved new drugs. Unapproved new drugs are any drugs, including 
foreign-made versions of U.S.-approved drugs, which have not been 
approved by FDA for marketing in the United States. Certain Internet 
websites have stated that personal importation of up to a 90-day supply 
of prescription medications is legal. This statement is not true.
    FDA drug approvals are manufacturer-specific, product-specific, and 
they include many requirements relating to the product, such as 
manufacturing location, formulation, source and specifications of 
active ingredients, processing methods, manufacturing controls, and 
container/closure system. The drugs must be produced in FDA-inspected 
facilities. These facilities, and the drugs produced in them, are 
currently covered by the U.S. regulatory system. When individuals 
import unapproved drugs directly from foreign sources, they bypass the 
protections provided by FDA's drug approval process.
    We must emphasize that from a public health standpoint, importing 
unapproved prescription drugs for personal use is a potentially 
dangerous practice. Neither FDA nor the American public have any 
assurance that unapproved products from foreign sources are effective, 
safe, or produced under current Good Manufacturing Practices (cGMP). 
Unapproved products may not have been stored under proper conditions, 
or may not be the real product. Foreign unapproved drugs may be 
contaminated, sub-potent, super-potent or counterfeit. In addition, 
some foreign drug outlets offer to dispense prescription drugs without 
a physical examination, bypassing the traditional doctor/patient 
relationship. As a result, patients may receive inappropriate 
medications because of misdiagnoses, fail to receive appropriate 
medications or other medical care, or take a product that could be 
harmful or fatal if taken in combination with other medicines. The 
personal importation policy is explained in full on FDA's website at 
http://www.fda.gov/downloads/drugs/guidancecompliance
regulatoryinformation/importsandexportscompliance/ucm297909.pdf.

    Question 3. If a drug company has evidence that a drug is more or 
less safe than what is indicated on the label, then that company should 
submit this new information to FDA and, if warranted, request a change 
in their label. However, FDA proposed a guidance last year on the 
distribution of medical publications that lets sales representatives 
for drug companies talk to doctors and hand out articles saying their 
drugs are less dangerous than FDA labeling says they are. Do you agree 
or disagree with this?
    Under no circumstances should the pharmaceutical industry's 
financial interests come before patient safety. It is my hope that you 
believe--and will commit--to working with FDA to revise this draft 
guidance and reiterate that companies should not be able to promote 
drugs using different risk information than what they provided to the 
agency. When new scientific information about a drug's risk is 
determined, the company should inform FDA and, if appropriate, pursue a 
label change.
    Answer 3. Under FDA's regulations, drug companies are responsible 
for updating their approved labeling, when new information becomes 
available that causes the labeling to become inaccurate, false, or 
misleading. Nothing in FDA's draft guidance, ``Distributing Scientific 
and Medical Publications on Risk Information for Approved Prescription 
Drugs and Biological Products--Recommended Practices,'' is intended to 
change companies' existing obligations to update their labeling to 
accurately reflect what is known about the safety profile of the drug, 
to ensure that the labeling is not false or misleading, or for other 
reasons.
    As stated in the draft guidance, FDA recognizes that the safety 
profile of a drug evolves throughout its life cycle as the extent of 
exposure to the product increases, and that it can be helpful for 
health care practitioners to receive significant new information about 
a risk identified in the labeling of an approved product in a timely 
manner. Accordingly, FDA issued the draft guidance to provide 
recommendations for drug companies that choose to distribute new risk 
information in the form of a reprint or digital copy of a published 
study. FDA's proposed recommendations are intended to help ensure that 
new risk information meets appropriate standards for reliability and is 
presented with appropriate disclosure of its limitations and with the 
approved labeling.
    The guidance was issued in draft to enable public comment on the 
proposed recommendations. FDA reviews the comments it receives on draft 
guidances to inform preparation of final versions of guidance 
documents. I will work with FDA on these efforts, including efforts to 
revise the guidance as appropriate.

    Question 4. On October 6, 2013, the Washington Post published an 
article, ``Pharmaceutical firms paid to attend meetings of panel that 
advises FDA, e-mails show,'' documenting FDA's convening a panel 
(IMMPACT), on the clinical testing of painkillers, a multibillion 
market in the United States, and charging pharmaceutical companies 
$25,000 to participate (``pay-to-play''). Despite NIH's warning that 
these payments would give the appearance that the panel was ``paid for 
by a few large pharmaceutical firms who are assumed to be influencing 
the outcomes,'' FDA proceeded with the private meeting. The opioid 
epidemic has only worsened since these meetings; according to CDC, the 
death rate from drug overdose in the United States has more than 
doubled since 1999. In light of FDA's history blurring conflict of 
interest lines, especially when it comes to relationships with the 
industries it regulates, and even in cases with significant public 
health ramifications such as a panel on opioids where transparency 
should have been maximal, will you commit to prohibiting any FDA 
participation in ``pay-to-play'' meetings in the future? If you decline 
to make this commitment, please explain why and provide examples of 
meetings FDA may convene where private, pay-to-play meetings are both 
necessary and justified.
    Answer 4. Your question refers to FDA involvement in the Analgesic, 
Anesthetic, and Addiction Clinical Trial Translations, Innovations, 
Opportunities, and Networks (ACTTION), a partnership between the 
University of Rochester, academia, FDA and other government agencies, 
industry, professional organizations, patient advocacy groups, 
foundations, and philanthropic organizations. Its goal is to streamline 
the development process for new analgesic drug products for the benefit 
of public health.
    ACTTION is one example of the numerous public-private partnerships 
in which FDA participates. These partnerships bring together expertise 
from all areas of drug development, including academia, government 
agencies and pharmaceutical companies, for constructive dialog and 
information sharing. Collaborations such as these, including those 
falling under the Agency's Critical Path initiative, play important 
roles in identifying and addressing knowledge gaps, public health 
questions, and unmet medical needs that plague many therapeutic areas.
    They provide a forum in which FDA representatives and external 
stakeholders can collaborate to share their considerable expertise and 
respective views, which can play an important role in streamlining and 
fostering innovation in drug development. Both the IOM and the 
President's Council of Advisors on Science and Technology have called 
for the development of additional consortia to address areas of unmet 
medical need.
    FDA takes the concerns raised about IMMPACT and ACTTION and other 
public-private partnerships very seriously. The Agency has conducted 
in-depth reviews of those specific collaborations, and has not found 
evidence that FDA officials engaged in any inappropriate behavior. 
Although FDA's PPPs produce many scientific and public health benefits, 
the credibility of FDA's public health decisions related to PPP efforts 
depends on public confidence that those decisions are impartial and 
science-based. To maintain that credibility, FDA PPPs should not create 
an opportunity for unfair access to FDA, undue influence on the 
Agency's decisions, or their appearance. FDA is currently drafting 
procedures to ensure that such collaborations are not influenced by 
conflicts of interest or the appearance of such conflicts.

    Question 5. Since your arrival at FDA in January\18\ 2015, the 
transparency of FDA deliberations regarding approvals for cardiac 
drugs, your area of expertise, appears to have deteriorated. This year, 
FDA approved two new drugs for heart failure, Entresto and Corlanor 
(Entresto approval letter) (Corlanor approval letter) without exposing 
them to public scrutiny at advisory committee meetings despite both 
drugs having publicized suspicions of safety problems, e.g., 
Alzheimer's disease for Entresto (Wall Street Journal) and higher 
mortality for Corlanor (Corlanor label). While FDAAA requires the 
action packages for new drugs to be posted on the FDA website within 30 
days, FDA did not post the action package for Corlanor--approved on 
April 15--until November 20, more than 6 months later. FDA did post the 
action package for another recently approved cardiac drug, Savaysa, but 
then the medical reviews disappeared from the action package several 
months later and are still missing. For each of these cases, please 
explain why FDA did not comply with the laws under which it is supposed 
to operate and please describe your knowledge of or involvement with 
these cases.
---------------------------------------------------------------------------
    \18\ Original question stated ``January,'' however, Dr. Califf 
actually arrived at FDA in February 2015.
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                          advisory committees
    Answer 5. Advisory Committee meetings are not required for all 
applications. By long-standing practice, FDA convenes Advisory 
Committees as warranted. For reasons explained below, FDA chose not to 
convene advisory committee meetings to consider these two new drug 
applications (NDAs).
    Entresto is a combination of two drugs: sacubitril and valsartan. 
Sacubitril is a new molecular entity, whereas valsartan has been 
marketed for many years. The company provided a conventionally designed 
study with typical cardiovascular endpoints. The study was well-
executed, and the clinical benefit was clear, with 20 percent 
reductions in both hospitalizations for heart failure and 
cardiovascular mortality, and a 16 percent reduction in all-cause 
mortality.
    Sacubitril poses a theoretical risk for central nervous system 
toxicity, based on its mechanism of action. The drug was found to 
affect beta-amyloid protein levels in the spinal fluid of animals and 
humans. Beta-amyloid is the protein that builds up in the brains of 
patients with Alzheimer's disease, so the finding is noteworthy; 
however, the drug did not affect beta-amyloid in the brains of animals, 
and it is not known whether there would be any effect in humans over 
the long term. No toxicity was observed in the principal study 
supporting approval (8,442 subjects studied over more than 3 years). 
But given the theoretical concerns, the company was given a post-
marketing requirement to assess the issue further. In light of the 
clear benefits of the drug and what is only a theoretical risk, the 
reviewing division and office deemed approval to be appropriate, 
without the need of convening an advisory committee for discussion.
    The rationale for not convening an advisory committee to discuss 
Corlanor (ivabradine) was similar. In a 6,500-patient trial, Corlanor 
was shown to reduce the combination of hospitalization for heart 
failure and cardiovascular death by 18 percent. There was a trend in 
favor of a lower rate of cardiovascular death on Corlanor, although the 
difference was not statistically significant. As with Entresto, there 
were no controversial issues, and a decision was made not to delay 
approval in order to take the application before an advisory committee.
                          savaysa and corlanor
    Savaysa was approved on January 8, 2015, and the action package for 
the NDA was posted on the web on February 13, 2015. In May 2015, we 
removed the medical officer review section of the action package from 
the web because we received a complaint related to the amount of 
information redacted from this review and needed to reassess the 
redactions. The medical review section of the action package included a 
review that had not been considered by the approving official when the 
approval action was taken. This review had not been considered because 
it was unexpected (filed to the application outside the normal review 
process). It had been written by a medical officer who had not been 
assigned to the Savaysa NDA and who had not collaborated with the 
review team. This unsolicited review was also included as an attachment 
to a review document that was part of the action package for Corlanor, 
which was approved on April 15, 2015. The posting of the Corlanor 
action package was held until the issues related to this unsolicited 
review could be resolved. Now that this unsolicited review has been 
considered and addressed by issuance of a supervisory review memo and 
the disclosure staff has confirmed that any information being withheld 
from these reviews is justified under the Freedom of Information Act, 
we have begun posting this information.

    Question 6. You testified that it is not FDA's role to set the 
prices of drugs. However, FDA's actions can assist drug companies in 
securing high prices for their new drugs. One way that FDA's decisions 
can have an impact: if care in the control arms of trials is 
compromised, as may have occurred, for example, in the following five 
trials: ROCKET AF, CHAMPION PCI, CHAMPION PLATFORM, CHAMPION PHOENIX, 
and PLATO, (such as by delaying clopidogrel administration in the 
control arms of the PLATFORM and PHOENIX trials or POGO's finding that 
the device used in the control arm of the ROCKET AF trial was faulty), 
then the new drug will appear ``superior'' to the old drugs, although 
artificially so. For additional background, see the concerns raised by 
the FDA Medical Team Leader's review at: http://www.fda.gov/downloads/
AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/
CardiovascularandRenalDrugsAdvisoryCommittee/UCM385234.pdf.
    A new drug that is ``superior'' to the old drugs may command a 
higher price, while the same drug that is ``non-inferior'' (or not much 
worse than) the old drugs may not. Please explain whether you believe 
this mechanism was active for the five trials and please provide the 
relevant data.
    Answer 6. The labeling for the affected drugs--rivaroxaban 
(ROCKET), cangrelor (CHAMPION studies), and ticagrelor (PLATO)--
appropriately describes the results of the five trials. These decisions 
and relevant data reviewed are documented in memos available on line at 
[email protected], a searchable website that contains official information 
about FDA-approved innovator and generic drugs and therapeutic 
biological products..
    It is not clear or established what the relationship is between 
drug prices and efficacy or clinical impact. For example, for patients 
with atrial fibrillation, anticoagulants reduce the risk of stroke by 
some 60 percent. For patients with life-threatening infections, 
antibiotics can be lifesaving. Yet other types of new drugs, such as 
certain cancer treatments, may have relatively small effect sizes but 
be higher priced.
                             senator casey
    Question 1. I appreciate your answers during the hearing to 
questions about your ability to remain impartial as FDA Commissioner. 
In law, we say that lawyers must not only refrain from impropriety, but 
refrain from any appearance of impropriety. Similarly, as FDA 
Commissioner, how would you, both with respect to your own actions and 
with respect to the rest of the Agency's employees, ensure independence 
and also avoid the appearance of a lack of independence?
    Answer 1. At Duke, I was honored to lead a team of researchers who 
were pioneers and advocates for the expansion of measures to enhance 
the transparency, disclosure, and public discussion of funding sources.
    Prior to joining FDA, I went through a comprehensive screening 
process for conflicts of interest, working closely with HHS staff. I 
hold my FDA colleagues to the same standards to which I hold myself. 
The United States--indeed the entire world--depends on a strong, 
unbiased FDA that can work with industry to advance critical 
technologies, but still make independent determinations to ensure safe 
and effective products. But this activity must adhere to societal 
guidelines and expectations for governing conflict of interest. 
Developing new technologies that revolutionize patient care calls for a 
community of dedicated people across the health care ecosystem. I have 
first-hand experience appropriately collaborating across industry, 
academia, the patient community, and government, which is a critical 
skill in today's science-based regulatory environment.
    Following my appointment as Deputy Commissioner for Medical 
Products and Tobacco, the Office of the Commissioner established a 
process for screening invitations that I receive for speaking 
engagements and other requests for my participation to identify 
potential situations which would require my recusal. A team of 
individuals was convened, including a representative of the Office of 
the Commissioner and the Office of Chief Counsel. These individuals 
have extensive knowledge of my ethics agreement and recusal 
obligations. This team meets on a regular basis (often as frequently as 
weekly) and on an ad hoc basis, as needed. A member of my staff submits 
detailed information regarding specific invitations/requests for my 
participation, and the team determines whether I should be recused. If 
the team has any questions as to whether something is covered by the 
recusal, the HHS Designated Agency Ethics Official's office is 
consulted. The team has a standing teleconference with a representative 
of this office in order to facilitate consultations and determinations.
    If my nomination is confirmed, I understand that I will be subject 
to more extensive recusal obligations under the President's 2009 
Executive order, and accordingly, that additional monitoring procedures 
may be needed.

    Question 2. Fitting combination products, such as products with 
both drug and device components, into the current regulatory framework 
can sometimes be challenging. However, we do not want to miss 
opportunities to innovate with combination products that would advance 
the public health because of regulatory challenges. Dr. Califf, you 
mentioned that FDA would be able to develop a proposal within a year to 
address these challenges. What does FDA envision?
    Answer 2. FDA has found that sponsors face the challenges you 
identify under the existing pathways for device-led combination 
products. Device-led combination products range from simple products 
that pose little risk and address relatively simple treatment needs 
(such as a drug-coated bandage for minor wounds) to complex, riskier 
products intended to address more significant medical needs (such as 
drug-eluting stents). The device program as currently structured, 
however, is sharply divided between 510(k) and PMA pathways. The PMA 
pathway is more akin to the innovator drug and biologic pathways (NDA 
and BLA), generally requiring an independent showing of safety and 
effectiveness. Under the 510(k) pathway, on the other hand, FDA has 
faced challenges in obtaining information critical to evaluating a drug 
or biologic component, and also on ensuring reasonable use of the 
510(k) predicate system.
    FDA believes a new premarket pathway for device-led combination 
products could significantly improve certainty and predictability for 
these products while enabling both protection and promotion of the 
public health. A pathway to achieve these goals would:

     ensure FDA has the tools necessary to assess the risks and 
benefits of device-led combination products,
     direct FDA to base data requirements on the potential 
risks and benefits of the product and what is already known regarding 
the safety and effectiveness of its constituent parts, and
     grandfather combination products that have been cleared 
under 510(k) to date and allow combination products that include the 
same drugs and substantially equivalent devices to rely on these 
grandfathered products as predicates, unless FDA finds that review 
under the new pathway is needed to establish reasonable assurance of 
safety and effectiveness for the product.

    Question 3a. Following up on my question during the hearing, I 
wanted to continue with a question about drug labeling for neonates. 
According to reports from the FDA, up to 90 percent of the drugs used 
in NICUs are used off-label. Independent research estimates that the 
percentage is even higher. As such, the labels for these drugs do not 
include information on dosing, safety or efficacy for neonates. This 
represents a serious gap in effective regulation.
    What are the most commonly used drugs in the NICU and do they have 
FDA-approved pediatric labeling?
    Answer 3a. The top 10 most commonly used drugs in the neonatal 
intensive care units (NICUs), based on a recent study by Hsieh, et al., 
from Duke University, published in the American Journal of Perinatology 
in 2014, include the following: ampicillin, gentamicin, caffeine 
citrate, vancomycin, beractant, furosemide, fentanyl, dopamine, 
midazolam, and calfactant.
    Of these top 10 commonly used drugs in NICUs, gentamicin, caffeine 
citrate, vancomycin, beractant, calfactant, furosemide, and midazolam 
included dosing information for neonates. Gentamicin and vancomycin are 
antibiotics, beractant and calfactant are surfactant products used to 
treat respiratory distress syndrome, caffeine citrate is used to treat 
apnea of prematurity, midazolam is used for pre-operative/pre-
procedural sedation, and furosemide is to treat edema, secondary to 
edema-forming states and acute pulmonary edema.
    Pediatric dosing, but not neonatal dosing, is present for 
ampicillin, an antibiotic, and fetanyl, a short-acting analgesic used 
during anesthesia. Dopamine does not have specific pediatric or 
neonatal dosing information.
    Of the most commonly reported medications identified in this study, 
only 35 percent are FDA-approved in the newborn (for more information, 
see the attached publication by Hsieh, et al.). Many of these drugs 
were approved years ago and without the same data to support approval, 
as are required today. For example, furosemide was approved in 1966. Of 
the 409 drugs with pediatric-specific labeling changes between 1997 and 
2010, only 28 included information for use in neonates (7 percent). 
Even more recently, of the 156 drugs with pediatric-specific labeling 
changes since 2012, only nine products were approved for use in 
neonates (6 percent).

    Question 3b. What percentage of drugs used in the NICU are off-
patent versus on-patent? How has FDA worked with NIH through the BPCA 
NIH program to approve pediatric labeling for off-patent drugs used in 
neonates and what have we learned about the safety and efficacy of 
these drugs?
    Answer 3b. FDA does not formally track the percentage of drugs used 
in the NICU and their current patent status. However, as stated above, 
many of the drugs most commonly used in NICUs were approved many years 
ago and would not be expected to have remaining patent protection. 
Implementation and coordination of the BPCA NIH activities is conducted 
by NICHD's Obstetric and Pediatric Pharmacology and Therapeutics Branch 
(OPPTB). FDA has worked closely with colleagues in NICHD through the 
BPCA NIH program to increase the information to support pediatric 
labeling for off-patent drugs in all appropriate pediatric populations. 
For example, recent pediatric-specific labeling changes, including 
dosing information in neonates, were approved for sodium nitroprusside, 
used to treat hypertensive crisis, and meropenem, an antibiotic, 
included dosing information in neonates. Additionally, FDA meets with 
the NICHD monthly to review progress made toward increasing pediatric 
labeling for off-patent drugs.

    Question 3c. If confirmed, what actions will you consider to ensure 
that therapeutics for neonates are studied in that population so they 
can be used with appropriate safety and effectiveness?
    Answer 3c. FDA has clearly recognized the need to increase efforts 
to develop therapeutics for neonates. In October 2014, FDA convened the 
first Neonatal Scientific Workshop. This workshop was co-sponsored by 
the Critical Path Institute, Burroughs Wellcome, and FDA. The workshop, 
entitled ``Roadmap for Applying Regulatory Science to Neonates,'' 
considered the feasibility of the development of a global neonatal 
research consortium, including discussions of the governance structure. 
In May 2015, as a result of discussions initiated at the FDA workshop, 
the International Neonatal Consortium (INC) was launched by Critical 
Path Institute. The INC includes global collaboration including FDA, 
EMA, NIH, neonatal advocacy groups, pharmaceutical companies, academic 
researchers and neonatal nurses. The mission of the INC is to 
accelerate the development of safe and effective therapies for 
neonates. The creation of a global neonatal consortium, dedicated to 
advancing the development of safe and effective therapies for neonates 
is a major achievement and FDA will continue to support this global 
effort.
    In addition, FDA will continue to support increasing the 
availability of safe and effective therapies for neonates through 
efficient, effective implementation of BPCA and PREA.

    Question 4. As you are aware, there has been increasing scrutiny 
over the last 2 years on the safety of certain medical devices. I 
understand from communications with your predecessor that one of the 
challenges FDA can face when the safety of a medical device is called 
into question include a fractured and still quite limited system for 
medical device surveillance. Following up on Senator Murray's question 
at the hearing, from your perspective, what would a robust, proactive 
surveillance system for devices look like to ensure that new safety 
indicators are quickly identified and addressed?
    Answer 4. Medical device post-market surveillance presents unique 
challenges due to the greater diversity and complexity of medical 
devices, the iterative nature of medical product development, the 
learning curve associated with technology adoption, and the relatively 
short product life cycle.
    Although the United States has a robust medical device post-market 
surveillance system, we believe it can be strengthened by developing a 
more integrated national system, now being referred to as the National 
Medical Device Evaluation System (NMDES). This system would not be 
owned or run by FDA; rather, it would be operated through an 
independent public-private partnership and governed by a board with 
representation from the primary medical device ecosystem communities, 
e.g., patients, providers, payers, industry, and government. The system 
would ensure the security and privacy of the information used but would 
not own the data. Data ownership would be retained by the original data 
holder, such as health care systems.
    The FDA's plan to develop NMDES provides a pathway to realizing a 
national system that harnesses novel data sources, modern analytical 
techniques and the participation of all stakeholders to optimize 
patient care. The system is envisioned to be able to develop and 
communicate an evolving understanding of devices' benefits and risks 
throughout their marketed life using high-quality, linked electronic 
health information, identify potential safety signals in near real-time 
from a variety of privacy-protected data sources serving as a safety 
net, reduce burdens and costs of medical device post-market 
surveillance, and facilitate clearance and approval of new devices or 
new uses of existing devices.
    The NMDES evolved out of a vision for a medical device post-market 
surveillance system described in two FDA white papers. The initial 
report, ``Strengthening Our National System for Medical Device Post-
Market Surveillance,'' was issued in 2012 and provides an overview of 
FDA's medical device post-market authorities and the current U.S. 
medical device post-market surveillance system. The update to the 
report, issued in 2013, details the concrete steps that will promote 
more efficient collection of better and more timely data, helping to 
identify issues more quickly. A multi-stakeholder planning board to 
promote this vision was convened by the Engelberg Center for Health 
Care Reform of the Brookings Institution. In February 2015 the planning 
board issued a report titled ``Strengthening Patient Care: Building a 
National Post-Market Medical Device Surveillance System,'' which sets 
out the key steps to take toward development of a national system for 
development, regulation, and effective use of medical devices, while 
supporting improvements in patient safety and health outcomes. The 
system, which will support the needs of the entire community of 
stakeholders, was renamed an ``evaluation system'' with the release of 
the report ``Recommendations for a National Medical Device Evaluation 
System: Strategically Coordinated Registry Networks to Bridge the 
Clinical Care and Research'' in August 2015. MDEpiNet, a public-private 
partnership, produced this report and is working to build 
infrastructure for the national system and development.

    Question 5. There is mounting evidence documenting the value of 
immunization to protect pregnant women and their newborns from 
infectious diseases, such as influenza and pertussis. In the coming 
years, new maternal vaccines are expected to be developed at a faster 
rate, and to present FDA with a range of new considerations to take 
into account. If confirmed, what will you do to encourage maternal 
vaccine development and ensure timely approval of safe and effective 
maternal vaccines?
    Answer 5. FDA shares the goal of having vaccines available to 
protect pregnant women and their newborns from infectious diseases. To 
help facilitate more optimal development of such vaccines, on November 
13, 2015, we sought advice from our Vaccines and Related Biological 
Products Advisory Committee on appropriate clinical study designs to 
support the safety and effectiveness of investigational vaccines, as 
well as study designs of licensed vaccines that are recommended for use 
during pregnancy to protect newborns in addition to their mothers. FDA 
received helpful advice from the Advisory Committee members on ways to 
advance the development of these vaccines, and is committed to working 
closely with sponsors in this important area.

    Question 6. Specialized nutrition and medical foods are critically 
important to patients with conditions such as phenylketonuria (PKU) as 
well as many other conditions. In this rapidly changing and evolving 
field, what are your goals and priorities for specialized nutrition and 
medical foods? Additionally, while there has been growing level of 
interest and innovation, coverage and reimbursement for these products 
often lag behind new developments. To what extent can FDA work more 
closely with agencies such as CMS to help patients gain better access 
to specialized nutritional solutions?
    Answer 6. FDA recognizes the critical role of medical foods in the 
lives of patients with inherited metabolic disorders such as 
phenylketonuria (PKU). The Agency's goals for medical foods include 
staying abreast of the science in this rapidly evolving field; working 
to ensure the availability of safe and appropriately labeled products 
for patients with inherited metabolic disorders; and providing sound 
guidance to patients, health care providers, and industry.
    For example, a current FDA medical food priority is to address 
stakeholder requests for updated medical foods guidance. FDA 
incorporated the most recent available science in its updated Draft 
Medical Foods Guidance, published in August 2013. We are currently 
considering the comments we received on the draft guidance, along with 
the latest science, as we work to finalize the Medical Foods Guidance.
    FDA also prioritizes communication and collaboration with medical 
food stakeholders on scientific issues. For example, a recent NIH study 
revealed that a medical food intended for a single specific metabolic 
disorder was being inappropriately used to treat patients with a 
combination metabolic disorder, resulting in adverse effects. FDA, NIH, 
and a manufacturer of one such product collaborated on the matter, 
which led to the manufacturer changing their labeling to warn health 
care practitioners against its use for the specific combination 
disorder at issue. The manufacturer and NIH have agreed to continue 
working in partnership to further study the disorder (and other related 
metabolic disorders), with FDA providing any needed regulatory 
knowledge and guidance.
    The advances in medical food research that are critical to patients 
with inborn errors of metabolism are also an important part of FDA's 
Office of Orphan Products Development (OOPD) goals and priorities to 
advance promising products for rare disease patients. OOPD provides 
funding support for clinical studies that advance the development of 
promising medical products for rare diseases, including medical foods 
to manage rare diseases such as PKU. For example, OOPD is currently 
funding a 4-year, Phase 2 PKU medical food study conducted by the 
University of Wisconsin. The $1.5 million dollar study evaluates the 
glycomacropeptide diet with the amino acid diet for PKU patients. 
OOPD's priority on funding the best studies that can further the 
development of medical product for rare disease will advance medical 
food options for patients with inborn errors of metabolism.
    Coverage and reimbursement of specialized nutrition and medical 
foods is outside the scope of FDA's authority, but the Agency is 
committed to work collaboratively with our Federal agency partners and 
with Congress, as appropriate, to help patients with specialized 
nutritional issues.

    Question 7. As you may know, the issue of teens abusing the over-
the-counter cough suppressant, dextromethorphan (DXM) or ``dex,'' is an 
issue I have been working to address for several years now. Years ago, 
as many as 6 percent of teens aged 13-17 abused dex by drinking cough 
syrup, sometimes as much as a full bottle or more. Since then, many 
stakeholders in the retail, pharmacy and OTC pharmaceutical sectors 
have worked together to establish voluntary restrictions on the sale of 
dex to minors, and to educate parents, educators and medical 
professionals about this problem. These efforts have led to a 
significant decrease in dex abuse, to the current rate of 3.3 percent 
for teens aged 13-17. We know that FDA has long been concerned with 
this effort and held an advisory committee hearing in 2010 on the abuse 
of dex, at which time the Agency suggested the benefit of a statutory, 
nationwide minimum age of 18 for dex purchases. I would ask that you 
continue to work with me on this issue as I continue to pursue a 
legislative solution.
    Answer 7. The Agency has been working with you and your staff, as 
well as your colleagues in the House, on this very important issue. We 
have recently provided updated technical assistance and will continue 
to work with you and your staff moving forward.
                             senator bennet
    Question 1. Dr. Califf, in the last few years, there have been 
numerous reports on the public health threat of antibiotic resistance. 
Experts warn that unless we take action, we could find ourselves in a 
post-antibiotic era. In such an era, the risk of infection would make 
many elective surgeries too dangerous to justify, where a simple wound 
could turn deadly, or where patients with compromised immune systems--
those being treated for cancer for example--would not have medicines to 
combat the infections to which they are highly susceptible. Senator 
Hatch and I have introduced the PATH Act, which would create a new 
regulatory pathway for antibiotics to treat potentially fatal 
infections for which there are few or no other options--in essence, the 
drugs we need the most. We have been working closely with the FDA and 
the HELP Committee as we finish our work on the legislation. Can you 
talk about how the PATH Act would work to help encourage the 
development of new, life-saving antibiotics?
    Answer 1. Thank you for your leadership combating the public health 
threat of antibiotic resistance and on the ``Promise for Antibiotics 
and Therapeutics for Health (PATH) Act''. The PATH Act would establish 
in statute an approval pathway for ``limited population'' antibacterial 
drugs.
    We understand that the objective of this pathway is to help 
expedite the development and approval of antibacterial drugs intended 
to treat a serious or life-threatening infection and meet unmet medical 
needs in limited subpopulations of patients. Drugs eligible for this 
proposed pathway could be approved based on streamlined clinical 
development programs showing that the risk-benefit profiles of those 
drugs are appropriate for limited subpopulations of patients with unmet 
medical need, such as patients with serious infections caused by multi-
drug-resistant organisms, even if the risk-benefit profile would not 
support approval for a broader population.
    A statutory ``limited population'' pathway as proposed would 
provide FDA tools (e.g., a ``limited population'' designation on the 
label, pre-review of promotional materials) to ensure appropriate post-
approval use of these antibacterial drugs in the indicated sub-
population and focus on establishing a consistent and predictable 
program for drug sponsors.
    However, it is critical that any legislation be carefully crafted 
so as not to undermine FDA's ability to approve drugs under our 
existing authorities. FDA is focused on balancing the need to encourage 
the development of critically needed antibacterial drugs while ensuring 
that the current FDA drug approval standard is maintained.

    Question 2. What will you do as head of the FDA to ensure that 
medical device implants do not wear out prematurely and that patients 
are given verifiably accurate information on the life of their implant?
    Answer 2. As a complement to its premarket review process, FDA's 
plan to develop a National Medical Device Evaluation System (NMDES) 
provides a pathway to realizing a national system that harnesses novel 
data sources, modern analytical techniques, and the participation of 
all stakeholders to optimize patient care. The system is envisioned to 
be able to develop and communicate an evolving understanding of 
devices' benefits and risks throughout their marketed life using high-
quality, linked electronic health information, identify potential 
safety signals in near real-time from a variety of privacy-protected 
data sources serving as a safety net, reduce burdens and costs of 
medical device post-market surveillance, and facilitate clearance and 
approval of new devices or new uses of existing devices. A strong NMDES 
will facilitate the ready availability of accurate information about 
implant lifespan and also support the rapid identification of 
problematic implants early in the market life of the device.

    Question 3. As the FDA continues to issue draft guidance for 
comments, can you discuss your process of consulting with health care 
scientific experts? If commenters disagree with the science behind 
draft guidance after sending in a set of comments, are there any other 
opportunities to: (1) address these concerns with FDA directly; and (2) 
better understand why FDA disagrees with their position?
    Answer 3. FDA's Good Guidance Practices (GGPs) regulations (21 CFR 
10.115) lay out the ways in which affected parties may participate in 
the guidance development process and how the Agency goes about 
soliciting input from affected parties.
    FDA has many ways to solicit and receive comments from outside 
stakeholders before, during, and after issuance of guidances. Before 
issuance of a draft guidance document, FDA can seek or accept early 
input from individuals or groups outside the Agency. When a draft 
guidance document is issued, FDA will publish a notice in the Federal 
Register and invite comments. FDA can also hold public meetings or 
workshops during this time and FDA can also present the draft guidance 
to an advisory committee for review at this time. FDA will then review 
any comments received and, when appropriate, incorporate the suggested 
changes into the final guidance document. FDA also can decide to issue 
a revised draft of the guidance document after reviewing comments on 
the draft guidance document. Even after a guidance is finalized, the 
docket remains open and comments can be submitted at any time.
    If affected parties disagree with the science behind a draft or 
final guidance, they are able to suggest that FDA revise the guidance 
or withdraw an already existing guidance by submitting comments to the 
docket.

    Question 4. Under the Biologics Price Competition and Innovation 
Act (BPCIA) of 2009, the FDA was given authority to review and approve 
biosimilars. While the FDA has approved the first biosimilar, many are 
still awaiting final guidance from the FDA on what biosimilars should 
be named, the makeup of their label, and interchangeability with the 
original biologic. When do you expect for this guidance to be released?
    Answer 4. FDA has published the following final guidances related 
to biosimilars: Scientific Considerations in Demonstrating 
Biosimilarity to a Reference Product; Quality Considerations in 
Demonstrating Biosimilarity of a Therapeutic Protein Product to a 
Reference Product; Biosimilars: Questions and Answers Regarding 
Implementation of the Biologics Price Competition and Innovation Act of 
2009; and Formal Meetings Between the FDA and Biosimilar Biological 
Product Sponsors or Applicants.
    FDA has also published the following draft guidances since 2012: 
Clinical Pharmacology Data to Support a Demonstration of Biosimilarity 
to a Reference Product; Reference Product Exclusivity for Biological 
Products Filed Under Section 351 (a) of the PHS Act; Biosimilars: 
Additional Questions and Answers Regarding Implementation of the BPCI 
Act of 2009; and Nonproprietary Naming for Biological Products.
    The Agency is committed to carefully reviewing the comments 
received as we move forward in finalizing the draft guidances noted 
above. Upcoming draft guidances are expected to include: Considerations 
in Demonstrating Interchangeability to a Reference Product; Statistical 
Approaches to Evaluation of Analytical Similarity Data to Support a 
Demonstration of Biosimilarity; and Labeling for Biosimilar Biological 
Products.
    FDA is diligently working to issue guidance on issues that have 
been identified by the FDA and key stakeholders as key topics of 
interest. While the Agency cannot provide a specific timeline for the 
release of any guidance, we continue to provide information to assist 
biological product developers--sponsors/companies--with bringing 
biosimilar and interchangeable products to market. The FDA is 
continuing to clarify its approach to implementation of the BPCI Act to 
further facilitate sponsors' development of biosimilar and 
interchangeable biological products.

    Question 5. Dr. Califf, as you know, there has been an ongoing 
concern about the rising cost of medicines. The Generic Drug User Fee 
Agreement enacted in 2012, gave FDA new resources to ensure the timely 
access to quality generic drugs. Unfortunately, there are estimated to 
be 4,000 generic drug applications still pending approval by the FDA. 
Can you please explain how the Agency is addressing and prioritizing 
these applications?
    Answer 5. Pursuant to the Generic Drug User Fee Amendments of 2012 
(GDUFA), ``backlog'' is a defined term. It means all Abbreviated New 
Drug Applications (ANDAs), ANDA amendments and ANDA supplements pending 
as of October 1, 2012 (the date of enactment). GDUFA was negotiated by 
FDA and Industry and passed by Congress as part of the Food and Drug 
Administration Safety and Innovation Act of 2012 (FDASIA).
    Pursuant to GDUFA, Industry pays FDA certain agreed-upon fees, and 
in exchange FDA agrees to certain quantitative review performance 
goals. FDA's GDUFA goal for the backlog (as defined above) is for the 
Agency to take action on 90 percent of the legacy, pre-GDUFA 
``backlog'' submissions by the end of fiscal year 2017. We have already 
taken action on 82 percent of the pre-GDUFA ``backlog,'' well ahead of 
schedule to fulfill our negotiated commitment. There were approximately 
2,866 ANDAs in the pre-GDUFA backlog. Many of these submissions were 
long pending when GDUFA started, providing one of the key reasons that 
Industry entered into GDUFA in the first place.
    GDUFA explicitly assumed that Industry would send FDA approximately 
750 new ANDAs each year of the program, an assumption upon which the 
Agency budgeted and planned accordingly. In fiscal years 2012, 2013 and 
2014, Industry submitted 1,103; 968; and 1,473 ANDAs, respectively. 
Given that GDUFA assumed, and industry users fees reflect, a much 
smaller workload, the Agency is striving to take action on all of these 
submissions before the end of fiscal year 2017.
    The status of our pre-fiscal year 2015 workload is detailed below. 
Of the 5,720 total ANDAs that the Agency has received:

     1,316 ANDAs have been approved.
     The Agency ``refused to receive'' (RTR) 226 ANDAs--meaning 
we did not accept them for review because they were not ``sufficiently 
complete to permit a substantive review.''
     422 ANDAs were withdrawn.
       Note: ANDAs that have been approved, RTR'd or withdrawn are no 
longer part of our review workload.
     1,113 ANDAs are ``pending industry.'' This includes:

          846 submissions where FDA issued a Complete Response 
        (CR) Letter. A CR Letter lists deficiencies an applicant must 
        fix to obtain approval. FDA cannot take further action on these 
        846 submissions until the applicant responds to the issues 
        raised in the CR Letters.
          It also includes 267 Tentative Approvals (TA). TAs 
        reflect the fact that the patent or exclusivity on the new drug 
        product hasn't expired, and thus the Agency is barred from 
        issuing a final approval, the ANDA is otherwise approvable from 
        a regulatory perspective.\19\
---------------------------------------------------------------------------
    \19\ Pursuant to the Drug Price Competition and Patent Term 
Restoration Act, often referred to as the ``Hatch-Waxman'' Amendments, 
FDA generally cannot approve a generic until any relevant patents and 
statutory exclusivity on the new drug product expire. For many 
potential first generic ANDAs in our workload, expiry occurs at a 
future date and we cannot lawfully approve them at the time our review 
is complete, though some may be issued a Tentative Approval, as noted 
above.

---------------------------------------------------------------------------
     2,643 ANDAs are pending an FDA action.

          7 are pending a filing review to determine whether or 
        not they will be accepted or RTR'd.
          498 have been successfully filed, but we have not 
        communicated review deficiencies to the applicant concerning 
        these ANDAs yet.
          For the remaining 2,138 ANDAs, we have issued at 
        least one review communication to applicants. In fiscal year 
        2015, we issued over 4,700 communications concerning ANDA 
        review deficiencies to industry.

    In summary, out of 5,720 submissions, over 90 percent have been 
approved, RTR'd, withdrawn, are pending industry, or are under active 
review. Applicants are still waiting to hear from FDA on less than 10 
percent of our overall pre-fiscal year 2015 ANDA workload.
    As for prioritization, in August 2014 the Agency's Center for Drug 
Evaluation and Research (CDER) updated its Manual of Policies and 
Procedures (MAPP) entitled Prioritization of the Review of Original 
ANDAs, Amendments, and Supplements. This MAPP, which is publicly 
available, describes how the review of ANDAs, ANDA amendments, and ANDA 
supplements are prioritized.
    FDA considers certain types of ANDAs to be public health 
priorities, and expedites their review accordingly. Specifically, FDA 
considers potential ``first generic'' ANDAs to be public health 
priorities. First generics are the first generic to enter the market 
for a given branded product. Potential first generics are about 15 
percent of our workload. All of them have been tagged as priorities, 
and their review has been expedited. This is true regardless of when 
the ANDA was submitted. In the past 3 years, we have approved hundreds 
of first generics for more than 200 new drug products. FDA also 
considers shortage-related drugs a priority, and expedites their 
review.

    Question 6a. Dr. Califf, we appreciate the FDA's efforts to 
diligently implement Title II of the Drug Supply Chain Security Act and 
are encourage that thus far, implementation of the law appears to be 
progressing across the supply chain. As this implementation moves 
forward, we have the following questions.
    Currently, there are several guidances that are in development such 
as grandfathering, and licensures for 3pls and wholesale distributors. 
What is the status of these items and do you expect FDA will meet the 
statutory deadlines? If not, will FDA provide alternative deadline for 
supply chain stakeholders?
    Answer 6a. As you know, FDA is tasked with developing many 
guidances and regulations to implement the Drug Supply Chain Security 
Act. We are focused on accomplishing these tasks as quickly as possible 
while simultaneously addressing the myriad, complicated issues raised 
by stakeholders and providing guidance to the industry as needed. 
Unfortunately, we have not been able to promulgate the required 
national standards and licensing rules as quickly as we would like 
owing to the complexity and magnitude of the drug supply chain business 
models, the procedural requirements associated with rulemaking, and the 
Agency's limited resources. However, the national standards and 
licensing rules are a priority and we continue to work on them and the 
guidances required by the Act, including the grandfathering guidance.

    Question 6b. Regarding licensure of 3pls and wholesale 
distributors, does FDA have a plan in place for outreach and direction 
to States about: (1) how they should adopt the pending standards and 
(2) how their authority may change due to Federal preemption in this 
area under the Drug Supply Chain Security Act?
    Answer 6b. FDA's outreach includes engagement of State officials, 
and FDA has presented at various meetings hosted by the National 
Associations of Boards of Pharmacy, a group that brings together the 
State Boards of Pharmacy and others responsible for States' licensure 
of wholesale distributors and third-party logistics provider (3PLs). 
Additionally, on November 18, 2015, FDA held an inter-governmental 
working meeting on the Drug Quality and Security Act. At this meeting, 
FDA hosted representatives from the State Boards of Pharmacy and other 
State Officials responsible for licensure of wholesale distributors and 
3PLs. The following issues were discussed: timing and implementation 
issues for States related to the licensing of wholesale distributors 
and 3PLs, what issues State Officials felt clarification would be 
helpful, and how FDA and States can improve collaboration. FDA will 
continue to work with the States as it implements the licensing 
standards under the DSCSA.

    Question 6c. Colorado and many other States run nonprofit drug 
donation programs across the United States, helping get donated drugs 
to uninsured or under-insured patients. In Colorado alone, a nonprofit 
organization called the Supporting Initiatives to Redistribute Unused 
Medicine (SIRUM) has already provided 8,900 prescriptions to needy 
patients. These nonprofits never take ownership or possession of the 
drug. However, current FDA guidance threatens the ability of nonprofit 
drug donation programs and organizations transfer donated medicines to 
affiliates. The Drug Supply Chain Security Act contemplates the idea of 
a nonprofit organization distributing donated medications to 
affiliates. In that case, the transfer of medicines is not considered a 
``transaction''. Because these nonprofits have a unique structure that 
does not take ownership or possession of the drug product, would the 
FDA be willing to provide technical assistance to these programs to 
ensure that nonprofit drug donation programs around the country can 
continue to provide the thousands of medicines a year to the uninsured 
and the underinsured?
    Answer 6c. FDA continues to conduct outreach and education to many 
stakeholders, in additional to hearing about specific issues related to 
different and complicated business models that present unique 
challenges in implementing the DSCSA. Congress enacted DSCSA to allow 
FDA to implement a robust system to better protect the quality of drugs 
throughout the pharmaceutical distribution supply chain. DSCSA exempts 
from the definition of ``transaction'' (section 581(24)(viii))

        ``the sale, purchase, or trade of a drug or an offer to sell, 
        purchase, or trade a drug by a charitable organization 
        described in section 501(c)(3) of the Internal Revenue Code of 
        1986 to a nonprofit affiliate of the organization to the extent 
        otherwise permitted by law.''

    DSCSA also exempts from the definition of ``wholesale 
distribution,''--

          ``the distribution of a drug or an offer to distribute a drug 
        by a charitable organization to a nonprofit affiliate of the 
        organization to the extent otherwise permitted by law''

(section 503(3)(4)(F) of the FD&C Act). FDA is examining these issues 
and intends to provide information to stakeholders, as necessary, to 
clarify how charitable donations are treated under DSCSA.
                            senator baldwin
    Question 1a. It is imperative that consumers get the most up-to-
date, accurate information about medical products to make the best 
health decisions and that the medicines they take are safe. I believe 
that more must be done to improve both transparency and the oversight 
of drug products after they reach the market to ensure safety. For 
example, in 2012, Ranbaxy Pharmaceuticals Inc. issued a voluntary 
recall of lots of their generic version of Lipitor because small glass 
particles were found in certain batches of the product. The company had 
already been under investigation--and later pleaded guilty--for failing 
to conduct proper safety and quality tests of several of its 
manufacturing plants in India since 2008. Further, once Ranbaxy 
announced the recall, the FDA initially issued conflicting public 
statements about the safety of these drug products, confusing patients 
and doctors.
    This raises a number of important issues that I hope the next FDA 
Commissioner will address to fulfill the agency's mission of protecting 
the public health. Specifically:
    Do you believe that FDA needs mandatory recall authority for drugs 
to guarantee that dangerous products are swiftly taken off the market?
    Answer 1a. Yes, FDA needs mandatory recall authority and the Agency 
has repeatedly sought this authority. While it is true that drug 
companies typically issue a recall voluntarily when FDA determines it 
is necessary, absent clear authority for the Agency to require a 
company to issue a recall we often lose critical time negotiating the 
terms of the recall, during which patients continue to be exposed to 
dangerous or ineffective products. Under the current system, a company 
may disagree with FDA as to the need for a recall or the scope of a 
recall. While we work out those matters collaboratively, patients are 
left vulnerable to potentially dangerous products.

    Question 1b. What steps has FDA taken, including with respect to 
internal protocols, to improve its communication to consumers and other 
stakeholders about voluntary drug recalls since 2012?
    Answer 1b. As a matter of policy, FDA will promptly post or issue 
public notification in situations that present an imminent health risk 
to consumers.
    Firms often also issue a public warning, typically in the form of a 
press release. Firms are requested to provide a draft of the press 
release for FDA to review and comment. FDA has developed recall press 
release templates for firms to follow which are posted on FDA's website 
under industry recall guidance: http://www.fda.gov/Safety/Recalls/
IndustryGuidance/default.htm. FDA may issue its own public warning in 
instances where a firm declines to issue public warning, where a firm's 
public warning is inadequate, or where FDA believes that additional 
warning is needed to inform the public.
    In 2012, the enforcement report, where FDA publishes recall 
information, was automated thereby enhancing availability of recalls to 
the public. Further improvements to this automated process are expected 
in the near future to provide more timely and accurate data to the 
trade and public.
    FDA constantly evaluates its processes to self-identify where 
improvements are needed that serve better the health of the public. As 
part of this process and FDA transparency, FDA created the FDA Track 
Web page where the Agency provides performance metrics on different 
programs the Agency administers.\20\ One of the metrics available at 
the Web page is recall classification timeframes. This is the time it 
takes the Agency to classify a recall once a firm provides the Agency 
with a recall notification and all the pertinent information to 
evaluate the recall.
---------------------------------------------------------------------------
    \20\ See http://www.accessdata.fda.gov/scripts/fdatrack/view/
track.cfm?program=cder&status
=public&id=CDER-DQC-Percentage-of-recall-classification-meeting-
timeframe&fy=All.
---------------------------------------------------------------------------
    Data reported on the Web page shows how steps taken such as 
increasing the automation of recall classification process and hiring 
of employees, has helped decrease the classification timeframes and 
help maintain a consistent high level of performance. This consistent 
high level of performance allows the Agency to publish recall 
information soon after the recall is classified.
    FDA is conducting a pilot program seeking to expedite notifications 
of human drug product recalls to the public. In addition to the 
information about classified recalls found in the weekly Enforcement 
Report, the Agency will include actions that have been determined to be 
recalls, but that remain in the process of being classified as a Class 
I, II, or III recall.

    Question 1c. Can you please provide an update on how many 
inspections FDA has conducted of domestic and foreign establishments 
and how many adverse findings that resulted in corrective actions, 
since the risk-based inspection schedule for drug facilities was 
enacted in the FDA Safety and Innovation Act of 2012?
    Answer 1c. Following FDASIA passage in 2012, our fiscal year 2013 
and 2014 domestic and foreign human drug inspectional data (GMP-
related) is as follows.

                  Number of Inspections by Fiscal Year
------------------------------------------------------------------------
                                                           2013    2014
------------------------------------------------------------------------
Domestic................................................    1851    1869
Foreign.................................................     827     993
                                                         ---------------
    Total...............................................    2678    2862
------------------------------------------------------------------------
Fiscal year 2015 data is not yet finalized.

    FDA issues FDA-Form 483s to companies, and an overwhelming number 
of companies undertake satisfactory corrections to the cited 
objectionable conditions. An FDA-Form 483 is issued to firm management 
at the conclusion of an inspection when an investigator(s) has observed 
any conditions that in their judgment may constitute violations of the 
FD&C Act and related acts.\21\ These are confirmed during the next 
scheduled inspection, or in an accelerated re-inspection. While 
corrections to specific citations are routinely corrected, FDA at times 
finds that problems recur, and additional interventions are necessary. 
These firms are reflected in our Import Alert, Injunction, and Seizure 
data from fiscal year 2013, 2014, and 2015, which is as follows.
---------------------------------------------------------------------------
    \21\ http://www.fda.gov/ICECI/Inspections/ucm256377.htm.

                           Data by Fiscal Year
------------------------------------------------------------------------
                                              2013    2014       2015
------------------------------------------------------------------------
Injunction.................................       5       1            3
Seizure....................................       1       2            1
Import Alerts..............................     146     101          144
Warning Letters............................      86      94     Data not
                                                                     yet
                                                               available
------------------------------------------------------------------------
In addition, Warning Letter Closeout data is available at: http://
  www.accessdata.fda.gov/scripts/warningletters/
  wlPSearchResult.cfm?qryStr=&sortColumn=12+desc&Go=Go&_1_issueDt=&_2_is
  sueDt=&company=&subject=&Poffice=&hasResponseLetter=Both&hasCloseoutLe
  tter=Yes&recsPerPageDef=500.


    Question 2. Medical foods play an important role in meeting the 
distinct nutritional requirements for patients with certain diseases 
and conditions. For example, medical foods are medically necessary for 
children and adults living with phenylketonuria (PKU), an inherited 
metabolic disorder that is characterized by the inability of the body 
to process the essential amino acid phenylalanine. I am encouraged by 
the FDA's past work in recognizing medical foods and their role in 
managing disorders such as PKU, and it is critical that patients and 
providers continue to have access to the latest safe treatments.
    What more can the FDA do to apply the most recent advances in 
nutrition science to improve health outcomes for patients with PKU and 
other diseases?
    Answer 2. FDA recognizes the critical role of medical foods in the 
lives of patients with inherited metabolic disorders such as 
phenylketonuria (PKU). FDA continues to work to ensure medical food 
products are safe and appropriately labeled so that medical 
practitioners are able to make informed decisions about the best care 
of their patients, leading to overall improved health outcomes. We are 
committed to staying abreast of new science that emerges concerning 
these disorders and working with other stakeholders to improve health 
outcomes for affected patients.
    As an example, a recent NIH study revealed that a medical food 
intended for a single specific metabolic disorder was being 
inappropriately used to treat patients with a combination metabolic 
disorder, resulting in adverse effects. FDA, NIH, and a manufacturer of 
one such product collaborated on the matter, which led to the 
manufacturer changing their labeling to warn healthcare practitioners 
against its use for the specific combination disorder at issue. The 
manufacturer and NIH have agreed to continue working in partnership to 
further study the disorder (and other related metabolic disorders), 
with FDA providing any needed regulatory knowledge and guidance.
    FDA has also incorporated the most recent available science in its 
updated Draft Medical Foods Guidance published in August 2013. We are 
considering the comments we received on the draft guidance, along with 
the latest science as we work to finalize the Medical Foods Guidance.
    Advances in medical food research are critical to patients with 
inborn errors of metabolism and an important part of FDA's Office of 
Orphan Products Development (OOPD) rare disease mission. OOPD provides 
funding support for clinical studies that advance the development of 
promising medical products for rare diseases, including medical foods 
to manage rare diseases such as phenylketonuria (PKU). For example, 
OOPD is currently funding a 4-year Phase 2 PKU medical food study 
conducted by the University of Wisconsin. The $1.5-million study 
evaluates the glycomacropeptide diet with the amino acid diet for PKU 
patients. We welcome competitive grant applications that will further 
the evaluation of recent medical food research to provide better 
medical food options for patients with inborn errors of metabolism.

    Question 3. Routine screening for social and emotional distress, or 
``distress screening'', is a key recommendation of the 2008 Institute 
of Medicine report, Cancer Care for the Whole Patient: Meeting 
Psychosocial Health Needs.\22\ According to the report, up to 43 
percent of cancer patients experiences psychosocial distress, which 
negatively impacts both quality of life and long-term survivorship 
rates. Distress and lack of social support services also contributes to 
low clinical trial participation rates among eligible patients, as well 
as decreased retention once the trials begin.
---------------------------------------------------------------------------
    \22\ Institute of Medicine (US) Committee on Psychosocial Services 
to Cancer Patients/Families in a Community Setting; Cancer Care for the 
Whole Patient: Meeting Psychosocial Health Needs, National Academies 
Press (US); 2008; http://www.ncbi.nlm.nih.gov/books/NBK4015/.
---------------------------------------------------------------------------
    What role can distress screening play in improving the efficiency 
of the clinical trials through recruitment and retention? In what ways 
can the FDA incentivize increased use of distress screening and support 
services for clinical trial participants, especially in oncology 
trials?
    Answer 3. We support excellence in patient-centered clinical care, 
in standard practice as well as clinical trials. FDA agrees that 
psychosocial distress can be an important issue for cancer patients and 
that identifying and providing services for cancer patients with 
increased levels of psychosocial distress can be a valuable component 
of routine clinical practice.
    If sponsors wish to pursue these services within the context of a 
clinical trial, these are issues relevant to an institutional review 
board's review of the informed consent process and we would be willing 
to work with stakeholders as appropriate.
                             senator murphy
    Question 1. The passage of the Food Safety Modernization Act (FSMA) 
shifted the focus of food safety regulations from a crisis-management 
approach to a preventative model that seeks to identify risks and put 
policies and procedures in place to mitigate those risks.
    Following FSMA's passage, the FDA was required to release and 
subsequently implement a total of seven new food safety regulations. 
Two of these regulations are particularly important for Connecticut 
farmers--the preventive control for human food and the produce rule.
    I commend the FDA for taking a collaborative, thoughtful, and 
thorough approach to finalizing regulations under FSMA. As we move 
forward, it is critical Congress fully fund the FDA's budget request, 
particularly the $109.5 million increase in dedicated funding this year 
to implement FSMA. Fully funding FSMA is not only important to ensure a 
reliable and safe food supply, it is critical for ensuring farmers, 
producers, processers, and stakeholders can depend on an engaged and 
responsive regulator.
    Connecticut is not a big agricultural State, but since 1982 there 
has been a 60 percent increase in the number of farms in the State. 
Connecticut is now home to nearly 6,000 farms. Although the number of 
farms has increased dramatically, the acreage of farm land has not 
grown at nearly the same rate. As such, most of Connecticut farms are 
small and sell directly to consumers at farmers markets or through 
Community Supported Agriculture.
    Dr. Califf, under your leadership, what type of education, 
training, and technical assistance can small farmers, State agencies, 
and other stakeholders, particularly those that will be subject to 
FSMA, expect from the FDA to support a transition to FSMA compliance?
    Answer 1. Please be assured that I understand the importance in 
providing assistance to affected stakeholders, especially small 
farmers, to help them comply with the new requirements. As you may 
know, in October 2015, the Agency released a FSMA training strategy, 
which outlines training options and delivery formats as well as 
introduces the partners in government, industry, and academia who are 
working with FDA on the development and delivery of training to the 
global community of food suppliers.\23\
---------------------------------------------------------------------------
    \23\ http://www.fda.gov/Food/GuidanceRegulation/FSMA/ucm461513.htm.
---------------------------------------------------------------------------
    Industry training will be an important component of successful 
implementation of FSMA. The Agency recognizes that one-size-doesn't-
fit-all, and that the most important goal that FDA expects of any 
training program is the outcome--that it advances knowledge among the 
food industry to meet FSMA requirements. The needs of small- and mid-
sized farms and facilities are at the center of FSMA training 
development and will be met through multiple efforts.
    The vision of FSMA training began in 2010 through 2012 with the 
creation of public-private alliances, funded in part by FDA, as a 
resource for industry and to facilitate widespread compliance with the 
new standards. The Produce Safety Alliance, Food Safety Preventive 
Controls Alliance, and Sprout Safety Alliance (Alliances) are 
developing training to help domestic and foreign food producers--
including small and very small farms and facilities--meet the 
requirements of the preventive controls and produce safety rules. The 
curricula developed through the Alliances are designed to be standard 
curricula with training modules that can be added to meet unique needs.
    In addition to working with the Alliances, FDA is collaborating 
with the U.S. Department of Agriculture's National Institute of Food 
and Agriculture (NIFA) to administer and manage the National Food 
Safety Training, Education, Extension, Outreach, and Technical 
Assistance Program, as mandated in Section 209 of FSMA. This 
competitive grant program will provide food safety training, education, 
extension, outreach, and technical assistance to owners and operators 
of farms, small food processors, and small fruit and vegetable merchant 
wholesalers.
    Grants issued through this program will fund a National 
Coordination Center (NCC) and four Regional Centers (RCs), which will 
be involved in both key components of training--primarily facilitating 
training delivery but also, in certain situations, facilitating 
curricula development targeted to specific audiences. FDA has awarded 
the International Food Protection Training Institute a grant of up to 
$600,000 over 3 years to establish the NCC, which will lead 
coordination of curriculum development and delivery to those food 
businesses covered by the FSMA Section 209 mandate for implementation 
of FSMA. The NCC will coordinate and support the delivery of 
standardized and/or alternate training curricula through the RCs.
    The RCs will be charged with understanding and communicating the 
landscape of training opportunities available to target businesses in 
their region. They will identify any need to develop or tailor 
curricula to meet specific unmet regional needs and/or to target a 
specific audience. Training programs may differ to meet those needs. 
The NCC will facilitate communication between the RCs, the Alliances, 
and other partnering groups about the development of such region- and/
or audience-specific materials.
    The RCs will be established in the Southern, Western, North 
Central, and Northeast regions of the country. These centers will work 
with representatives from non-governmental and community-based 
organizations, as well as representatives from cooperative extension 
services, food hubs, local farm cooperatives, and other entities that 
can address specific needs of the communities they serve.
    As these efforts indicate, we fully recognize and respect the 
importance of small farms and processors in our economy and our food 
safety system. We look forward to continuing to work with these 
communities throughout implementation of FSMA to facilitate the 
successful transition to the new preventive food safety framework.

    Question 2. Biologics have provided major advances in the treatment 
of cancer, rheumatologic disease, and other conditions but they also 
come at great cost to our health care system due to the expense of 
developing and manufacturing a drug. For example, even though they 
account for less than 1 percent of all prescriptions dispensed in the 
United States, expenditures on biologics amount to 28 percent of 
prescription drug spending, and both their use and their cost are 
forecast to grow sharply. This increased cost is borne by our health 
care system as a whole but more specifically by patients as more and 
more insurance companies place higher cost-sharing burdens on 
biologics.
    While we may never get close to the price reductions that are seen 
in the generic market, biosimilars will likely be 15-30 percent cheaper 
than the reference biologic. These reductions will result in 
significant savings to the health care system and patients as the 
biosimilar market matures. However, FDA still has not released draft 
guidance on such key issues as labeling and interchangeability.
    Dr. Califf, do you expect draft guidance on biosimilar labeling and 
interchangeability to be issued before the end of the year as the 
Center for Drug Evaluation and Research 2015 Guidance Agenda suggests?
    Answer 2. FDA has published the following final guidances with 
respect to biosimilars: Scientific Considerations in Demonstrating 
Biosimilarity to a Reference Product; Quality Considerations in 
Demonstrating Biosimilarity of a Therapeutic Protein Product to a 
Reference Product; and Biosimilars: Questions and Answers Regarding 
Implementation of the Biologics Price Competition and Innovation Act of 
2009; and Formal Meetings Between the FDA and Biosimilar Biological 
Product Sponsors or Applicants.
    FDA has also published the following draft guidances since 2012: 
Clinical Pharmacology Data to Support a Demonstration of Biosimilarity 
to a Reference Product; Reference Product Exclusivity for Biological 
Products Filed Under Section 351 (a) of the PHS Act; Biosimilars: 
Additional Questions and Answers Regarding Implementation of the BPCI 
Act of 2009; and Nonproprietary Naming for Biological Products.
    The Agency is committed to carefully reviewing the comments 
received as we move forward in finalizing the draft guidances noted 
above. Upcoming guidances are expected to include: Considerations in 
Demonstrating Interchangeability to a Reference Product; Statistical 
Approaches to Evaluation of Analytical Similarity Data to Support a 
Demonstration of Biosimilarity; and Labeling for Biosimilar Biological 
Products.
    FDA is diligently working to issue guidance on issues that have 
been identified by the FDA and key stakeholders as key topics of 
interest. While the Agency cannot provide a specific timeline for the 
release of any guidance, we continue to provide information to assist 
biological product developers--sponsors/companies--with bringing 
biosimilar and interchangeable products to market. The FDA is 
continuing to clarify its approach to implementation of the BPCI Act to 
further facilitate sponsors' development of biosimilars and 
interchangeable biological products.

    Question 3. As FDA Commissioner, you will be charged with 
regulating a number of prominent industries that you have interacted 
with in the past. Can you inform the committee on the steps that you 
have taken thus far to steer clear of any potential conflicts of 
interest and the ongoing monitoring that is planned as new matters 
arise before the FDA?
    Answer 3. Following my appointment as Deputy Commissioner for 
Medical Products and Tobacco, the Office of the Commissioner 
established a process for screening invitations that I receive for 
speaking engagements and other requests for my participation to 
identify potential situations which would require my recusal. A team of 
individuals was convened including a representative of the Office of 
the Commissioner and the Office of Chief Counsel. These individuals 
have extensive knowledge of my ethics agreement and recusal 
obligations. This team meets on a regular basis (often as frequently as 
weekly) and on an ad hoc basis as needed. A member of my staff submits 
detailed information regarding specific invitations/requests for my 
participation and the team determines whether I should be recused. If 
the team has any questions as to whether something is covered by the 
recusal, the HHS Designated Agency Ethics Official's office is 
consulted. The team has a standing teleconference with a representative 
of this office in order to facilitate consultations and determinations.
    I am recused from all particular government matters that would 
affect Duke's financial interests, any matter in which Duke is a party 
or which would have a special or distinct effect on Duke, or that 
potentially could include particular matters involving Duke-affiliated 
research. If a particular matter potentially implicates Duke-affiliated 
research, before participating, I will consult with HHS and FDA ethics 
officials to determine whether my recusal allows for participation.
    If my nomination is confirmed, I understand that I will be subject 
to more extensive recusal obligations under the President's 2009 
Executive order, and accordingly that additional monitoring procedures 
may be needed.
                             senator warren
Input of Pharmaceutical Industry Sponsors on Clinical Trials Conducted 
        at Duke Clinical Research Institute
    Question 1a. For the clinical trials you conducted or oversaw while 
at the Duke University School of Medicine and the Duke University 
Medical Center, can you detail for us exactly what input pharmaceutical 
sponsors did and did not have in the:

     design of the trials?

    Answer 1a. Pharmaceutical (and device) sponsors provided input into 
the design of trials including the intervention, control measures, 
eligibility criteria, randomization, study endpoints, blinding methods, 
and sample size. In order for Duke to conduct the trial as the 
coordinating center, agreement must be reached by the academic leaders 
and the industry sponsor. All aspects of the design are included in the 
protocol, which is subject to review and approval by FDA, and for 
international trials, by regulatory authorities from each involved 
country and the European Medicines Agency. Finally, any participating 
research site has a Principal Investigator and an Institutional Review 
Board (IRB) that must review and approve the protocol in order to 
proceed with enrollment.

     analysis of trial data?

    Answer. Pharmaceutical sponsors provided input into the development 
of the statistical analysis plan. The plan is included in the protocol, 
which is subject to review and approval by FDA, by regulatory 
authorities in other countries, and the data monitoring committee (a 
committee of non-conflicted experts in the relevant medical specialty, 
clinical trial methodology, and ethics of human studies) Finally, as 
noted above, any participating research site has a Principal 
Investigator and an Institutional Review Board (IRB) that must review 
and approve the protocol with its included analysis plan in order to 
proceed with enrollment. The details of how the analyses are actually 
conducted are provided below.

     publication of trial results?

    Answer. After a publication was written by the academic 
investigators (including Duke investigators and other participating 
academic leaders), the pharmaceutical sponsor was given the opportunity 
to review and comment on the publication within a period of time that 
is specified in the contract. Final decisions about publication are 
made by the trial executive committee (which is comprised of the 
academic leaders). The industry sponsor has the right to review and 
comment, but no right to censor or dictate content or verbiage.

    Question 1b. For each of the activities listed above:

     Which group had the final decisionmaking authority if 
differences arose between Duke academics and industry sponsors?
    Answer 1b. In situations in which the Duke academics were not in 
agreement with an industry sponsor regarding the design of a trial, the 
Duke academics did not participate in the trial. With regard to 
analysis of trial data and publication of trial results, the Duke 
academics always had the final decisionmaking authority per the terms 
in the contract regarding access to data and the right to publish. For 
example, the right to a copy of the database is what allows the 
academic group to perform an independent analysis and interpretation of 
the trial results.

     Did industry sponsors have veto authority over decisions 
related to data analysis and the publication or presentation of trial 
results?
    Answer. In trials coordinated by the DCRI, or in which I 
participated as a lead investigator, industry sponsors never had veto 
authority over decisions related to data analysis and the publication 
or presentation of trial results. As noted above, the majority of 
industry-sponsored multi-site clinical trials do not have an 
independent academic coordinating center, so I believe the approach we 
developed at DCRI is best practice because it provides the independent 
voice in analysis and publication of results.

    Question 1c. Referring to the input of pharmaceutical sponsors on 
the analysis of clinical trial data you said at the Senate HELP 
Committee hearing on November 17:

          ``Typically we'll have an analysis done by the company and an 
        analysis done by our statisticians, then we compare the results 
        to see if they match up, and resolve any discrepancies. But in 
        no case did we allow the company to do the analysis and we just 
        were recipients of what they said the answer was.''

    Answer 1c. As a prelude to this series of questions, it is 
important to have some key background about industry-sponsored clinical 
trials:

     The majority of multi-site, industry-sponsored clinical 
trials do not have an academic coordinating center. They are 
coordinated by industry and for-profit contract research organizations. 
In cardiovascular medicine and many other highly evidence-driven 
specialties, the independent role of the academic is an important 
element to ensure that the results are not biased, given the industry-
sponsor's direct financial interest in the outcome. While most major 
academic medical centers have some coordinating center function, a 
limited number can conduct multi-national large trials, like the DCRI.
     The role of coordinating center is distinctly different 
from the role of a research site. The coordinating center assures that 
the trial is being conducted as designed by participating sites, 
collects the data from the sites, monitors the conduct of the trial, 
and does the analyses. The research site enrolls the patients, conducts 
the study protocol, and submits the data to the coordinating center. 
The research sites do not have a copy of the aggregate trial data and 
for the most part are not capable of doing the overall trial analysis.

          Why might discrepancies between statistical analyses 
        arise?

          Answer. Data bases from large, international clinical trials 
        are complex with hundreds of thousands of pages of data and 
        millions of data items. The analytical code to actually perform 
        the analysis takes hundreds of hours to write and it is checked 
        multiple times. There is also an audit trail to assure that 
        analytical steps are not altered after unblinding. Because of 
        this enormous complexity, there is great value in redundant 
        checking both within the academic coordinating center and on 
        the industry side and in checking between the two entities. All 
        of this is done before unblinding the trial.
         Academically coordinated trials that are not intended for 
        regulatory review often do not have this level of rigor, which 
        has led to concern about reproducibility. At the DCRI the 
        procedures of checking and redundancy are standard for both 
        industry-funded and government-funded trials.

          How often did these discrepancies arise?
          Answer. Because of the careful and extensive nature of this 
        pre-unblinding work, it is very rare to have discrepancies that 
        are significant, and, in fact, I'm not aware of any such 
        instances. But small differences in coding and interpretation 
        do occur, and it's critical to resolve these. Importantly, 
        during this checking phase on the primary analysis, the 
        statisticians are unblinded, but the clinical investigators and 
        clinical development experts for the sponsor remain blinded.

          Can you describe the process for ``resolving 
        discrepancies? ''
          Answer. When discrepancies arise in primary analyses, as 
        described above, they are resolved prior to unblinding to 
        eliminate bias. For secondary analyses and subsequent 
        manuscripts, the academic coordinating center performs the 
        analyses used for the study. These analyses typically are 
        planned out in less detail prior to unblinding, but statistical 
        analysis plans are constructed. Industry is welcome to provide 
        a perspective from their own analyses, but control of the 
        interpretation and message resides with the academic authors of 
        the manuscript.

          What factors are involved in making a final 
        determination related to the analysis?
          Answer. As stated above, the types of discrepancies 
        encountered in the primary analysis are small and I have not 
        encountered a situation in which a difference has occurred that 
        would affect the interpretation of the trial.

          Did Duke academics or the industry sponsor have the 
        final decision over what analysis was submitted to the FDA?
          Answer. Sponsors have the responsibility for regulatory 
        submissions, which involve not only FDA, but the European 
        Medicines Agency and dozens of national authorities for 
        countries in which the product will be marketed. Accordingly, 
        the sponsor has primary responsibility for the FDA submission, 
        but the key analyses are duplicated by the academic 
        coordinating center.

            Was the analysis published by Duke academics?
          Answer. Duke academics published in the context of the 
        purview of the executive committee and the steering committee. 
        The final decision was made by the executive committee of the 
        trial. The sponsors, such as Johnson and Johnson and Bayer, had 
        input into the primary manuscript, but no right to alter the 
        decision of the executive committee.

           Was results published by the industry sponsor?
          Answer. The industry sponsor is not charged with publishing 
        key results of the trial independently of the academic 
        coordinating center and steering committee. After the steering 
        committee has published its primary manuscripts, the industry 
        sponsor may make its data available for others to do analyses 
        and publish the results.

    Question 1d. How many publications have you authored or co-authored 
that report results from an industry-sponsored study regarding the 
safety or efficacy of that sponsor's product?
    Answer 1d. Please see question E below.

    Question 1e. Please list publications you have authored or co-
authored that report a negative result from an industry-sponsored study 
regarding the safety or efficacy of that sponsor's product.
    Answer 1e. The enclosed ``Table A\24\, Clinical Trials and 
Outcomes'' contains a list of clinical trials in which I played a major 
role in the design, conduct, or oversight. The first column gives the 
acronym by which the trial was known.
---------------------------------------------------------------------------
    \24\ The Table referred to may be found at the end of Senator 
Warren's Questions and Responses. Due to the high cost of printing, the 
listing of Peer-Reviewed Journal Publications of Mr. Califf are being 
retained in the committee files.
---------------------------------------------------------------------------
    The second column gives the publication reference. In cases in 
which I was an author, the manuscript is denoted by the number on my CV 
that was submitted to the committee. Some trials are listed in which I 
played a major role, but was acknowledged in the list of committees or 
in subsequent articles. In these cases the reference is given.
    The third column gives the trial outcome:

     Positive means that the trial finding and interpretation 
favored benefit for the sponsor's product.
     Negative means that the trial finding was not beneficial 
for the sponsor's product.
     Mixed means that the finding was equivocal for the 
sponsor's product or more than one product was evaluated with mixed 
results.
     Non-inferior means that the sponsor's product was found to 
be non-inferior to the comparator, and the trial was designed for this 
purpose. So, a non-inferior trial should be considered a positive 
finding from the sponsor's perspective.
     Neutral means that trial did not reach a conclusion about 
the product.

    Of the 55 trials in total, 28 (51 percent) were negative; 15 (27 
percent) were positive; six (11 percent) were non-inferior; and six (11 
percent) were either neutral (two) or mixed (four).
    The fourth column identifies the medical product that was evaluated 
and the final column gives a brief summary of the finding.
    As expected, the majority of trials did not show a positive outcome 
for the sponsor's product. From the perspective of an academic 
researcher, the desired outcome of a trial is that it answers an 
important clinical question (regardless of whether that finding was 
positive or negative). A review of all trials done by DCRI would have a 
similar distribution, reflecting the tremendous need for more trials to 
guide clinical practice. (See Table A. Clinical Trials and Outcomes).

    Question 1f. How does the conduct of privately funded clinical 
trials (wholly or in part) at Duke Clinical Research Institute differ 
from the conduct of clinical trials at other major medical centers in 
the United States?
    Answer 1f. To fully understand the response to this question, it is 
critical to know that clinical trials have 2 major organizational 
functions: the research site and the coordinating function. Most major 
academic medical centers and integrated health systems participate in 
hundreds of industry-sponsored clinical trials as one of many research 
sites in each trial. As a research site, after agreeing that the study 
is meritorious and after independent review by the Institutional Review 
Board, the site conducts the trial and submits its data to a 
coordinating center. The individual research site is not equipped to 
analyze the trial data and does not have a copy of the aggregate data, 
nor should it, since the multi-site trials are needed to provide 
adequate sample sizes representative of the population likely to be 
treated with the therapy under evaluation, so that a single site 
analysis would not provide a valid scientific conclusion for the trial 
as a whole.
    The coordinating center oversees the overall study organization, 
distributes and collects regulatory and operational documents and takes 
responsibility for overseeing the quality of the trial through a 
combination of auditing and monitoring the conduct of the trial and 
quality of the data. The coordinating center then does the analyses and 
manages the Steering Committee functions and interactions with the Data 
Monitoring Committee.
    The Duke Clinical Research Institute (DCRI) is one of a small 
number of major academic medical centers in the United States with the 
capability of coordinating large global clinical trials. Most major 
medical centers participate in clinical trials in the role of a 
research site (i.e., enrolling patients at their institution in multi-
site trials). So, DCRI performs many ``coordinating center'' functions 
which are not performed by most academic centers (such as clinical 
monitoring and safety surveillance). Coordinating center functions are 
also performed by commercial contract research organizations (CROs) 
which conduct this activity on a fee-for-service basis. Unlike 
academically based coordinating centers, however, CROs do not have 
requirements for independent access to data and publication rights. A 
growing number of institutions have developed coordinating functions 
similar to DCRI for the same reasons, but few have the global reach or 
capacity of the DCRI.

    Question 1g. Are the standards for preserving academic independence 
in sponsored research at Duke more stringent, less stringent or similar 
to standards at other peer institutions?
    Answer 1g. As noted above, an academic center may serve in the role 
of a coordinating center for a multi-site clinical trial or an 
individual research site responsible for enrolling patients at its 
institution in a multi-site trial.
    The standards (i.e., contractual requirements) for preserving 
academic independence are different based on the institution's role in 
the study. For example, since a specified sample size is required to 
discern whether a treatment is more or less safe and effective compared 
to another treatment (or to a placebo), the analysis of data from an 
individual research site is not scientifically valid. An individual 
research site would not typically require the right to publish the 
results of its own data, but rather would require that the aggregated 
data from all sites be subject to an independent analysis, 
interpretation and publication by the academic leadership of the trial.
    Accordingly, an assessment of the stringency of the standards for 
preserving academic independence in the setting of a coordinating 
center requires comparison with those of other academic coordinating 
centers, rather than with those of individual research sites. Because 
Duke's standards for independent access to data and publication rights 
as a coordinating center are absolute, there is no situation in which 
its standards for preserving academic independence in sponsored 
research are less stringent than those of any peer institution.

Post-market Surveillance of Medical Devices
    Question 2a. In response to a question from Senator Murray 
regarding post-market surveillance of medical devices during the Senate 
HELP Committee hearing on November 17, you stated:

          ``The Sentinel System . . . is a model in drugs; we have 170 
        million Americans' claims data so when there is a problem with 
        a drug we can look almost in real time. We need the same system 
        on the device side.''

    Unique Device Identifiers (UDI) will make post-market surveillance 
of devices possible, but only if they are captured in electronic health 
information.
    What steps need to occur before the FDA can integrate UDIs and 
medical device information into the Sentinel System, as mandated by 
Congress in the 2012 Food and Drug Administration Safety and Innovation 
Act?
    Answer 2a. FDA, the Office of the National Coordinator for Health 
IT (ONC), and the Centers for Medicare & Medicaid Services (CMS) are 
working closely on the shared goal of incorporating UDIs into 
electronic health records (EHRs), starting with implantable devices. 
The recently finalized rules on the 2015 HIT Certification Criteria 
(ONC) and Medicare and Medicaid Electronic Health Record Incentive 
Programs--Stage 3 and Modifications to Meaningful Use in 2015 Through 
2017 are important steps in this process as both support the addition 
of UDIs for implantable medical devices to the Common Clinical Data Set 
which would be able to be exchanged and available to providers who care 
for the patient.
    In addition, FDA and CMS look forward to continuing to explore 
options that would improve surveillance in a timely and effective 
manner. These agencies are committed to capturing appropriate data and 
sharing information transparently to improve the quality and safety of 
care delivered to people across the Nation. FDA and CMS also support 
the recommendation by the National Committee on Vital and Health 
Statistics to consider conducting voluntary pilot tests of the 
benefits, costs, and feasibility of UDIs in claims reporting between 
providers and commercial payers.
    Voluntary pilots should address key challenges to adding UDIs to 
claims, including significant technological hurdles and costs (for 
providers, payers and others), as well as difficulties in validating 
UDIs reported on claims.

    Question 2b. As a cardiologist and clinical trials expert who has 
experience with real-world data sources, how do you understand that UDI 
information in medical claims could support the evaluation of medical 
devices after approval--such as through enhancements to registries like 
those operated by the American College of Cardiology and to expand the 
Sentinel system?
    Answer 2b. The current Sentinel data model focuses on querying 
administrative and claims data maintained by partner organizations who 
share aggregated results with FDA. FDA does not receive or hold 
personally identifiable information, but can query privacy-protected 
data and receive aggregated data from local environments that together 
cover approximately 126 million patients.
    These records generally lack manufacturer or brand-specific device 
identifiers and therefore cannot be leveraged to perform meaningful 
medical device post-market surveillance. While CDRH is actively engaged 
in promoting the integration of UDI into electronic health information, 
we are also undertaking complementary efforts to develop a more 
comprehensive evaluation system for medical devices. FDA is exploring 
the means to expand Sentinel by linking national device registries to 
these claims data. We are currently linking clinical registries to 
claims data to enable the evaluation of longitudinal data. Clinical 
registries collect information that uniquely identifies and provides 
curated clinical data in selected medical device areas. These 
activities, along with establishing linkages to electronic health 
records, are envisioned to be the building blocks of a broader National 
System for Medical Device Post-market Surveillance [http://www.fda.gov/
AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/
CDRHReports/ucm301912.htm] that would use evidence from clinical 
experience in a network of existing electronic data systems to improve 
patient safety, enhance our understanding of device performance, and 
facilitate device innovation.

    Question 2c. If UDI information is not included in claims data, 
what negative repercussions would that have for the Sentinel system to 
evaluate specific medical devices?
    Answer 2c. The current Sentinel data model focuses on querying 
administrative and claims data maintained by partner organizations, who 
share aggregated results with the FDA. FDA does not receive or hold 
personally identifiable information, but can query privacy-protected 
data and receive aggregated data from local environments that together 
cover approximately 126 million patients. These records generally lack 
manufacturer or brand-specific device identifiers.

    Question 2d. What are the benefits of the integration of UDIs into 
electronic health records?
    Answer 2d. UDIs incorporated into electronic health information, 
especially electronic health records and medical device registries, can 
help create additional, more robust, and cost-effective post-market 
monitoring and surveillance data sources and support additional device 
research by leveraging real world clinical data. UDIs allow us to more 
easily link the use of a device with a patient's experience with that 
device.
    UDIs incorporated into electronic health information will also help 
the FDA, the health care community, and industry to:

     More accurately report and analyze device-related adverse 
events by ensuring that devices associated with these events are 
correctly identified.
     More rapidly develop solutions to reported problems.
     More efficiently resolve device recalls, including the 
removal of potentially harmful devices from the market.
     Reduce medical errors by enabling health care 
professionals and others to rapidly and precisely identify a device, 
obtain important information concerning the device's characteristics, 
and improve the identification of the device through the distribution 
chain to the point of patient use.

    The Unique Device Identifier (UDI) system is essential to 
transforming postmarket surveillance of medical devices; a critical 
cornerstone of FDA's strategy is the incorporation of UDIs into 
electronic health information, particularly electronic health records 
(EHRs) and device registries. In the 2012 Food and Drug Administration 
Safety and Improvement Act, Congress required FDA to expand Sentinel to 
include medical devices.

    Question 2e. How do you plan to work with the Centers for Medicare 
and Medicaid Services, the Office of the National Health Coordinator 
for Health Information Technology, private payers, and the medical 
device industry to facilitate the integration of UDIs into multiple 
sources of electronic health information?
    Answer 2e. FDA, the Office of the National Coordinator for Health 
IT (ONC), and the Centers for Medicare & Medicaid Services (CMS) are 
working closely on the shared goal of incorporating UDIs into EHRs, 
starting with implantable devices. The recently finalized rules on the 
HIT Certification Criteria (ONC) and Medicare and Medicaid Electronic 
Health Record Incentive Programs--Stage 3 and Modifications to 
Meaningful Use in 2015 Through 2017 are important steps in this process 
as both support the addition of UDIs for implantable medical devices to 
the Common Clinical Data Set which would be able to be exchanged and 
available to providers who care for the patient.

Antibiotic Resistance--Antibiotic Use in Animal Agriculture
    Question 3a. While FDA policies (Guidance for Industry (GFI)#209 
and #213 and the Veterinary Feed Directive Final Rule) make the use of 
antibiotics to promote animal growth illegal and subject all remaining 
uses of antibiotics to veterinary oversight, I remain very concerned 
that these policies leave the door open for dangerous antibiotic 
regimens to continue. FDA officials have previously communicated to me 
that they plan to monitor the removal of growth promotion from 
labels.\25\ However, measuring how many companies make promised changes 
in their drug labels is not an adequate measure of whether the policies 
have been successful at ending the misuse and over-use of antibiotics 
in animal agriculture.
---------------------------------------------------------------------------
    \25\ Secretaries Burwell, Carter, and Vilsack to Senator Warren, 
Aug. 17, 2015.
---------------------------------------------------------------------------
    Additionally, FDA's policies will work only if veterinarians follow 
appropriate prescribing guidelines that take into account not only the 
health of the animals in front of them, but also consider the public 
health. GFI #213 describes principles that veterinarians should 
consider when determining the appropriateness of antibiotic use for 
disease prevention. FDA has stated that the agency ``intends to work 
with veterinary and animal producer organizations to reinforce the 
importance of these principles.'' \26\ However, representatives from 
many animal producer organizations have publically voiced doubts about 
the need to reduce antibiotic use and the impact that the FDA's 
policies will have on the amount of drugs used.\27\
---------------------------------------------------------------------------
    \26\ Kraus, Thomas A., Associate Commissioner for Legislation, FDA 
to Senators Warren, Feinstein and Gillibrand, Sept. 8, 2014; FDA, 
Guidance for Industry #213: New Animal Drugs and New Animal Drug 
Combination Products Administered in or on Medicated Feed or Drinking 
Water of Food Producing Animals: Recommendations for Drug Sponsors for 
Voluntarily Aligning Product Use Conditions with GFI #209. December, 
2013. (pg.7)
    \27\ Christine Hoang, American Veterinary Medical Association 
(AVMA), on ``The Trouble with Antibiotics,'' PBS Frontline, October 
2014; AVMA Antimicrobial Use and Antimicrobial Resistance FAQ; Ron 
Philips, Animal Health Institute, in Flynn, Dan (27 May 2011) ``Ag 
Coalition Says Antibiotic Facts are on Its Side.'' Food Safety News; 
Coalition letter to David Hoffman, PBS Frontline Producer, August 2014; 
Juan Ramon Alaix, Zoetis in Loftus, Peter. (2013 Nov. 19). Zoetis Chief 
Leads Animal-Health Firm Following Split from Pfizer. The Wall Street 
Journal.
---------------------------------------------------------------------------
    Given documented disagreements among stakeholders, and given that 
veterinary adherence to appropriate antibiotic prescribing guidelines 
is a critical part of FDA's policies, how will you, as Commissioner, 
monitor, evaluate, and take necessary actions with regard to compliance 
with GFI #213's appropriate antibiotic prescribing guidelines?
    Answer 3a. The Food and Drug Administration (FDA or the Agency) is 
confident that the changes under its judicious use policy, as outlined 
in Guidance for Industry (GFI) #209 and GFI #213, will be effectively 
implemented. FDA has received written commitments from all affected 
pharmaceutical companies to align their products with the GFI #213 
recommendations. There has been positive engagement of key 
stakeholders, including the animal pharmaceutical industry, the animal 
feed industry, and veterinary and animal producer organizations. 
Furthermore, once the affected products are aligned, it will be illegal 
to use these medically important antibiotics for production purposes or 
to use these products for the remaining therapeutic purposes without 
the authorization of a licensed veterinarian. Veterinarians play a 
critical role in the diagnosis of disease and in the decisionmaking 
process related to instituting measures to treat, control, and prevent 
disease.
    The President's National Action Plan calls on FDA to collaborate 
with veterinary organizations, animal producer organizations, the 
animal feed industry, and others to develop and implement educational 
outreach efforts to ensure that veterinarians and animal producers 
receive the necessary information and training to support 
implementation of GFI #213. As part of these efforts, FDA is working 
with the U.S. Department of Agriculture (USDA) to ensure that 
veterinarians have access to timely, updated information and training 
for the appropriate use of medically important antibiotics in the feed 
and water of food-producing animals. For example, FDA is developing 
guidance on the Veterinary Feed Directive (VFD) form, which 
veterinarians will use, as well as supporting changes to veterinary 
curricula, and leveraging many opportunities to provide necessary 
education via our partnerships with various stakeholders.
    As part of its compliance efforts, FDA will utilize its authority 
to conduct inspections that will provide important information for 
determining compliance with GFI #213. For example, VFD records will be 
examined as part of inspections conducted at feed manufacturing 
facilities. Examination of such records is an important tool for 
determining whether these drugs are being appropriately authorized. In 
addition, as part of the recent revisions to the VFD regulation, FDA 
updated requirements for the establishment (by veterinarians) of a 
veterinary-client-patient relationship (VCPR) when a veterinarian 
authorizes the use of a VFD drug. Since veterinarians are licensed at 
the State level, FDA is working closely with the State boards of 
veterinary medicine on this issue.
    Ongoing surveillance of antibiotic use and resistance is also a 
critical element of FDA's strategy for assessing the impact of FDA's 
GFI #213. FDA's data collection efforts include enhancements to the 
collection and reporting of data collected under the National 
Antimicrobial Resistance Monitoring System (NARMS), enhancements to the 
collection and reporting of Antimicrobial sales and distribution data, 
as well as ongoing collaboration with USDA to collect additional on-
farm data on antibiotic use and resistance. FDA co-sponsored a public 
meeting with USDA and the Centers for Disease Control and Prevention 
(CDC) on September 30, 2015, to obtain input from the public on 
approaches for enhancing collection of data on antibiotic use and 
resistance in animal agricultural settings. These efforts will allow 
FDA to better assess the effects of antibiotic stewardship policies and 
analyze the association between antibiotic use and resistance.
    The efforts that are currently underway represent a significant 
step forward in addressing antimicrobial resistance. We acknowledge 
that this is an ongoing effort and additional measures may be needed. 
In addition to effectively eliminating growth promotion use and 
instituting veterinary oversight, we recognize the importance of 
ensuring that meaningful stewardship principles are applied in 
conjunction with the use of medically important antimicrobial drugs for 
therapeutic purposes, including for disease prevention. FDA is 
committed to working in collaboration with USDA, CDC, veterinarians, 
animal producers, and other stakeholders on this important effort.

    Questions 3b and c. As Commissioner, what currently available data 
sources will you use to measure the success of FDA's current antibiotic 
use in animal agriculture policies at addressing the overall public 
health threat?
    How will you work with USDA to prioritize the development of 
additional data sources, including measures of how antibiotics are used 
on farms?
    Answers 3b and c. Gathering information on the way medically 
important antibiotics are used is essential to assessing the impact of 
FDA's judicious use strategy. FDA has several data sources currently 
available to measure antibiotic use in animal agriculture.
    Under section 105 of the 2008 Animal Drug User Fee Amendments 
(ADUFA 105), drug sponsors must report to FDA annually on all 
antimicrobials sold or distributed for use in food-producing animals. 
FDA collects, summarizes and reports this information annually in its 
ADUFA 105 report. In 2014, FDA enhanced the format of its annual 
summary report so that it now includes information on the importance of 
the drug in human medicine and provides aggregate data on the approved 
route of administration of antimicrobial drugs sold or distributed for 
use in food-producing animals, whether such drugs are available over-
the-counter or require veterinary oversight, and whether they are 
approved for therapeutic indications, or both therapeutic and 
production indications.
    FDA also reanalyzed previous years' reports in the same manner. In 
May 2015, FDA proposed revisions to the ADUFA 105 reporting 
requirements in order to obtain estimates of sales by major food-
producing species (cattle, swine, chickens, and turkeys). The 
additional data would help FDA further target its efforts to ensure 
judicious use of medically important antimicrobials. The public comment 
period closed on August 18, 2015, with varying reactions from 
stakeholder groups. The final rule is an FDA priority, and we hope to 
publish it next May.
    In addition, FDA collaborates with USDA and CDC to collect data on 
antimicrobial resistance among foodborne pathogens as part of NARMS. 
Recent enhancements to the NARMS program make the data more useful for 
measuring the effects of GFI #213, particularly a new USDA Food Safety 
Inspection Service slaughter-sampling program, launched in March 2013, 
which increases national representativeness of the animal samples. FDA 
is also working with State partners to perform whole-genome sequencing 
on NARMS samples, which will provide unprecedented details on the 
traits of resistant strains of foodborne bacteria from animals and 
animal-derived foods. In August 2015, FDA released its 2012-13 NARMS 
Integrated Report, which overall reveals mostly encouraging findings, 
with some areas of concern.
    On September 30, 2015, FDA, in collaboration with USDA and CDC, 
held a jointly sponsored public meeting to obtain public input on 
possible approaches for collecting additional on-farm antimicrobial 
drug use and resistance data. Information from the public meeting will 
help FDA determine the most efficient way to collect the additional on-
farm use data needed to assess GFI #213's impact on antimicrobial 
resistance. Combined with existing sales data on antibiotic drugs sold 
for use in food-producing animals and the data from NARMS, the new on-
farm data will provide a more comprehensive and science-based picture 
of antibiotic drug use and resistance in animal agriculture. This data 
collection plan is intended to provide the data needed to: (a) assess 
the rate of adoption of changes outlined in the FDA's GFI #213, (b) 
help gauge the success of antibiotic stewardship efforts and guide 
their continued evolution and optimization, and (c) assess associations 
between antibiotic use practices and resistance trends over time.
    In addition, FDA and USDA are collaborating with a Cornell 
University researcher through the National Institute of Mathematical 
and Biological Synthesis (NIMBioS) to develop a new mathematical 
modeling methodology that would inform the approach to monitoring and 
assessing the impacts of GFI #213. The work of this group is still 
ongoing. The working group has so far met in September 2014 and 
February 2015 (meeting summaries are available at http://
www.nimbios.org/workinggroups/WG_amr).

    Question 3d. What result or results--based on those data sources--
would indicate to you that the policies have been successful or 
unsuccessful?
    Answer 3d. FDA believes it is important to assess progress in the 
context of five key components or phases of the overall effort. First, 
FDA focused on engaging the animal pharmaceutical industry and the 
animal agriculture community more broadly to work cooperatively with 
FDA to implement the changes outlined in FDA's judicious use strategy. 
FDA has been able to successfully gain commitments from all affected 
drug companies.
    Second, FDA is focused on working with these affected drug 
companies to complete the transition from old labeling to new labeling, 
to remove all growth promotion indications, and bring the remaining 
therapeutic indications for these products under veterinary oversight. 
FDA is currently in the middle of the 3-year implementation period for 
implementing these label changes by the target date (end of December 
2016). FDA expects all affected products to be aligned by this target 
date.
    Third, FDA continues to engage consumer advocacy groups to ensure 
transparency of our efforts and that the appropriate public health 
risks related to antimicrobial use in food producing animals are 
identified and addressed.
    Fourth, FDA is currently working with USDA and CDC to develop 
approaches for collecting additional on-farm data on antibiotic use. 
Having better data on actual antibiotic use practices at the farm level 
will enhance our ability to assess whether our policies are having the 
desired effect to align such antibiotic use practices with good 
stewardship/judicious use principles.
    Finally, FDA is also working with USDA and CDC to develop 
approaches for collecting additional on-farm data on antibiotic 
resistance. This additional information, along with other sources of 
resistance information such as that provided by NARMS, will better 
enable us to assess whether our policies are having the desired effect 
to reduce resistance.
    The additional data collection efforts described above will all 
play an important role in assessing the impact of current as well as 
future measures that are implemented to address this important public 
health issue.
MSM
    Question 4a. Earlier this year, the FDA released the ``Revised 
Recommendations for Reducing the Risk of Human Immunodeficiency Virus 
Transmission by Blood and Blood Products: Draft Guidance for Industry'' 
which, if finalized, would change the blood donation policy for men who 
have sex with men (MSM) from a lifetime deferral to a 1-year deferral 
from last sexual contact with another man. I am pleased that the FDA 
has finally taken this first step toward lifting the lifetime deferral. 
However, the 1-year deferral policy is still not based on science, not 
based on an individual donor's risk of carrying a transfusion 
transmissible infection, still prevents many low-risk individuals from 
donating blood, continues to let higher risk individuals donate, and 
gives no signal from the FDA that the agency is committed to achieving 
a fully risk-based system for all donors. If you are confirmed 
Commissioner, are you committed to ending the lifetime deferral policy 
for MSM?
    Answer 4a. The Food and Drug Administration (FDA) takes its 
responsibility to regulate the blood supply and to ensure its continued 
safety for patients who receive potentially lifesaving blood products 
very seriously, and also understands the need to update these policies 
to reflect current science. In collaboration with other government 
agencies, and considering input from advisory committees, the FDA has 
carefully examined the available scientific evidence relevant to the 
blood donor deferral policy for men who have sex with men (MSM) and 
recommended a change in the blood donor deferral period for MSM from 
indefinite deferral to 12 months since the last sexual contact with 
another man. We intend to issue final guidance in the near future. In 
addition, FDA is committed to continuing to work with stakeholders to 
develop the most optimal deferral strategies, including investigating 
individual risk assessment.

    Question 4b. When the draft guidance is finalized, how do you plan 
to reach out to the MSM community to explain the change in the lifetime 
deferral policy and encourage these individuals to donate?
    Answer 4b. FDA intends to reach out to stakeholders, including the 
LGBT community as part of the rollout for the final guidance, when it 
publishes. We will explain the changes to the policy and answer any 
questions regarding blood donation.

    Question 4c. What is your plan to ensure that the 1-year deferral 
policy is only a first step toward implementing a risk-based blood 
donation policy for all blood donors, including MSM?
    Answer 4c. FDA has examined the available scientific evidence 
relevant to the blood donor deferral policy for men who have sex with 
men (MSM) and recommended a change in the blood donor deferral period 
for MSM from indefinite deferral to 12 months since the last sexual 
contact with another man. We intend to issue final guidance in the near 
future. In addition, FDA is committed to continuing to work with 
stakeholders to develop the most optimal deferral strategies, including 
investigating individual risk assessment.
    FDA has already taken steps to implement a national blood 
surveillance system that will help the agency monitor the effect of a 
policy change and further help ensure the continued safety of the blood 
supply and to develop scientific evidence potentially relevant to 
making further changes to the blood donor deferral policy in the 
future.
    Implementation of the surveillance system is not contingent upon 
changing FDA's blood donor deferral policy for men who have sex with 
men. The system will monitor a majority of the blood collected in the 
United States for a number of different transfusion-transmitted viral 
infections, including HIV. We anticipate that the system will provide 
important information that will be helpful as we continue our efforts 
to further enhance the high level of safety of the U.S. blood supply 
and potentially support further revisions to our blood donor deferral 
policies.

Clinical Trial Data Sharing
    Question 5a. A study entitled ``Clinical trial registration, 
reporting, publication and FDAAA compliance: a cross-sectional analysis 
and ranking of new drugs approved by the FDA in 2012,'' published last 
week in the British Medical Journal, found that several major drug 
companies have not met the standards for clinical trial results 
reporting under the Food and Drug Administration Amendments Act (FDAAA) 
of 2007. FDAAA established civil monetary penalties of up to $10,000 
per day for non-compliance, and yet the FDA has never been imposed.
    What do you do you believe the impact of greater transparency of 
clinical trial data and results would be on: (a) Clinical trial 
efficiency; (b) The cost of drug development; (c) Drug safety; and (d) 
Biomedical innovation.
    Answer 5a. FDA supports the view that transparency of clinical 
trial data and results is in the public interest. FDA is committed to 
increasing the transparency of information available regarding clinical 
trials and supports the principle of providing increased access to 
registration information and clinical trial data and results. The 
requirements in Title VIII of FDAAA have resulted in greater access to 
information for significant numbers of clinical trials. The public, and 
particularly clinical trial participants, benefit from access to these 
results. An additional benefit of the transparency provided by 
ClinicalTrials.gov is that it may provide FDA reviewers with a fuller 
picture of the trials under way in a particular area. Such information 
could contribute to current efforts to improve the design and quality 
of clinical trials and provide additional analytical tools and 
methodologies for analyzing clinical trial data and results.
    FDA's role in protecting and helping to ensure the safety and 
efficacy of medical products, however, does not depend on data reported 
to the ClinicalTrials.gov data bank. FDA's regulatory and surveillance 
mechanisms for identifying potential medical product problems and 
alerting patients and health care professionals are broad and continue 
to improve through programs such as the Sentinel Initiative. 
Dissemination of research results is a fundamental and long-standing 
principle of science and affords clinical trial participants the 
opportunity to know the value of their participation. Such access 
informs future research and can improve study design as well as prevent 
duplication of unsafe trials. Ultimately, greater transparency of 
clinical trials results will enhance public trust in clinical research. 
The additional impacts on safety as a result of this transparency and 
any effects such transparency may have on the costs of drug 
development.

    Question 5b. If you are confirmed Commissioner:

    (1) How do you plan to work with the NIH to finalize the Proposed 
Rule issued this spring to fully implement and clarify the FDAAA 
policy?
    (2) How will you ensure compliance to the disclosure policy 
implemented by FDAAA? and
    (3) Will you enforce the law using civil monetary penalties or by 
other means?

    Answer 5b. FDA worked with NIH to issue the Proposed Rule 
(published in November 2014) and continues to work with NIH to develop 
a final rule to implement the FDAAA requirements. The comments made to 
the Proposed Rule were complex and raised a number of issues that FDA 
is reviewing carefully and cooperatively with NIH. Although NIH is the 
lead for developing and finalizing the regulations and for implementing 
the ClinicalTrials.gov data bank, FDA has the responsibility for 
enforcing the FDAAA ClinicalTrials.gov requirements. However, 
enforcement actions are not the only tools used by FDA to ensure 
compliance with the statutory requirements. FDA has undertaken 
significant compliance efforts with regard to the ClinicalTrials.gov 
requirements, even in the absence of a final rulemaking, and will 
continue to do so even after a final rule is effective. However, 
without a final rule explaining the statute's requirements, thus 
putting all affected parties on a level playing field, a full 
enforcement program cannot be implemented. When NIH finalizes the rule, 
FDA will be in a better position to increase its compliance/ 
enforcement actions. The use of civil money penalties will depend on 
each case and the applicability and appropriateness of seeking such 
penalties. It will be part of the enforcement ``tool set.''

Patient Medication Information
    Question 6. While the FDA strictly regulates the prescribing 
information meant for doctors and requires the Drug Facts on over the 
counter medications, patient information about a medication and its 
potential risks is largely unregulated. The FDA has been working in 
collaboration with the Brookings Engelberg Center for Health Care 
Reform since May 2010 to engage in research and facilitate discussions 
among stakeholders regarding the design, implementation, and evaluation 
of a PMI document. Janet Woodcock testified before the Senate Aging 
Committee in December 2013 to discuss the FDAs ongoing work to develop 
consumer-friendly patient medication information (PMI) documents. I 
sent a letter asking about the FDAs timeline for implementation with 
Senators Gillibrand, Nelson, and Blumenthal in March 2014, but received 
no information in the agency's response. As Commissioner, are you 
committed to issuing regulations that will require consumer-friendly 
patient medication information to be provided with prescription 
medications before the end of this administration?
    Answer 6. FDA is in the process of developing proposed rulemaking 
for PMI and regulations of this type require significant public input, 
consumer research, and economic analysis. In order to obtain 
information to determine the best path forward for patient medication 
information, FDA has conducted research and continues to engage with 
interested stakeholders including patients, industry, and others, on 
how to improve the content and availability of PMI. These meetings have 
included an open public hearing on PMI in September 2010, as well as 
four public workshops with the Engelberg Center for Health Care Reform 
at the Brookings Institution since 2010 that discussed optimizing, 
implementing, and evaluating the adoption of PMI, the last of which was 
held on July 1, 2014. In addition, RTI published the results from the 
qualitative portion of FDA's PMI study (75 FR 78252) on October 14, 
2014, in an article entitled, ``Preferences for Patient Medication 
Information: What Do Patients Want? ''
    FDA is in the process of developing proposed standards for PMI 
format and content, a central repository to serve as a source for PMI, 
and methods of distribution to patients and pharmacies.
    FDA continues to be committed to the development of a PMI framework 
where the focus is on patient comprehension and issuing regulations in 
a timely manner.
Biosimilars
    Question 7a. The Affordable Care Act established a pathway for the 
approval of biosimilar drugs that will create competition in the 
biologic drug market. Over 5 years since this pathway became law, FDA 
has still not established clear rules of the road for drugmakers, and 
many key guidance's, including those on naming, labeling, and 
interchangeability have not been finalized. If you are confirmed 
Commissioner, what timeline will you implement for finalizing the 
outstanding guidances?
    Answer 7a. FDA has published the following final guidances related 
to biosimilars: Scientific Considerations in Demonstrating 
Biosimilarity to a Reference Product; Quality Considerations in 
Demonstrating Biosimilarity of a Therapeutic Protein Product to a 
Reference Product; and Biosimilars: Questions and Answers Regarding 
Implementation of the Biologics Price Competition and Innovation Act of 
2009; and Formal Meetings Between the FDA and Biosimilar Biological 
Product Sponsors or Applicants.
    FDA has also published the following draft guidances since 2012: 
Clinical Pharmacology Data to Support a Demonstration of Biosimilarity 
to a Reference Product; Reference Product Exclusivity for Biological 
Products Filed Under Section 351 (a) of the PHS Act; Biosimilars: 
Additional Questions and Answers Regarding Implementation of the BPCI 
Act of 2009; and Nonproprietary Naming for Biological Products.
    The Agency is committed to carefully reviewing the comments 
received as we move forward in finalizing the draft guidances noted 
above. Upcoming guidances are expected to include: considerations in 
demonstrating interchangeability to a reference product; statistical 
approaches to evaluation of analytical similarity data to support a 
demonstration of biosimilarity; and labeling for biosimilar biological 
products.
    FDA is diligently working to issue guidance on issues that have 
been identified by the FDA and key stakeholders as key topics of 
interest. While the Agency cannot provide a specific timeline for the 
release of any guidance, we continue to provide information to assist 
biological product developers--sponsors/companies--with bringing 
biosimilar and interchangeable products to market. The FDA is 
continuing to clarify its approach to implementation of the BPCI Act to 
further facilitate sponsors' development of biosimilars and 
interchangeable biological products.

    Question 7b. How do you plan to work with the medical and patient 
community to educate them about biosimilars to avoid inaccurate 
perceptions--like those that are still prevalent about generic drugs 
over 30 years since Hatch-Waxman?
    Answer 7b. FDA has a multi-phase plan for communicating with 
stakeholders about biosimilars. The first phase of communication is to 
lay a solid foundation with basic definitions and descriptions about 
biosimilars that health care professionals and consumers can easily 
understand and adopt. Concurrent with the approval of Zarxio, the first 
biosimilar licensed in the United States, FDA used a number of tools to 
help reach the medical and patient community, including working with 
stakeholder groups, including professional associations, to share the 
details on the new approval and encouraging them to disseminate to 
their memberships; updating the consumer tools on our website, 
including development of a user-friendly consumer update, and providing 
Web content that includes background information such as definitions of 
biosimilar products and interchangeable products, information on how 
these products are prescribed, and the differences between biosimilar 
products and generic drugs. FDA plans to communicate information in 
various formats to consumers as more biosimilar products are licensed 
and enter the marketplace, and as FDA issues additional guidance on 
topics such as labeling, naming, and interchangeability. In addition to 
developing communication materials, as part of its multi-phase plan, 
FDA is conducting research on prescriber's knowledge and perceptions of 
biosimilars. This research will help inform future outreach and 
education efforts to both health care professionals and consumers. 
Moving forward, FDA will continue to implement other phases of its 
biosimilars communication plan to increase health care provider and 
consumer confidence in this new category of products.

    Question 7c. How do you plan to work with CMS and private insurers 
to help inform their biosimilar policies to be sure that they are 
consistent with science, encourage market competition, and encourage 
innovation?
    Answer 7c. While the FDA does not have a role in coverage and 
payment decisions by CMS or other insurers, however, FDA and CMS 
regularly communicate about pharmacovigilance.
    FDA recognizes that healthcare providers have consistently 
indicated the importance of assurance that biosimilars will not have 
clinically meaningful differences from the originator, or reference 
product. FDA applies a scientifically rigorous review process and 
approval standard to earn and sustain confidence in biosimilar products 
and interchangeable products. We are committed to providing this 
assurance and recognize its importance to the acceptance of these 
products, and the future success of the biosimilars program.
Opioids
    Question 8a. America is in the midst of an opioid epidemic. 
According to the Substance Abuse and Mental Health Services 
Administration, 4.3 million Americans reported use of prescription 
painkillers for non-medical reasons in the last month, and according to 
the Centers for Disease Control, 16 million Americans died of an opioid 
overdose in 2013. Congress has signaled an especially vested interest 
in reducing the impact opioids have on pregnant women by passing the 
Protecting Our Infants Act of 2015, championed by my colleague from 
Massachusetts, Representative Katherine Clark.
    What role do you believe the FDA has in combating this epidemic?
    Answer. 8a. Misuse, abuse, addiction, and overdose of opioid 
medications have become a public health crisis in this country. FDA 
plays an important role in helping to address this issue. Our work 
supporting the development of non-opioid pain medications, the 
development of abuse-deterrent formulations of opioid drugs (including 
generics), and improving prescriber education are Agency priorities.
    I am committed to doing what we can to curb the abuse of these 
drugs. We also understand the need to balance efforts to address the 
abuse and misuse of prescription opioid medications with legitimate and 
safe use of pain medicines by patients who need them.
    Our hope is that there will be alternative treatment options for 
pain management using non-opioid pain medications. We are actively 
encouraging and supporting the development of such products.
    At the same time, FDA will continue to work to reduce the risks of 
opioid abuse and misuse, but we cannot solve this complex problem 
alone. A comprehensive and coordinated approach is needed; one that 
includes Federal, State and local governments, public health experts, 
health care professionals, addiction experts, researchers, industry, 
and patient organizations.

    Question 8b. If you are confirmed as Commissioner, what FDA 
authorities could you use to help address the opioid crisis?
    Answer 8b. FDA will act within its authorities, based on science, 
to address the opioid crisis. When appropriate, the Agency is using its 
expedited programs to speed the development of products like non-opioid 
pain medications, abuse-deterrent formulations and formulations of 
naloxone that are easier to use.
    Also, FDA can require a risk evaluation and mitigation strategy 
(REMS) when necessary to ensure that the benefits of a drug outweigh 
the risks. In 2012, using this authority, FDA required manufacturers to 
make available continuing education programs on opioid prescribing 
practices for prescribers. Under the REMS for extended-release/long-
acting (ER/LA) opioid analgesics, manufacturers have also developed a 
patient-friendly counseling tool for prescribers to give to every 
patient, when they write a prescription for an ER/LA opioid. The REMS 
also includes a product-specific Medication Guide to be provided to the 
patient when they pick up their prescriptions. Included in these 
materials is information on how to safely store medications, while 
still in use, and what to do with the leftover supply, when it is no 
longer needed. We are in the process of evaluating the effectiveness of 
the ER/LA opioid analgesics REMS and whether any changes are 
appropriate.
    Additionally, FDA held a public meeting and opened a public docket 
in February 2013 to hear from researchers, patients, health providers 
about issues concerning opioids, including the approved labeling for 
opioid medications and how it is used in clinical practice.
    We listened and reviewed the science. As a result, FDA required 
important changes to the labeling of all ER/LA opioid analgesics. In 
April 2014, we finalized these required changes to the labeling for 
these drugs, changing their indication to inform prescribers that these 
drugs should only be used for pain severe enough to require daily, 
around-the-clock, long-term opioid treatment for which alternative 
treatment options are inadequate to provide sufficient pain relief. At 
the same time FDA significantly strengthened the safety warnings for 
these opioids. We want prescribers to use these medicines with care, 
and today the labeling for ER/LA opioid medicines have some of the most 
serious warning language that can be found in drug labeling, including 
a boxed warning about their potential for abuse, and clear language 
that calls attention to their potentially life-threatening risks.
    There are additional existing post-marketing requirements for all 
of the ER/LA opioid analgesics that include a requirement to conduct 
one or more studies to provide quantitative estimates of the serious 
risks of misuse, abuse, addiction, overdose, and death associated with 
long-term use of opioid analgesics for management of chronic pain, 
among patients prescribed ER/LA opioid products.\28\ We are working 
with sponsors to develop this information and these studies are 
currently underway.
---------------------------------------------------------------------------
    \28\ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/
ucm367726.htm.

    Question 8c. How do you plan to expand our knowledge base about the 
safety of all drugs in pregnant and lactating women?
    Answer 8c. Understanding that adequate information on the use of 
medications in pregnant and lactating women is extremely sparse, the 
Agency supports efforts to spur greater research and development in 
these patient populations. Such efforts must focus on building a 
greater foundation for both the quality and quantity of research, such 
as basic pharmacokinetic data, as well as addressing key policy issues 
that hinder additional research on the use of drugs in pregnant and 
lactating women.
    Of note, the Agency intends to publish two revised guidances to 
reflect the Agency's current thinking regarding expert/scientific 
opinions and to ethical issues surrounding clinical evaluation of drugs 
used in pregnancy and lactation. These revised policy documents, DRAFT 
Guidance for Industry: Clinical Lactation Studies--Study Design, Data 
Analysis & Recommendations for Labeling, and DRAFT Guidance for 
Industry: Pharmacokinetics in Pregnancy--Study Design, Data Analysis, 
and Impact on Dosing and Labeling are in the final stages of the 
drafting process. In addition, following the May 2014 Pregnancy 
Registry Public workshop, the Agency has been engaged in revision of 
the Guidance for Industry: Establishing Pregnancy Exposure Registries 
to reflect key conclusions from this public meeting.
    The Agency is also focused on improving communication of known 
information on the use of prescription drug and biological products in 
pregnant and lactating women in the labeling of these products. On 
December 4, 2014, the ``Content and Format of Labeling for Human 
Prescription Drug and Biological Products: Requirements for Pregnancy 
and Lactation Labeling'' rule, also known as the Pregnancy and 
Lactation Labeling Rule (PLLR), was published in the Federal 
Register.\29\ The rule went into effect on June 30, 2015. The rule 
amends the Physician Labeling Rule\30\ requirements for how information 
is presented in the pregnancy and lactation subsections of labeling for 
prescription drugs and biological products. The rule replaces the 
product letter categories--A, B, C, D and X--used to classify the risks 
of using prescription drugs during pregnancy with a description of 
risks within the real-world context of caring for pregnant women who 
may need prescription drug and/or biological products. These changes in 
product labeling will help ensure labels more effectively communicate 
important health information where prescribing decisions during 
pregnancy and lactation are generally individualized and involve 
complex maternal, fetal and infant risk-benefit considerations. The 
PLLR content and formatting requirements provide a more consistent way 
to include relevant information about the risks and benefits of 
prescription drugs and biological products used during pregnancy and 
lactation based on available information.
---------------------------------------------------------------------------
    \29\ Content and Format of Labeling for Human Prescription Drug and 
Biological Products, Requirements for Pregnancy and Lactation Labeling 
(79 FR 72063, December 4, 2014).
    \30\ Requirements on Content and Format of Labeling for Human 
Prescription Drug and Biological Products, published in the Federal 
Register (71 FR 3922; January 24, 2006).
---------------------------------------------------------------------------
    There is a major need to invest in clinical research in pregnant 
women. The success of treatment of congenital and childhood diseases 
has dramatically increased the need for pharmacologic treatment of 
chronic diseases during pregnancy. Yet, we have only a fraction of the 
information that we have obtained in children, because very few studies 
have been done. Recent FDA rules have improved the labeling of drugs 
for pregnant women because the old pregnancy letter category system was 
overly simplistic and often misleading. The new format is structured to 
more clearly describe available data that can be used to aid in complex 
risk/benefit discussions between prescribers and their patients. 
However, in many cases there is still a lack of high-quality data to 
inform about the risks of a drug when used during pregnancy. In such 
cases, the new labeling format also includes required statements to 
communicate that data are lacking.

                     Comprehensive Clinical Trials
[GRAPHICS NOT AVAILABLE IN TIFF FORMAT]


    [Whereupon, at 12 p.m., the hearing was adjourned.]