[Senate Hearing 115-458]
[From the U.S. Government Publishing Office]


 
   AGRICULTURE, RURAL DEVELOPMENT, FOOD AND DRUG ADMINISTRATION, AND 
          RELATED AGENCIES APPROPRIATIONS FOR FISCAL YEAR 2019

                              ----------                              


                        TUESDAY, APRIL 24, 2018

                                       U.S. Senate,
           Subcommittee of the Committee on Appropriations,
                                                    Washington, DC.
    The subcommittee met at 2:30 p.m. in room SD-124, Dirksen 
Senate Office Building, Hon. John Hoeven (chairman) presiding.
    Present: Senators Hoeven, Collins, Moran, Merkley, Tester, 
Udall, and Baldwin.

                   U.S. FOOD AND DRUG ADMINISTRATION

STATEMENT OF HON. SCOTT GOTTLIEB, M.D., COMMISSIONER


                opening statement of senator john hoeven


    Senator Hoeven. This hearing will come to order.
    Today's hearing will focus on the Food and Drug 
Administration's fiscal year 2019 budget request.
    I want to thank Commissioner Gottlieb, Dr. Gottlieb, for 
being here today to discuss FDA's priorities for the upcoming 
year. Thanks for your public service. We really appreciate you 
being in this post, your hard work, and your diligence.
    I think we will dispense with opening statements in the 
interest of time. There is at vote at 3 o'clock. So our intent 
is to just go on through and then hopefully adjourn by, say, 
3:20 or so which would give the members time to go over and 
vote. But we will see how it goes. If we have to adjust, of 
course we will do that. So we will dispense with our opening 
statements.
    But I would invite Dr. Gottlieb, if you do have some 
opening comments, to go ahead and make those opening comments.


              summary statement of hon. dr. scott gottlieb


    Dr. Gottlieb. Thanks a lot, Mr. Chairman, Ranking Member 
Merkley, and Members of the Subcommittee. Thank you for the 
invitation to testify today to discuss the President's fiscal 
year 2019 budget request and for this Subcommittee's continued 
strong support of the agency.
    The investment you made in the 2018 omnibus helped support 
programs that made 2017 the most successful in FDA's history, 
with a record number of approvals of innovative and generic 
drugs and novel medical devices.
    The President's budget request for FDA builds on these 
goals. Overall, the budget requests $5.8 billion in total 
resources for FDA, which includes an increase of $473 million 
in budget authority and $190 million in user fees. The budget 
requests new resources for the FDA to make significant 
investments in advancing critical areas of science, domestic 
technology, and public health.
    Today I want to focus my remarks on two of these proposals.


                         generic drug platform


    The first is our proposal to modernize our generic drug 
platform. This effort comprises two policy components.
    The first element will help make the approval of new 
generic drugs more efficient by establishing a structured 
application. We believe a structured application that allows 
key sections of the generic drug file to be captured in a 
structured template will speed the review of the application to 
cut down on the number of review cycles that applications must 
undergo and reduce generic drug development timelines.
    The second component of this initiative is aimed at 
promoting more widespread use of existing generic drugs by 
looking for ways to keep generic drug labels up to date with 
the latest information about each medicine's safety and 
benefits. The current statute generally requires generic drugs 
to have the same labeling as the brand drug that they 
reference. The burden to update the label with new information 
is typically borne by the brand company. However, when the 
brand reference drug voluntarily withdraws their marketing 
applications and therefore stops updating their labeling, FDA 
loses the mechanism to update generic labels. By having out-of-
date labels, in turn, it can depress use of generic drugs. By 
one rough estimate, 1,170 reference drugs are tagged as 
discontinued or withdrawn by their original branded sponsors 
for reasons other than safety or effectiveness. If the brand 
drug sponsor has voluntarily withdrawn their marketing 
application, there is no sponsor who is responsible for making 
the necessary label updates that other generic applicants would 
follow. So these labels basically get frozen in time. These 
drugs may be old medicines, but many are still very useful, and 
some form the backbone of modern cancer regimens.
    FDA can assume more responsibility ourselves to help bring 
these drug labels up to date. I believe if we actively take on 
this role, it can promote more widespread use of generic 
medicines. Our budget requests money to do just this.


                 medical product innovation initiatives


    Our budget also includes a request for funding to support 
another initiative to allow us to make sure that medical 
products are developed as efficiently and quickly as possible. 
This second effort will also help to make sure patients and 
providers have the most up-to-date information on which to make 
informed decisions in addition to improving the use of real-
world evidence for the many of the products we oversee. We seek 
to expand our active surveillance systems to enhance our real-
time understanding of medical product performance by broadening 
our use of health care data to better take advantage of the 
data available from electronic health records. To accomplish 
this, several things must happen. First, the data must be high 
quality and interoperable, meaning that the data can be 
collected in one system but used in many different systems to 
inform patient care. And second, we must enable better 
integration of clinical care and clinical research.
    Right now, our active post-market data monitoring systems, 
principally our NEST database for medical devices and our 
Sentinel system for drugs and biologics, depend largely on the 
secondary use of claims data because that is what is available 
to us. And as helpful as this is, we know the nation can do 
better. Real-time surveillance is first and foremost about 
safety.
    But having a real-time post-market and real-world 
experience system will also give us more ways to use real-world 
evidence to expand what we know about the effectiveness of new 
products. New products are often safer because they can be 
designed to address safety issues identified through better 
surveillance. But we can also use data from electronic health 
records to broaden the indications for use of approved 
products, eventually conducting more late-stage development in 
the real world, making our pre-market development process more 
efficient.


                      new medical data enterprise


    The 2019 budget includes $100 million to advance the use of 
real-world experience to inform patient care and provide 
efficient and potentially lower cost ways to develop clinical 
data to expedite medical product development. The proposal 
gives us the capability to conduct near real-time evaluation of 
individual health records for at least 10 million individuals 
from a broad range of settings.
    In closing, these are transformative initiatives that can 
modernize the foundation of FDA oversight and improve patient 
safety. Your support through the appropriations process allows 
us to modernize how FDA fulfills its vital consumer protection 
mission. And I look forward to explaining our budget request 
and answering your questions in detail. Thanks a lot.
    [The statement follows:]
               Prepared Statement of Scott Gottlieb, M.D.
    Good afternoon Chairman Hoeven, Ranking Member Merkley, and Members 
of the Subcommittee. Thank you for the opportunity to appear before you 
today to discuss the President's fiscal year 2019 Budget request for 
FDA.
    First, I would like to thank the Committee for your continued 
support of the Agency. FDA has received strong bipartisan support 
throughout the appropriations process in recent years and fiscal year 
2018 was no different. I believe this support reflects our shared 
commitment to the vital role FDA has protecting and promoting the 
public health. The funding this Subcommittee provides is essential to 
the Agency fulfilling its mission. The professional staff of FDA is 
grateful for the support of their work and the funding increases the 
Subcommittee provided FDA in fiscal year 2018.
    Last year was a record year for medical products at FDA in several 
ways: novel drug approvals, generic drug approvals, and novel medical 
device approvals. The record number of approvals in 2017 reflects the 
remarkable opportunities we have at this critical inflection point in 
science and technology. Advances in medicine and science are providing 
opportunities that can fundamentally change health in America and the 
outlook for many patients with life threatening and chronic diseases. 
At the same time that we have many new opportunities offered by 
advanced medical technologies; we cannot lose sight of our commitment 
to the public health basics--reducing smoking rates, preventing kids 
from initiating use of tobacco products, supporting healthy food 
choices that can lead to better nutrition and reduced risk of disease, 
and increasing vaccination rates. FDA is committed to all of these and 
other public health goals. With your continued support, we have more 
opportunity to deliver on the promises of science than at any other 
time in the past.
    The funding provided in the President's fiscal year 2019 Budget 
will allow the Agency to sustain its current work--protecting the 
safety of the food and medical products consumers use every day--and 
build on these efforts by requesting additional resources to make 
significant progress on several important fronts; including, fostering 
innovation and competition to bring better and more affordable products 
to market, combatting the opioid epidemic, and implementing the 21st 
Century Cures Act (Cures).
    Overall, the Budget requests $5.8 billion in total resources for 
FDA--which is an increase of $663 million or 13 percent above the 
fiscal year 2018 Annualized Continuing Resolution. At this total level, 
the Budget includes an increase of $473 million in budget authority and 
an increase of $190 million in user fees. The Budget requests 
considerable new resources for FDA and makes significant new 
investments in advancing critical areas of science, domestic 
technology, and public health.
    As the regulatory Agency responsible for ensuring the safety and 
effectiveness of more than $2.4 trillion worth of products used by 
consumers, I remain steadfast that these funds are critical investments 
in our public health agency. They will allow us to more efficiently 
advance safe and effective new opportunities to Americans.
                      fiscal year 2019 initiatives
    The Budget includes an increase of approximately $400 million in 
additional resources to advance initiatives to promote public health 
and spur growth in the domestic economy. These new initiatives provide 
a renewed focus to some of the Agency's most intensely followed 
issues--facilitating regulatory pathways to increase patients' access 
to safe and effective drugs, biologics, and medical devices, and access 
to higher quality compounded drugs for the patients who need them; 
better informing patients and providers about pre-and post-market 
safety of medical products; and, increasing competition among generic 
drugs in order to lower the cost of generic drugs.
    I believe that these new efforts represent discrete areas where 
targeted additional resources can help the Agency make a meaningful 
difference for American consumers. A few examples of the new 
initiatives are described below.
      advancing modern drug and biological product manufacturing 
 technologies, through the development of efficient regulatory pathways
    Advanced manufacturing technologies, such as continuous 
manufacturing, can improve the agility, flexibility, cost and 
robustness of drug and biologic manufacturing processes. These 
technologies have great potential to accelerate new, more targeted 
therapies, enhance product quality and bolster stability in the U.S. 
drug supply to meet patient needs. For example, continuous 
manufacturing has the potential to help address and eliminate drug 
shortages and reduce recallsrelated to problems with product or 
facility quality. Further, with continuous manufacturing platforms for 
biologics, vaccine manufacturing, for example, could be ramped up on 
short notice, and vaccines themselves adapted over a shorter time 
period to address infectious diseases, such as the flu. This would help 
address the challenge we face annually with the flu season. As a result 
of the long manufacturing cycle required when using traditional egg 
based manufacturing technologies, manufacturers must select the flu 
strain that will be included in the upcoming flu season's vaccinessix 
months prior to the flu season. By reducing the amount of time it takes 
to ramp up manufacturing, we can start manufacturing closer to the 
start of flu season to minimize or eliminate the matching issues we 
face, to varying degrees, each year and increase the efficacy of the 
flu vaccine. Advances in manufacturing could provide a more certain, 
and nearer-term opportunity to address challenges with flu vaccine 
supply and effectiveness while we continue to work on longer term, 
newer vaccine technology such as a universal vaccine.
    Despite the promise of these manufacturing improvements, industry 
remains reluctant to invest in these platforms. Additional regulatory 
principles and tools to help manufacturers implement and assess these 
platforms could accelerate their adoption. It would give manufacturers 
greater certainty that products developed through continuous 
manufacturing can be efficiently reviewed and gain market entry.
    In these ways, FDA can encourage industry to utilize these new 
technologies by developing a science-based framework that includes the 
regulatory tools and guidance for how products developed in these 
systems will be evaluated. As an additional benefit, these small-
footprint, high-technology manufacturing platforms are likely to be 
domiciled in the U.S. As a result, their adoption could return more 
product manufacturing to domestic sites, which could help public 
health, enhance our national security, and foster job creation. The 
Budget requests $58 million in fiscal year 2019 for advancing this 
initiative.
 establishing the outsourcing facility sector as a robust and reliable 
                     source of compounded products
    Since Congress passed the Drug Quality and Security Act in 2013 
(DQSA), patient access to better quality compounded drugs has been a 
chief concern for the Agency, physicians, and patients alike. 
Outsourcing facilities have the ability to produce and distribute 
larger amounts of compounded products to meet the needs of individual 
patients for whom such drugs are appropriate, including by making 
office stock that is used by hospitals and clinics. Outsourcing 
facilities are an important component to our health system and the 
Agency is committed to clarifying and appropriatelytailoring policies 
so they can continue to provide drugs, based on the clinical need for a 
compounded medicine, so patients have access to the products they need.
    The Budget proposes the creation of a ``Center of Excellence on 
Compounding for Outsourcing Facilities'' and expanded FDA engagement 
with outsourcing facilities and states to help the pharmacy outsourcing 
industry grow to meet its intended function and adhere to good 
manufacturing practices (GMPs) to protect patient health. We see an 
opportunity to make investments in regulatory policy and personnel that 
could help more compounding pharmacies become outsourcing facilities. 
This, in turn, would allow these pharmacies to grow and serve more 
patient needs, including through the provision of office stock 
compounded under GMP standards, promoting access to better quality 
compounded drugs for patients who have medical needs that otherwise 
cannot be met by an FDA approved drug. These new outsourcing facilities 
would represent a largely domestic industry and a new area of growth in 
the healthcare sector. The Budget requests $25 million in fiscal year 
2019 for this initiative.
bring medtech manufacturing home: advance medical device manufacturing 
                              and quality
    The Budget proposes to establish a voluntary program for device 
manufacturers to receive an independent assessment of manufacturing and 
product quality criteria intended to demonstrate sustained 
organizational excellence. This would make the process for introducing 
innovations in how medical devices are manufactured more efficient and 
predictable. In turn, this program would encourage device manufacturers 
to make investments to re-tool their manufacturing processes in ways 
that can facilitate manufacturing innovation, encourage investment in 
new production methods and materials, and lead to better medical 
products.
    This more modern and nimble framework would make it more efficient 
for device developers to innovate manufacturing processes in ways that 
can allow devices to better meet the needs of patients and the 
expectations of providers--such as through intelligent, automated 
processes that monitor and record manufacturing quality metrics, 
incorporating features and technological characteristics that can 
contribute to better options and higher quality that achieves their 
clinical purpose. Implementing this framework would help increase 
manufacturing innovation, accelerate availability of high-quality 
devices to patients and foster a competitive marketplace around device 
quality similar to other industries, such as automotive and aerospace, 
that could advance device innovations, reduce manufacturing costs and 
improve the quality and safety of medical devices. As medical devices 
become more complex--and given the frequent modifications made to 
devices--spurring advanced manufacturing and creating a competitive 
marketplace for device quality is critical for both driving 
technological innovations and assuring patient safety. The Budget 
requests $12 million in fiscal year 2019 for this initiative.
                  create a new medical data enterprise
    Advances in technology have the potential to improve the 
availability and utility of real world evidence (RWE) and real world 
data\1\ (RWD). This data provides researchers the opportunity to answer 
questions about treatment effects and outcomes more efficiently, saving 
time and money, while yielding answers more relevant to broader 
populations of patients than might be possible in a specialized 
research environment. This data can also help streamline clinical 
development and inform the safe and effective use of medical products.
---------------------------------------------------------------------------
    \1\ Examples of RWD include data derived from electronic health 
records (EHRs), claims and billing data, data from product and disease 
registries, patient-generated data including in-home use settings, and 
data gathered from other sources such as mobile devices that can 
provide information about health status.
---------------------------------------------------------------------------
    The Budget proposes to advance the use of this real-world 
experience to better inform patient care and provide more efficient, 
robust and potentially lower-cost ways to develop clinical data that 
can inform product review and promote innovation. The Budget requests 
funding to establish a new capability, including the development of 
data and analytical tools, to conduct near-real-time evidence 
evaluation down to the level of individual electronic health records 
for at least 10 million individuals in a broad range of U.S. healthcare 
settings.
    Expanding the FDA's capacity to use RWE to evaluate medical 
products would generate processes that could improve the efficiency of 
the regulatory process, better inform patients and providers about pre-
and post-market safety, reduce some of the burdens that drive up the 
time and cost required to bring beneficial innovations to the market, 
and address barriers that can make certain important safety and 
effectiveness information around the real-world use of products hard to 
collect and evaluate. Harnessing the power and potential of RWE is 
especially critical for finding treatments and cures for rare disease. 
Establishing a strong understanding of each disease and completing 
clinical trials is especially challenging; however, RWE holds enormous 
promise for improving understanding of disease and thus, development of 
treatments and cures. Funding in this area will allow FDA to develop 
regulatory standards for use of RWE to support medical product 
applications. The Budget requests $100 million in fiscal year 2019 for 
this initiative.
    facilitate growth and spur transformation of the digital health 
 technology industry by shifting regulation to an efficient and novel 
              framework for reliable post-market oversight
    Digital health products are at the forefront of helping us diagnose 
and treat our society's increasingly complex medical needs. Healthcare 
providers use the latest technological tools to help them screen, 
detect and treat diseases ranging from cancers to neurological 
conditions like Alzheimer's. Patients utilize mobile medical 
applications to manage conditions like diabetes and treat substance use 
disorder. However, the current regulatory framework is not well-suited 
for these modern technologies. Every single day, these technologies are 
helping patients and doctors make healthcare decisions.
    As part of our efforts to support timely access to safe and 
effective digital health products, the FDA is working collaboratively 
with industry, patients and providers to establish a new paradigm for 
digital health technologies under which a company could market lower-
risk products without FDA premarket review and market higher-risk 
products following a streamlined FDA premarket review if the company 
receives a prior third-party certification for engaging in high-quality 
software design and testing (validation) and ongoing maintenance. This 
regulatory model would be fully proven and expanded from its current 
pilot status to a broader program. For low-risk products, rather than 
evaluate each individual digital health product before the product 
comes to market, the FDA would instead focus its resources on 
validating the quality of a firm's software design and the firm's 
methods for certifying the quality and reliability of its underlying 
software performance. The agency would further reduce the time and cost 
of market entry of digital health technologies while assuring 
appropriate patient safeguards by relying on postmarket collection of 
real-world data to support new and evolving product functions. The 
Budget also proposes the creation of and resources for a Center of 
Excellence on Digital Health to establish this regulatory paradigm, 
build new capacity to evaluate and recognize third-party certifiers, 
and support an internal cybersecurity unit and an external public- 
private partnership of experts to complement the advances in software-
based devices. Implementing these regulatory innovations and 
information technology improvements are essential for advancing 
technologies to improve the health and quality of life of patients 
while assuring critical safeguards. The Budget requests $70 million in 
fiscal year 2019 for this initiative.
             modernize generic drug development and review
    Increasing patients' access to more affordable prescription drugs 
is a top issue for Americans and one that I am personally dedicated to 
addressing during my tenure as Commissioner. Last May, in one of my 
first actions as Commissioner, I announced FDA's Drug Competition 
Action Plan. The plan has three overarching principals: eliminate 
gaming by branded companies that can delay generic drug entry; 
resolving scientific and regulatory obstacles that can make it 
difficult to earn approval of generic versions of certain complex 
drugs; and improving the efficiency and predictability of FDA's generic 
review process to reduce the time it takes to get a new generic drug 
approved and lessen the number of review cycles undergone by generic 
applications before approval. As part of this process, we also 
prioritized review for certain generic applications where there was a 
lack of competition, a situation under which consumers could face high 
prices for some very old medicines.
    The Budget builds on this plan by proposing to establish a new 
review platform to modernize generic drug review and support efforts to 
update generics labels. This investment will foster greater use of 
lower-cost generics as a way to improve patient access and create 
competition in order to lower drug costs. For example, too many generic 
labels remain out-of-date because there is no longer a sponsor involved 
that is able to update the labels with new information about safe and 
effective new uses for these medicines. If we incorporate into generic 
drug labels all of the current information about their safe and 
effective use, it could promote more prescribing of generic drugs, 
reducing overall healthcare costs. The Budget requests $38 million in 
fiscal year 2019 for this initiative.
                                opioids
    One of my highest priorities as FDA Commissioner is combatting the 
ongoing crisis of opioid addiction. As part of this commitment, we are 
reexamining the Agency's authorities and policies in this area and 
working to ensure that FDA has the proper tools and resources to 
address this epidemic as it continues to evolve.
    Thanks to the support of this Subcommittee, FDA received a total of 
$94 million in the fiscal year 2018 Consolidated Omnibus Appropriations 
Act (Public Law 115-141) signed into law last month to address the 
interdiction of illegal drugs, including narcotics, through our work in 
the international mail facilities. Recognizing the Agency's 
responsibility in helping to curb the flow of these counterfeit and 
illegal drugs from entering our communities, and the critical public 
health obligation that the FDA was entrusted with through these 
additional resources, I am pleased to report the Agency will start to 
invest this new funding in purchasing equipment and assessing 
additional technologies we might deploy before the end of this fiscal 
year.
    But FDA's efforts related to addressing the opioid crisis are 
broad, and there are many new programs we would like to pursue in this 
mission. The Budget requests an additional $10 million to provide 
technical assistance related to clinical study design related to 
medication-assisted treatments, and to also accelerate the development 
of non-opioid treatments, devices to treat chronic pain, and generic 
versions of opioid drug products with abuse deterrent formulations. One 
way FDA will use the resources is funding studies to identify 
additional tools and methodologies that can be used to evaluate whether 
differences in formulations impact abuse deterrence. These are small 
steps, but collectively, over time I am confident they can work 
together, along with the efforts of so many other of our Federal, 
state, and local partners to make a difference.
                                 cures
    Implementation of Cures has been another top priority of the Agency 
over the past 16 months. Cures includes provisions that have the 
potential to impart far-reaching effects on scientific advancements in 
medical product development. The new law complements many efforts 
underway at FDA. All of these efforts are aimed at transforming the way 
we support product development and maintaining FDA's gold standard for 
safety and effectiveness. Toward these efforts, last June, the Agency 
published our required work plan for implementing Cures, which includes 
details of how the Agency will utilize the $500 million in authorized 
new funds over 9 years. For fiscal year 2019, the Budget requests a 
total of $70 million to support our implementation work.
    I want to thank you for your support on this vital work so far. I 
look forward to working with you on supporting the Agency's 
implementation efforts in the future.
                               conclusion
    The last year was historic for the Agency. We are diligently 
working on a number of fronts and the vital work we do provides 
Americans with better ways to improve their health and welfare, and 
empowers consumers to make informed choices about the products they use 
and the foods they feed to their families. The Budget will help FDA 
maintain and complement our current efforts, as well as provide a 
renewed focus and investment in some of the Agency's and the nation's 
top public health priorities. I look forward to answering your 
questions today and to working with all of you going forward.

    Senator Hoeven. Again, Doc, thanks for being here, and we 
will have 5-minute rounds of questions.

                    FISCAL YEAR 2019 BUDGET REQUEST

    The budget requests a 9.6 percent increase above last year, 
and that is about a 24 percent increase compared to 5 years 
ago. So is that a permanent increase, or do you have one-time 
funding increases included in there?
    Dr. Gottlieb. A lot of the new initiatives that we are 
asking for resources for are one-time funding. There are some 
recurrent components to these, but of the new initiatives, we 
are asking for additional funding. And I outlined two of them 
today that are important to us. There are 97 FTEs that we would 
hire and try to continue on in perpetuity. So the balance of 
the resources are really allocated towards one-time 
expenditures to try to make some foundational changes to our 
regulatory platform.
    Senator Hoeven. There have been recalls over eggs and 
romaine lettuce. Can you give us an update on that? And then 
also do you have adequate funding in there for food safety 
activities?

                                RECALLS

    Dr. Gottlieb. With respect to the egg recall, as you noted, 
Senator, we recalled recently 207 million eggs. Most of them 
had already been consumed, but we recalled eggs back to late 
2017 related to a single facility, but a very large facility 
where we had traced back a strain of salmonella using our 
investigative work. The strain had a particularly identifiable 
molecular fingerprint. So going in and sampling patients who 
had become ill, we were able to trace it back to this facility. 
So we think we have addressed the problem with this facility. 
They are taking proper steps to remediate their facility to try 
to reduce this risk.
    With respect to the romaine lettuce, it is an active 
investigation. We have isolated it to a particular region in 
Arizona where we believe it is coming from. We have information 
that suggests certain farms it may be coming from, but right 
now we have it isolated to a particular grower. So we put out 
general guidance that consumers should avoid romaine lettuce 
unless they can be certain that it did not come from Yuma, 
Arizona, which is the region that has been called into 
question.

                     INTERNATIONAL MAIL FACILITIES

    Senator Hoeven. For 2018, you got $94 million for 
increasing inspection capacity for catching opioids at 
international mail facilities. You and I talked about this. Can 
you give us an update on how you are doing with that?
    Dr. Gottlieb. Thank you, Senator. We are very appreciative 
for the resources that this Committee allocated to the agency 
to help in that fight.
    As you know, we play a role, in collaboration with Customs 
and Border Protection, doing interdiction work in the 
international mail facilities related to not just counterfeit 
drugs and foreign unapproved products that may create risk to 
consumers but also with respect to controlled substances.
    We are actively in the process of allocating that money 
now. We will have it fully allocated and programmed through 
2019. We have already started to allocate some of those 
resources. And this is going to allow us to increase the number 
of packages that we inspect annually from 40,000 to 100,000. To 
give you sort of a metric, when I arrived at the agency, we had 
seven inspectors inspecting about 10,000 packages a year in the 
international mail facilities. Through resources we 
reprogrammed on our own, we increased it to 21 inspectors 
opening 40,000 packages. This new money will allow us to 
dramatically increase our footprint and be able to inspect 
upwards of 100,000 packages, maybe more once we are fully 
staffed out in those facilities.
    Senator Hoeven. So you feel that is on track and that you 
have got the resources you need to do it.
    Dr. Gottlieb. We feel very good about our ability to 
allocate these resources. We feel very good about the resources 
that we have gotten. Look, we have 275 million packages a year 
coming through the international mail facilities. We estimate, 
based on some rough statistics that about 9 percent of those 
packages contain drugs. We are currently opening and inspecting 
.04 percent because we physically do not have the manpower to 
do more. So going from 40,000 to 100,000, we are still going to 
be looking at a fraction of a fraction, but if we are doing our 
job and we have good intelligence--and some of this money is 
going to towards building out our intelligence platforms--and 
we are targeting the right packages, we think we can get a 
meaningful representative sample of the highest risk packages 
that we can then conduct investigations, go back to the source, 
and try to shut this stuff down.

                      STATE COOPERATIVE AGREEMENTS

    Senator Hoeven. We also provided funding for the State 
cooperative agreements. You have seven States that are not 
signed up. Do you expect to have them signed up?
    Dr. Gottlieb. Not every State has applied, Senator. So the 
States that applied for 2018--we are actively working with the 
States to bring them into this. The States that have applied 
that were not previously part of those cooperative agreements 
are Kentucky, Mississippi, Hawaii, and American Samoa. But the 
States that have not gotten their applications in for 2018--we 
are actively working with them to get them in next year. So we 
hope to have all 50 States. It is very important from my 
standpoint--the success of FSMA and the Food Safety 
Modernization Act and our platform to have these States signed 
up in these cooperative agreements. And we will be working with 
all the States, including your State, Senator. And so we are 
grateful for the resources to do that.
    Senator Hoeven. I have some other questions. And I also 
received some questions on my way in today, and I will submit 
those for the record, Doctor.
    Dr. Gottlieb. Thank you.
    Senator Hoeven. Senator Merkley.

                             OPIOID FUNDING

    Senator Merkley. Thank you very much, Mr. Gottlieb.
    When you were addressing the opioid funding that was in the 
omnibus, I am not sure if you clarified whether or not, given 
that there is no money in the budget for this coming year, you 
can continue the same level of function you have under the 
omnibus without additional funds in this coming budget.
    Dr. Gottlieb. Well, I appreciate the question, Senator. 
There was $10 million in the budget this year. There was also 
an allocation made to HHS, if I remember correctly, of $3 
billion a year over 2 years, so $6 billion total. And we are 
actively working with HHS and OMB to see what portion of that 
money is going to be allocated to FDA. So we hope to receive 
additional resources to help us step up this fight.
    But I would be very open to working with Congress to make 
sure we can sustain the same level of effort with respect to 
the international mail facilities. As you know, this has been 
my top priority with respect to the enforcement activities 
related to our opioid interdiction work to get these IMFs 
staffed up and built out.
    Senator Merkley. Thank you. I think what I heard you say is 
that unless money comes from another department, we need to 
work together to sustain the effort that FDA has on opioids.
    Dr. Gottlieb. We do need to work together, yes.
    Senator Merkley. Thank you.

                              FSMA FUNDING

    Then let us turn to FSMA. And of course, we have this 
significant outbreak. There is no additional funding provided 
for food safety activities despite the nearly $400 million 
increase in your budget. I know that many have talked to me 
about the complexity of tracing foods back to their source, 
especially when there are mixed products, figuring out quickly 
whether it is the lettuce, it is the tomatoes, it is cucumbers, 
where from. Can you really do FSMA well without asking for any 
additional money?
    Dr. Gottlieb. Resources help, Senator. There is no 
question. Policy helps too. And we have taken some aggressive 
steps recently to try to increase the level of our footprint 
here to carry out our mission using mandatory recall authority 
for the first time recently, as you know, and also committing 
to disclose more information related to recalls. But there is 
no question we can do more with more and resources help. We 
appreciate the resources----

                              E-CIGARETTES

    Senator Merkley. Thank you. I will follow up on that 
question as to how much you can do with the resources you have 
and whether you need more.
    I am putting up a headline of an article in the ``New York 
Times'' from earlier this month. I cannot stop the schools' 
struggle with vaping explosion. And the article notes that e-
cigarettes have been touted by their makers to help adult 
smokers kick the habit. But school officials are struggling to 
control an explosion of vaping among high school and middle 
school students across the country. And they are fearful that 
they are creating a new generation of nicotine addicts.
    As one said, it is our demon, referring to how it is 
affecting the students in their school and saying that they 
have an explosion of the use of this new, easily concealed 
device with a sleek, high-tech design that looks like a flash 
drive. It has turned the word ``JUUL,'' the brand-maker into a 
verb.
    And there are studies that have now come out that show that 
the pods in vaping devices have a higher concentration of 
nicotine than individual cigarettes, accelerating the 
addiction, and a body of research indicating that vaping is 
leading adolescents to try cigarettes, which I know is the 
opposite of the argument made.
    We now know that the additives include propylene glycol and 
glycerol that can form carcinogenic compounds. There is another 
chemical that is used to flavor some of the vaping juice that 
is linked to popcorn lung. Many of these things have not been 
thoroughly studied, and yet we have this explosion.
    If we were to look at the numbers, we can see in middle 
school a huge explosion between 2011 and 2016. We do not have 
2017 numbers yet. In high school, we have an explosion as well, 
nearly a tenfold increase. This is why people are so concerned.
    My basic impression is that under the guise of saying that 
this is helpful to some adults to have candy flavors and fruit 
flavors to encourage them to quit smoking and turn to vaping 
instead, we are damaging an entire generation of our children. 
Do you share that concern at all?
    Dr. Gottlieb. I am deeply concerned about this. And I am 
not going to countenance on my watch addicting a whole 
generation of young people to nicotine through e-cigarettes.
    We took a robust series of actions today, and nobody 
watching this should underestimate our ability to follow up on 
those actions and take even stronger steps to shut down the 
youth access to these products, Senator. I do believe that the 
e-cigarettes, and ENDS products more generally, have the 
potential to offer a viable and potentially lower-risk 
alternative for adults who still want to access nicotine but do 
not want all the risks associated with combustion. But that 
cannot come at the expense of addicting a whole generation of 
young people to e-cigarettes, and we are not going to tolerate 
that. And that is why we took the actions we took today.
    We will be following up with additional enforcement actions 
in the coming weeks, and I look forward to talking to you about 
that.
    Senator Merkley. I do compliment you on pursuing companies 
that are selling to children directly in violation of the law 
and giving them warning letters. I just will keep coming back 
to the core point that as long as you allow devices that look 
like a flash drive, as long as they are not having to go 
through some kind of process, as long as you allow fruit and 
candy flavors, you are, in fact, facilitating the addiction of 
a generation of our children and it is not acceptable.
    Thank you.
    Senator Hoeven. Did you wish to respond, Doctor?
    Dr. Gottlieb. If I may. With respect, Senator, we will take 
additional enforcement actions in the coming weeks that I think 
are going to help illustrate both the scope of our ability to 
take action on the basis of something that--but just on the 
basis of whether or not someone could objectively believe that 
it is being designed in a way to appeal to youth. And I hope to 
come back to you and talk to you about that as well because 
there may be things we can do with respect to our current 
authorities that allow us to target on the basis of something 
that a reasonable person can believe it is designed in a way 
that might appeal to youth. But there are limitations to our 
current authorities as well. I think when we take our coming 
actions, we will demonstrate where that boundary currently is.
    Senator Hoeven. Senator Moran.
    Senator Moran. I will yield to Senator Collins. We were 
here at the same time, and she is senior to me.
    Senator Hoeven. Okay. Senator Collins.
    Senator Collins. What a guy.
    Senator Hoeven. Is he not something.
    Senator Collins. Is he not.
    Senator Hoeven. Senator Collins.

                       DRUG MARKET CONSOLIDATION

    Senator Collins. Thank you very much, Senator Moran.
    Commissioner, first let me commend you for your leadership 
at the FDA. I have been so pleased with the activist approach 
that you have taken. I think you are doing a terrific job, and 
I just want to start my questions by telling you that.
    I commend you for your leadership in eliminating barriers 
to competition in the prescription drug market, which you and I 
have discussed many times. You have cracked down on REMS 
abuses. You promoted the development and uptake of biosimilars, 
all actions that needed to be done.
    Recently you spoke about the dangers of market 
consolidation and the fact that the top three PBMs control more 
than two-thirds of the market; the top three wholesalers, more 
than 80 percent; and the top five pharmacies, more than 50 
percent. You suggested that patients should not be penalized if 
they need a drug that is not on a formulary.
    Earlier this month, Bloomberg reported that the Federal 
Trade Commission attorneys are looking for more cases to 
challenge companies' anticompetitive conduct. In my view, the 
FTC should not have to look very hard to find examples in the 
drug pricing arena, whether it be looking at mergers, market 
consolidation, pay for delay settlements, and patent thicket 
strategies.
    Does the FDA actually refer cases to the FTC in this area?
    Dr. Gottlieb. We have ongoing dialogue and collaboration 
with the Federal Trade Commission (FTC) in certain areas, 
Senator. And there are places where we would provide 
information and perhaps make a referral with respect to 
situations where we might see a branded company taking 
advantage of the rules in ways that are deliberately meant to 
forestall intended competition. So there is a lot of ongoing 
dialogue with the FTC. And quite frankly, we have had a good 
relationship with them. We have been working with them quite 
closely not just on this issue but other issues as well.
    Senator Collins. Good. I certainly hope to see more cases 
brought by the FTC.

                              DRUG REBATES

    The next issue that I wanted to discuss with you is the 
issue of rebates. A number of players in the health care system 
appear to profit from the soaring costs of prescription drugs, 
whether it is manufacturers, insurers, intermediaries, pharmacy 
benefit managers, and while these players are taking larger and 
larger cuts, patients are often left scrambling to come up with 
the funds to pay for lifesaving drugs that they need.
    I recently was at a pharmacy in Maine, and the couple who 
were in front of me in line, when they saw that their co-pay 
was going to be $111, just turned around and left. And the 
pharmacist, in response to my inquiry, told me this happens 
every day, and that is so troubling to me.
    So on its face, the idea of rebates that are paid by 
prescription drug manufacturers' sound like a good thing. PBMs 
negotiate drug prices with manufacturers and then provide 
rebates to insurers, which ought to bring down premiums for 
everyone. In practice, however, this means that for those who 
are least able to pay, including those who have very high co-
pay requirements or high deductible plans and those who do not 
have insurance at all and paid these prices out of pocket, end 
up, ironically, subsidizing the costs for others. Something 
seems broken here.
    How would you suggest that we rectify the rebate problem to 
bring down costs for patients?
    Dr. Gottlieb. I am a little bit outside my regulatory 
domain here, but there are a number of things we can to do to 
try to encourage straight discounting and not rebating, which I 
think your analysis is spot on in terms of the rebate money 
is--effectively the patient who is out of pocket is subsidizing 
the premiums for the patients who do not need health care. It 
is kind of the opposite of what we believe insurance should be. 
So there are things we can do.
    We can try to require more of the rebates to be paid to the 
patient at the point of care. You can probably, as a condition 
of contracting, make it harder for intermediaries to be paid on 
the list price versus the net price, and that would discourage 
rebating because you would compress the spread between list and 
net.
    We worry about this in the context of I see the stacked 
rebates in the market as a potential impediment to the entry of 
biosimilars into the market. And to the extent that we want to 
promote biosimilar development and market entry, the rebates do 
form one impediment to market access.
    Senator Collins. Thank you.
    Thank you, Mr. Chairman. And thank you, Senator Moran.
    Senator Hoeven. Senator Tester.

                             GENERIC DRUGS

    Senator Tester. Thank you, Chairman Hoeven and Ranking 
Member, for having this hearing.
    Dr. Gottlieb, I want to echo Senator Collins' comments. I 
appreciate the work you have been doing, and I wish you the 
best moving forward. Hopefully you can keep it up.
    I want to talk about generic drugs because when there are 
multiple generic drugs on the market, that competition helps 
the consumer. Your agency has the final say in what products 
can go on the shelf and which ones cannot. In the past the FDA 
has been slow to approve cheaper generic drugs. I think a 
little over a year ago, they had about 4,000 generic drug 
applications that were waiting for approval.
    In the justification for your budget request, you said that 
the FDA has approved more generic drug applications this year 
than ever before. That is good news. I commend you on that.
    What I want to know is, with this budget request, are you 
asking for the resources to be able to keep up with the rate 
for generic drug approvals?
    Dr. Gottlieb. Thank you for the question, Senator.
    We have almost fully eliminated that backlog. Last year, as 
you noted, we approved over 1,000 generic drugs, which was a 
record for the agency, and we hope to best that record this 
year.
    The budget request that we are asking for with respect to 
the new initiative--the resources that would go towards the 
generic drug approval process we think can fundamentally 
transform that process by moving towards an application process 
that would be much more seamless and lower cost for the generic 
manufacturers. It would allow us to do assessments more quickly 
and give feedback on the quality of the application right up 
front so we can reduce what we call cycling.
    One of the reasons why the generic drug review process is 
longer than it ought to be and we want to get review times down 
is not because it takes us a long time to review the 
application, but the applications undergo multiple cycles of 
review. We have to go back to the sponsor and request more 
information. They resubmit the application. It undergoes 
another review cycle.
    We had a very similar problem and I will close here, but we 
had a very similar problem with respect to our new drug review 
process. When I was last at the agency 10 years ago, we made a 
deliberate effort to reduce the multiple cycles of review. We 
were successful in doing that. Now we are making a concerted 
effort to do the same thing on the generic drug side.
    Senator Tester. Doctor, what is the backlog right now?
    Dr. Gottlieb. I believe we might have fully eliminated the 
backlog. I can get you exact details on that.
    [The information follows:]

    Currently at FDA, there is a healthy generic drug pipeline assuring 
the continued expansion of the generic drug program and continuing 
access to high quality, affordable generic drugs for the American 
public.
    The Generic Drug User Fee Amendments (GDUFA) authorized the 
collection of additional funds for FDA to review generic drug 
applications, inspect facilities, and perform other regulatory actions. 
Under GDUFA, by the end of fiscal year 2017, FDA would take regulatory 
action on 90 percent of the applications that were submitted to the 
agency prior to the start of GDUFA, once referred to as the backlog. 
Taking regulatory action meant FDA was expected to review these 
applications and provide a response to the applicant in the form of an 
approval, tentative approval, refuse-to-receive decision, or a complete 
response letter. In 2016, FDA reached that 90 percent milestone 
delivering on this commitment more than a year ahead of schedule--and 
ending any backlog.
    As of March 2018, there were 4,194 ANDAs submitted to the FDA that 
have not yet been approved. Of those, 391 ANDAs are in tentative 
approval status. Roughly half are under assessment at FDA within their 
GDUFA goal dates and roughly half have been returned to industry with 
details of deficiencies that must be addressed. The Office of Generic 
Drugs shares this information on FDA.gov in the ``Activities Report of 
the Generic Drugs Program (fiscal year 2018)--GDUFA II Quarterly 
Performance.''
    It is one of FDA's highest priorities to encourage generic drug 
development to foster drug competition, and we want to keep that 
generic pipeline strong. In January 2018, the Agency issued a draft 
guidance for industry on ``Good ANDA Submission Practices,'' to help 
reduce the number of review cycles by helping applicants avoid the 
common deficiencies that lead to review delays. The Agency is committed 
to processing and assessing applications at these record levels.

    Senator Tester. That would be good.
    You just have to help me out here. A little over a year 
ago, there was a 4,000 generic drug application backlog. You 
approved 1,000 and you are caught up. What happened to the 
other 3,000?
    Dr. Gottlieb. I do not believe that the backlog was 4,000, 
but I can get you precise numbers on that, Senator. But the 
1,000 that we approved are new applications.
    Senator Tester. I guess the question is that of those 
applications, did any of them drop off the list, or do they 
stay there as a backlog?
    Dr. Gottlieb. I would have to come back to you and tell you 
what the backlog is, but it is substantially worked off.
    Senator Tester. And so can you give me any idea how long it 
takes right now from the time they come in and ask for generic 
approval, assuming everything goes fine?
    Dr. Gottlieb. We have committed that applications coming in 
that meet certain requirements we are going to review in 8 or 
10 months on the initial review.
    I will tell you, though, the one thing to keep in mind is 
that there is always going to be a certain number of 
applications that are with the agency because there are so many 
applications filed with the agency.
    Senator Tester. I have talked to many doctors that say, you 
know, generics come along, they do a good job. Somebody will 
buy up this generic. They will tweak it a little bit and jack 
the price through the roof. Do you have control over that? They 
will buy a generic. They will change it but really not enough 
to do any more than just say we have changed it.
    Dr. Gottlieb. Typically, so if you are talking about 
someone who might take a short-acting drug and turn it into a 
longer-acting formulation or reformulate it where it can be 
delivered through another route of delivery--typically we would 
not forestall that kind of incremental innovation. I think it 
is really incumbent upon the market to decide whether or not 
they want to pay for it.
    Senator Tester. I know but if that drug is not there 
anymore, if that prescription drug is not there anymore because 
they have changed it a little bit and pulled it off, and now it 
is basically the same drug with a minor modification--I do not 
know. I am not a chemist. So if I am not correct on this, you 
will have to tell me. But they modify it very minor and then 
jack the prices up because it is no longer the generic that was 
approved by you.
    Dr. Gottlieb. If the initial generic--so you are spot on. 
But if the initial generic drug was not withdrawn for safety 
reasons----
    Senator Tester. Yes.
    Dr. Gottlieb. Then that Reference Listed Drug (RLD), still 
exists and another generic company could come in and develop a 
generic copy to the original formulation.

                          DRUG RE-IMPORTATION

    Senator Tester. Okay. That is fine.
    I just want to talk just very briefly on re-importation 
because people think this is a panacea. And I have bought drugs 
for my kid when I was in Mexico when he could not breathe. 
Okay? And it was great. They were cheap.
    But there have been reports of counterfeit drugs coming 
into this country. I think a $34 million fine was levied on an 
outfit out of Canada that was exporting to us drugs that were 
not what they said they were.
    Do you have the capacity to be able to determine, if we 
were to go down that re-importation line or importation line, 
whichever, to have the capacity--how many people would that 
take to make sure that somebody who is taking insulin actually 
has insulin?
    Dr. Gottlieb. We have not costed it out recently. We would 
have to put in place a substantial regulatory architecture to 
provide anything that would approximate the level of assurance 
that we can currently provide with the closed pharmaceutical 
system. And it would still create, arguably, gaps.
    Senator Tester. Okay. Thank you.
    Senator Hoeven. Senator Moran.
    Senator Moran. Mr. Chairman, thank you.

                     ONCOLOGY CENTERS OF EXCELLENCE

    Dr. Gottlieb, thank you for your presence here. I would 
join my colleague, Senator Collins, in complimenting you. I 
appreciate the efforts that you make responding and keeping me 
and others informed. And I just want to express my gratitude 
for that being the case. You do your job as it should be done.
    I indicated to you and I wanted to indicate publicly that 
my association of NCI centers, National Cancer Institute 
Centers, was in my office this morning and they too were 
complimenting you and FDA in regard to the Oncology Centers of 
Excellence that we funded in the omnibus bill and how well they 
are working in the battle against cancer and the efforts that 
are occurring at FDA. It caused us to have a conversation about 
the importance of NIH and FDA's collaboration and efforts in 
the battle to rid us of diseases. And so I want to continue my 
efforts in regard to NIH, but I also want to be very helpful to 
the folks at FDA.

                             DIETARY FIBER

    I could not have a conversation without mentioning the 
issue of dietary fibers. The first time I met you we had this 
conversation and subsequently in every conversation. You were 
in my office recently and explained kind of the status of where 
this issue is. I would guess if I ask you the question. When 
can we expect a rule delaying the compliance deadline to be 
finalized? You would tell me soon. Would you tell me anything 
else?
    Dr. Gottlieb. I can tell you very soon.
    [Laughter.]
    Senator Moran. Proving my point about how good you are, but 
not necessarily how responsive you are.
    In that regard, you told me that there could be two 
tranches of decisions made in regard to specific applications. 
Am I saying that somewhat fairly?
    Dr. Gottlieb. That is right, Senator. So, as you know, the 
initial rule identified seven fibers that met the definition of 
dietary fiber, and then we received citizen petitions from 12 
additional petitioners to try to have their fibers elevated.
    FDA put out scientific guidance outlining how we are going 
to make decisions on those citizen petitions, and we put out 
some additional guidance to help petitioners understand how to 
approach the agency. We are going to ultimately make decisions 
on those citizen petitions again very soon. We will probably 
approve an initial tranche, and then there will be a period of 
time in which we will probably approve another tranche. What we 
are trying to do is work with as many of those sponsors as 
possible to get them over the line.
    Now that we have provided the scientific guidance and they 
understand how we make decisions, there might be cases where we 
want to go back to sponsors and help them develop some 
additional information if we believe we can get to yes, but 
they just need a little bit more information in to the agency 
to get over that line.
    So we have been in touch with all the petitioners. At this 
point, they should all have feedback where they stand, and the 
ones who need to do a little bit more work--we are trying to 
help them and work with them.
    Senator Moran. You explained that to me when you were in my 
office, and it made sense to me. It seemed like a common sense 
way of addressing this issue. After you left, the thought 
occurred to me that you need to make certain that those who are 
not accepted in the first tranche do not appear to be a de 
facto denial because there would be market consequences, I 
assume, as those they deal with would rush to those that were 
approved not knowing what is going to happen with the second 
tranche. So I think how you do that matters.
    Dr. Gottlieb. And we are going to be mindful in terms of 
how we message that. My concern here has been in part--and 
obviously, my concern is to get this right and make sure we do 
the right thing for consumers, but also that if there is a 
manufacturer who is close to being able to cross the line but 
needs a little bit more information, if we reject them, it 
could effectively forestall their opportunity to come back 
because you are right. Everyone is going to rush to the others. 
And so if I can work with that sponsor, who otherwise has a 
good product but was not sophisticated or did not know how to 
submit all the right information the first time, and try to 
help them get across the line, that is one of our goals here.
    Senator Moran. I am expressing support for your plan. I 
only add the caveat that there could be consequences to those 
that would be in a second tranche.
    Dr. Gottlieb. I appreciate that.

                      PARTIALLY HYDROGENATED OILS

    Senator Moran. Partially hydrogenated oils. Food 
manufacturers continue to work to remove partially hydrogenated 
oils from the marketplace. I understand some of the foods made 
with partially hydrogenated oils can have a shelf life of up to 
3 years or possibly longer.
    My question. There are a few more things I would frame this 
question, but as the clock runs--what is your plan in regard to 
foods that have a shelf life longer than the date in which you 
make a determination that they needed to be removed from the 
marketplace? I guess the question is, does the agency not 
consider it necessary for companies to recall products 
containing partially hydrogenated oils already in commerce on 
the date of the compliance date? Would they have to withdraw 
them that date or when they expire?
    Dr. Gottlieb. I would have to get back to you. I think the 
question relates to whether or not the agency is going to allow 
a de minimis level of PHOs to persist because most food 
manufacturers have reformulated to remove the partially 
hydrogenated oils.
    You know, what we do in this area I can tell you is going 
to be mindful that if food manufacturers do need to remove even 
de minimis levels and they have to contemplate reformulating 
their food, we would provide them sufficient time to do that 
and be mindful of the disruption issues and the costs of 
compliance here. I think that is what you are referring to.
    But I would have to get back to you specifically on whether 
or not there is someone still on the market past a point in 
which we would allow some level--how we would treat that.
    Senator Moran. If you would do so, that would be great.
    My final question is, Dr. Gottlieb, how do you define 
``very soon''?
    Dr. Gottlieb. Well, some of these decisions are outside my 
hands because we have to do this through rulemaking with OMB. 
It is not to pass the buck, but we are going to have an answer 
back within a matter of weeks and not months, Senator.
    Senator Hoeven. Just tell him somewhere between now and 
soon.
    [Laughter.]
    Senator Moran. Thank you for your help, Mr. Chairman.
    Senator Hoeven. Senator Udall.

                         ANTIBIOTIC RESISTANCE

    Senator Udall. Thank you, Mr. Chairman.
    Dr. Gottlieb, last month Congress lost Representative 
Slaughter, a dogged champion of efforts to combat antibiotic 
resistance. And I was proud to join another champion, Senator 
Feinstein, as the cosponsor of legislation both she and 
Representative Slaughter developed to reduce the overuse of 
antibiotics in agriculture that creates drug-resistant 
bacteria. The FDA's decision last year to end the use of 
medically important antibiotics for use in animal growth 
promotion was a good start to reducing overuse.
    But the agency can and must do more on this issue. We know 
that antibiotics are sometimes appropriate to ensure that 
animal health is maintained, but we need the right policies and 
data to make sure that we are using those drugs judiciously and 
using alternatives whenever possible. The FDA surveys species-
specific sales of antibiotics for use in animals but does not 
track why the antibiotics are being purchased and administered 
or their eventual use on the farm.
    To reduce antibiotic use, do we not need more data on why 
they are being used in the first place?
    Dr. Gottlieb. We could always benefit from more 
information. We do get some data on use on the farm already 
through the National Antimicrobial Resistance Monitoring 
System. USDA makes data available and collects and makes data 
available to us. But we can and will be doing more in this 
regard.
    And I had the opportunity to talk to Congresswoman 
Slaughter about our efforts here. We are going to be rolling 
out in the next couple of months our plan for what we will do 
to build on some of the good work that has already been done 
and looking at some additional steps we can take to make sure 
that there is judicious use of antibiotics in the farm setting.

               NATIONAL ANIMAL HEALTH MONITORING SYSTEMS

    Senator Udall. The USDA's National Animal Health Monitoring 
System has begun collecting voluntary on-farm data related to 
antibiotic use and resistance, and they will begin reporting 
this data later in the year.
    Do you agree with me that this is potentially a vital 
source of information that will help inform both public health 
stakeholders and the growers themselves about when antibiotics 
are working or not working, what resistance they may engender, 
and when it may be advantageous to consider antibiotic 
alternatives that may actually work better in a given 
situation?
    Dr. Gottlieb. You know, I do agree with you, Senator. That 
was the data I was referring to that USDA is collecting. That 
is the species-specific data on use on the farm. You know, more 
data is helpful certainly, and this information in particular 
is going to help us target our policies.
    Senator Udall. And I realize this is a cross-agency effort. 
Can I get your commitment to work with the USDA and other 
agencies to address the urgent issue of antibiotic resistance?
    Dr. Gottlieb. We work very closely with them. I meet 
personally with Secretary Perdue on a monthly basis. We have 
set up those meetings. We have an interagency working group, 
and we talk quite regularly. The relationship has been very 
strong and collaborative.

                              E-CIGARETTES

    Senator Udall. That is great.
    The Ranking Member asked about the e-cigarettes but did not 
address the specific part of the toxic chemicals that are in 
there. The FDA has a responsibility to minimize harm to the 
public. Part of this duty is minimizing harmful exposure to 
toxic chemicals emitted from e-cigarettes.
    Under your leadership, will the FDA pursue product 
standards to set safe thresholds for the level of toxic 
chemicals like formaldehyde used in e-cigarettes?
    Dr. Gottlieb. We are pursuing product standards in this 
regard, Senator. We are also actively contemplating what 
additional science we can do on our own right now to look at 
the toxicology associated with e-cigarettes. We will be putting 
out a guidance document very soon that will outline how 
companies can evaluate toxicology in the setting of e-
cigarettes. In the event that a sponsor wanted to take one of 
these through the OTC route and get it approved as a new drug, 
they would have to do toxicology studies to satisfy the new 
drug approval requirements. And we are going to be putting out 
guidance outlining how they can do that. That is in some ways 
an attractive opportunity to all parties but particularly to 
the FDA because it does allow us to get very precise data 
around these issues.
    Senator Udall. Great. Thank you very much. Thanks for your 
answers. I will put my opioid question in for the record so 
Senator Baldwin can get her question in before the vote.
    Senator Hoeven. Thank you, Senator.
    Senator Baldwin.

                  STANDARDS OF IDENTITY DAIRY PRODUCTS

    Senator Baldwin. Thank you, Mr. Chairman and Ranking 
Member.
    Welcome back, Commissioner.
    I want to bring up a topic that you and I have talked about 
before. I am really concerned about the proliferation of 
mislabeled products in the marketplace that are using dairy's 
good name but have absolutely no dairy ingredients. These 
products are violating the Food and Drug Administration's 
existing regulations, and they are getting away with it because 
of inaction by the agency.
    It is a matter of fairness to the farmers and dairy 
producers and processors who I have worked with over many 
years. You know, they market their dairy products using dairy 
terms. Farmers must meet exacting standards for the content of 
the milk they deliver. The processors abide by specific 
requirements for things like butterfat content that ensure that 
when a consumer selects a certain dairy product, they know what 
they are getting and that it will perform in recipes as 
expected. Imitation products should not be able to use dairy's 
good name when they are doing none of the things required to 
use that label.
    Now, the omnibus legislation that we passed included yet 
another instance of congressional direction on this issue, and 
it is time for the FDA to act.
    So I first want to ask you what FDA is doing to enforce 
existing standards of identity for dairy products.
    Dr. Gottlieb. Well, I appreciate the question, Senator. I 
announced about 3 weeks ago that we will be issuing a request 
for information related to our overall approach to standards of 
identity. And we are committed to taking a fresh look about 
what we are doing here.
    You are right that milk is defined in the current standard 
of identity as being something from a lactating animal, and 
people have been using the term on things that are not derived 
from a lactating animal, as you and I will agree. But FDA 
having not stepped into this in the past, there is now a lot of 
commercial activity going on.
    I think what we are going to be looking in particular and 
where I would like to see information, to the extent people can 
contribute to our dialogue on this and inform us--you mentioned 
this is an issue of fairness. I would not dispute that. But it 
is also a question of public health from our standpoint, and if 
consumers are being confused and misled about the nutritional 
status or quality of milk because of the way certain products 
are being labeled, that is something we would want to take a 
look at, and that is something that would certainly inform the 
decisions we make here.
    So we will be issuing an RFI. That is an opportunity for us 
to collect information that could form the basis of regulatory 
action here.
    Senator Baldwin. So I just have to comment, and I view this 
as an urgent issue. This could be addressed right away if the 
FDA issued guidance to industry and declared its intent to 
enforce existing regulations.
    Do you agree that you have the authority to proceed based 
on your existing regulations?
    Dr. Gottlieb. I think that we would want to develop a 
careful administrative record here. Look, I am not a lawyer, 
but a lot of the physicians at FDA talk about the law, so I 
will take liberties here as well.
    We have exercised enforcement discretion for a period of 
time now that for us to reverse our current posture might take 
more than just issuing guidance. We might want to develop a 
careful administrative record informed by data. And that is the 
intent of the RFI, which is to collect information that can 
inform a substantial administrative record that would sustain 
review.
    Senator Baldwin. So I would say for the record that I do 
not believe that there needs to be further review or study. 
What we need is the FDA to act and issue guidance on 
enforcement of its existing dairy standards of identity.
    Our dairy farmers are in crisis right now. They are seeing 
very, very challenging times. The price of milk has been low 
for quite some time, the price that our farmers are paid. Some 
of the Farm Bill risk management tools that have been passed 
are not working the way we hoped they would, and I am sure we 
will all work together to adjust that. The trade negotiations 
that are going on right now have an impact and some uncertainty 
with regard to export markets for our dairy farmers. Canadian 
pricing of a certain class of milk is causing additional 
injury.
    I am not saying this is the problem in totality. What I am 
saying is that there is a perfect storm of challenges to the 
dairy industry right now in my State. And when I have to 
explain what the Dairy Pride Act is, that it is a measure--I 
just cannot tell you how absurd this sounds outside the 
beltway--that it is a measure to ask an agency that is not 
following its own rules and that could be solved if the agency 
simply follows its own rules.
    Dr. Gottlieb. Well, I will affirm to you, Senator that I 
have actively stepped into this issue. And I hear your 
concerns. I appreciate your concerns. We are taking a very 
close and fresh look at this.
    Senator Baldwin. Thank you.
    Senator Hoeven. Thank you, Senator.
    Again, Dr. Gottlieb, thank you for being here today.

                     ADDITIONAL COMMITTEE QUESTIONS

    For Members of the Subcommittee, any questions that you 
would like to submit for the hearing record should be turned in 
to Subcommittee staff within 1 week, which is Tuesday, May 1st, 
and we would appreciate it if we could have responses back from 
FDA within 4 weeks. Does that sound reasonable?
    Dr. Gottlieb. It sounds reasonable, looking at my staff.
    Senator Hoeven. They are all nodding yes. That is a good 
sign.
    Dr. Gottlieb. They are smiling yes. Thank you.
    Senator Hoeven. Thanks to them. And, Doc, thanks for being 
here. We appreciate it very much.
    Dr. Gottlieb. Thanks, Mr. Chairman.
               Questions Submitted by Senator John Hoeven
                             rare diseases
    Question. Mr. Commissioner, under your leadership the FDA has 
continued to embrace the 2012 directive from Congress that the FDA 
should follow the science in considering therapies for rare diseases 
with great unmet medical need under the accelerated approval pathway. 
You have publicly stated on a number of occasions that this pathway is 
particularly appropriate for therapies to treat rare diseases with no 
existing biomarkers or where the patient population is so small that a 
traditional large clinical trial may be infeasible.
    Is this still a pathway you believe is the appropriate--and often 
only--pathway for the FDA to review novel therapies for certain rare 
diseases?
    Answer. The accelerated approval pathway has been instrumental in 
addressing unmet medical needs for serious or life-threatening diseases 
or conditions, many of which are rare diseases. Between 2007 and 2017, 
FDA approved 52 drugs and biologics under accelerated approval. Of 
these, 37 were for orphan-designated drugs, i.e., for rare diseases. 
The Agency notes, however, that accelerated approval is not the only 
appropriate pathway for studying and approving drugs and biologics for 
rare diseases. In some cases, use of other approaches such as 
innovative study designs or statistical methods, or studies involving 
surrogate endpoints that have been shown to correlate with clinical 
benefit can enable the gathering of sufficient data to support 
traditional approval, even if the trials are conducted in very small 
populations.
    Furthermore, sponsors of therapies for rare diseases have 
frequently used FDA's expedited programs for serious conditions, 
including breakthrough therapy designation and regenerative medicine 
advanced therapy designation, to engage early with FDA reviewers to 
help design clinical development programs that are as efficient as 
possible.
    Question. Would you agree that under current law a product approved 
under the accelerated approval process has full FDA approval and not 
something less?
    Answer. For serious disorders, the accelerated approval pathway 
provides a means for developing drugs and biological products based on 
either a surrogate endpoint or an intermediate clinical endpoint that 
is reasonably likely to predict clinical benefit. Approval of a drug or 
biological product under the accelerated approval pathway meets the 
statutory standard for approval. A surrogate endpoint is a marker, such 
as a laboratory measurement, radiographic image, physical sign or other 
measure that is not itself a direct measure of clinical benefit. A 
surrogate endpoint that is ``reasonably likely to predict clinical 
benefit,'' may support accelerated approval. One example is accelerated 
approval of antimicrobial drugs based on the surrogate laboratory 
measure endpoint of reduction of bacteria in the blood stream, which is 
reasonably likely to predict the clinical resolution of the infection. 
An intermediate clinical endpoint is a clinical endpoint that can be 
measured earlier than irreversible morbidity or mortality (IMM) that is 
reasonably likely to predict an effect on IMM or other clinical 
benefit. For drugs and biological products granted accelerated 
approval, post marketing confirmatory trials have been required to 
verify and describe the anticipated effect on IMM or other clinical 
benefit. These post-marketing studies are known as phase 4 confirmatory 
trials. If the confirmatory trial does not show that the drug provides 
clinical benefit, the statute provides for a more streamlined process 
to withdraw approval of the drug (or specific indication that received 
accelerated approval).
    Question. Is there more the agency can do to clarify any existing 
confusion in the patient community about the full approval status of 
therapies approved under the accelerated approval pathway?
    Answer. As noted in response to a previous question, approval of a 
drug or biological product under the accelerated approval pathway meets 
the statutory standard for approval. It is anticipated that a report 
showing the status of all marketing applications approved under the 
accelerated approval pathway since the program's inception in 1992 will 
be available for posting on the FDA site soon. In addition, FDA's May 
2014 final guidance, Expedited Programs for Serious Conditions--Drugs 
and Biologics, is helpful in explaining the accelerated approval 
program and its relationship to traditional approval.
                     nutrition innovation strategy
    Question. I would appreciate it if you could provide additional 
background on your March 29th presentation regarding the Nutrition 
Innovation Strategy.
    Specifically, will the FDA frame Nutrition Innovation Strategy as a 
voluntary incentive for innovation, or should the industry expect it to 
be a second mass labeling mandate?
    Answer. The Nutrition Innovation Strategy is intended to take a 
fresh look at opportunities to better promote public health through 
efforts to empower consumers to make better and more informed decisions 
about their diets and health, foster the development of healthier food 
options, and expand the opportunities to use nutrition to reduce 
morbidity and mortality due to chronic disease. In addition, many 
companies have requested certain changes regarding food labeling and 
standards of identity to meet consumer demands. FDA also seeks to 
streamline its process for reviewing qualified health claims, which are 
voluntary claims submitted to FDA by industry. Throughout this effort, 
FDA will be mindful of opportunities that may exist to allow industry 
flexibility for innovation while maintaining the basic nature and 
nutritional integrity of food products. The Nutrition Innovation 
Strategy is in the early stages of development and stakeholder input, 
including from industry, will be essential to further explore how best 
to promote public health in the evolving food and beverage marketplace. 
This summer, FDA will hold a public meeting and open a docket in the 
Federal Register to gather stakeholder input to further inform the 
strategy.
    Question. With FDA's updates to the daily values used in food 
labeling to guide dietary choices, many manufacturers reformulated 
their foods to maintain existing label claims. And now the FDA will be 
changing the criteria to make those same claims.
    How can the FDA approach this in a more efficient and less cost-
intensive manner?
    Answer. FDA is not planning to update the Daily Values as part of 
the Nutrition Innovation Strategy, as these values were recently 
updated as part of the Nutrition Facts label rulemaking. As part of 
FDA's Nutrition Innovation Strategy, the Agency will develop a 
comprehensive plan to modernizing our approach to health claims to 
support industry initiatives already underway and encourage other 
companies to introduce products that meet the growing consumer demand 
for healthier products. For example, FDA is looking to streamline its 
process for reviewing qualified health claims it receives from industry 
to enhance the efficiency of the review process. In addition, to help 
minimize the economic impact of label changes, FDA periodically 
announces uniform compliance dates for new food labeling requirements 
where possible. FDA is at the beginning stages of this process and 
plans to have extensive stakeholder engagement to seek input and 
further explore how to best promote public health in the evolving food 
and beverage marketplace. Part of this public engagement includes 
holding a public meeting this summer and opening a docket in the 
Federal Register to gather stakeholder input to further inform the 
strategy.
    Question. The FDA has an ambitious list of work in this area--
nutrient content claims, health claims, and specific claims such as 
natural and healthy.
    What does the FDA intend to prioritize first amongst this list and 
how does this benefit the American people?
    Answer. Today, chronic diseases such as heart disease and cancer 
are the leading cause of death and disability in the United States. 
Nearly 1 in 3 adults in the United States have high blood pressure, a 
leading cause of heart disease and strokes. Almost 40 percent of U.S. 
adults are obese, and among children and adolescents, almost one in 
five are obese. Poor nutrition plays a role in these patterns of 
chronic and preventable disease. The FDA is committed to finding new 
ways to reduce the burden of chronic disease through improved 
nutrition.
    FDA is committed to finishing work on updating the Nutrition Facts 
label. The Agency has--and will continue--to publish technical 
documents on issues, such as serving sizes, to help manufacturers meet 
the requirements of the final Nutrition Facts label final rules. FDA 
has started working on updating the claim ``healthy'' and already 
solicited comment through a request for information and a public 
meeting in March 2017.
    FDA's new Nutrition Innovation Strategy will take a fresh look at 
what can be done to reduce preventable death and disease related to 
poor nutrition. The strategy is still in the early stages of 
development, but FDA has identified several areas where it believes 
there is opportunity to improve public health and facilitate industry 
innovation--claims on labels, information about ingredients in food, 
and standards of identity. Stakeholder input will be essential to 
further explore how best to promote public health in the evolving food 
and beverage marketplace. This summer, FDA will hold a public meeting 
and open a docket in the Federal Register to gather stakeholder input 
to further inform the Strategy.
                          cancer immunotherapy
    Question. I am very encouraged by recent breakthroughs in cancer 
immunotherapy and the FDA's recent approval of several new treatments 
that harness this approach to fighting cancer. More than 1,500 immuno-
oncology clinical trials are in some stage of development.
    Given the substantial clinical benefit and unique mechanisms of 
action reported for tumor immunotherapy across a large number of 
cancers, how is the FDA planning to continue its forward momentum in 
immuno-oncology drug development for patients with cancer?
    Answer. Cancer immunotherapies have demonstrated clinical benefit 
across many different types of cancer, despite different sites of 
origin, based upon their unique mechanisms of action. The first such 
approval was in May 2017 for pembrolizumab for use in MSI-high or 
mismatch repair deficient solid tumors that have progressed following 
prior treatment when there are no satisfactory alternate treatment 
options. In addition to such monoclonal antibody-based cancer 
immunotherapies, many personalized immunotherapies, including 
genetically-modified cellular therapies such as chimeric antigen 
receptor T-cells and other cellular therapies, intended for the 
treatment of cancer are either approved or in development. Those in 
development are eligible for a variety of programs intended to expedite 
their development and review, including fast track designation, 
breakthrough therapy designation, priority review, accelerated 
approval, and Regenerative Medicine Advanced Therapy (RMAT) 
designation, established under the 21st Century Cures Act.
    Information about these expedited programs, as well as 
considerations for the clinical development of regenerative medicine 
therapies, are addressed in a draft guidance on Expedited Programs for 
Regenerative Medicine Therapies for Serious Conditions, issued in 
November 2017, as part of our comprehensive regenerative medicine 
policy framework.\1\ In the draft guidance, FDA reiterates our 
commitment to working with sponsors of regenerative medicine therapies 
indicated for the treatment of cancer and encourages flexibility in 
clinical trial design. In addition, FDA recently issued six draft 
guidances related to manufacturing issues for the development of gene 
therapies. FDA believes that the issuance of these guidance documents 
will provide information to sponsors to help advance the development of 
immunotherapies. In addition, a recent guidance (Targeted Therapies in 
Low-Frequency Molecular Subsets of a Disease) provides FDA's thinking 
on the development of therapies that target uncommon specific molecular 
defects such as those that occur in cancers or genetic disorders. This 
approach is applicable to immunotherapies and other types of drugs. 
Additionally, FDA is continuing the forward momentum on site agnostic 
oncology drug development by actively engaging with stakeholders at 
professional society meetings and providing further insight on this 
drug development approach in a perspective article published in the New 
England Journal of Medicine.\2\
---------------------------------------------------------------------------
    \1\ Our guidance on Expedited Programs for Serious Conditions--
Drugs and Biologics, issued in May 2014, may also be helpful to 
sponsors for developing these and other drugs and biologics.
    \2\ Lemery S, Keegan P, and R Pazdur, 2017, First FDA Approval 
Agnostic of Cancer Site--When a Biomarker Defines the Indication, N 
Engl J Med, 377:1409-1412.
---------------------------------------------------------------------------
    Question. Specifically, how will the FDA address the need for 
updated clinical trial eligibility, alternative clinical and biomarker 
endpoints, innovative study designs and accelerated review programs?
    Answer. FDA has a variety of mechanisms available to expedite the 
development and review of anticancer agents, including fast track 
designation, breakthrough therapy designation, priority review, 
accelerated approval, and Regenerative Medicine Advanced Therapy (RMAT) 
designation, established under the 21st Century Cures Act.
    As specified in FD&C Act authority added by the 21st Century Cures 
Act, sponsors of products that have been granted RMAT designation are 
afforded early interactions to discuss any potential surrogate or 
intermediate endpoints to be used to support accelerated approval. 
Accelerated approval for development programs with RMAT designation can 
be based either on surrogate or intermediate endpoints that are 
reasonably likely to predict long-term clinical benefit, or reliance 
upon data obtained from a meaningful number of sites, including through 
expansion to additional sites.
    In FDA's draft guidance, Expedited Programs for Regenerative 
Medicine Therapies for Serious Conditions, issued in November 2017, FDA 
encourages flexibility in clinical trial design for regenerative 
medicine therapies, and describes that FDA will consider clinical 
trials that incorporate adaptive designs, enrichment strategies, or 
novel endpoints. The guidance also describes innovative trial designs 
for these products.
    FDA held a public meeting in April 2018 on Evaluating Inclusion and 
Exclusion Criteria in Clinical Trials, which included discussion of a 
variety of topics related to eligibility criteria in clinical trials 
and their potential impact on patient access to investigational drugs, 
and how to facilitate the enrollment of a diverse patient population. 
Additionally, FDA is working on multiple draft guidances related to 
efficient trial designs and clinical endpoints to expedite the 
development of drugs and biologics.
    In March 2018, FDA conducted a workshop on the use of complex 
innovative designs (CID) in clinical trials of drugs and biological 
products to inform regulatory decisionmaking. The Agency plans to use 
the information learned at this workshop to inform the development of a 
pilot program as well as a draft guidance document on the same topic.
    FDA's annual Accelerating Anticancer Agent Development and 
Validation (AAADV) workshop was developed to expedite the development 
and validation processes for new anticancer and cancer prevention 
agents. Likewise, FDA's qualification program for drug development 
tools, including biomarkers, can help support the use of biomarkers 
across drug and biologic development programs. This can help aid in 
optimizing drug development and evaluation, potentially expediting drug 
development and review of regulatory applications.
                               otc switch
    Question. The FDA has indicated in its FDA 2018 Strategic Policy 
Roadmap that it is working on new guidance and regulations that would 
change the way it approves novel Rx-to-OTC switches. We are hearing 
from industry that new and existing switch development programs are 
stalled and would benefit from the Agency's guidance and regulations in 
their efforts to provide consumer with a wider range of nonprescription 
products. As you know, switching Rx drugs to OTC can save patients and 
the healthcare system money while at the same time increasing treatment 
options.
    What is the Agency's timeline to release the guidance and 
regulations?
    Answer. The FDA expects to publish draft guidance on Innovative 
Approaches for Nonprescription Drug Products in calendar year 2018.
    The FDA also intends to publish a proposed rule on Nonprescription 
Drug Products with an Additional Condition for Nonprescription Use. 
This proposed rule is listed on the Spring 2018 Unified Agenda of 
Regulatory and Deregulatory Actions with a projected publication date 
in 2019.
                     foreign high risk inspections
    Question. Over the past several years the Committee has provided 
FDA with additional resources to develop a targeted, risk-based, and 
efficient inspection model for high-risk establishments for onsite 
verifications.
    Given the challenges of expanded geography, constantly expanding 
inventory of foreign exporters, and finite budgetary resources, how 
will FDA operationalize third party site verification services to 
select and prioritize FDA foreign facility inspection for the following 
primary FDA Centers: Center for Drug Evaluation and Research (CDER), 
Center for Devices and Radiological Health (CDRH), and Center for Food 
Safety and Applied Nutrition (CFSAN)?
    Answer. For several years, FDA has successfully leveraged third 
party services to support its foreign facility inspection program, and 
the Agency expects that it will continue to do this in the future. For 
example, in fiscal year 2016, FDA spent $5.51 million provided to 
Office of Global Regulatory Operations and Policy (GO) on commercial 
foreign onsite verification reviews in support of the expanding global 
coverage. FDA contracted with Dun and Bradstreet (D&B) to provide site 
verification information on specific facilities. D&B performed site 
verifications across all FDA's regulated commodities. The remaining 
funds were used in support of the pharmaceutical Good Manufacturing 
Practice (GMP) Mutual Recognition Initiative, enhancing the Center for 
Drug Evaluation and Research (CDER) Site Selection Model, and enhancing 
regulatory oversight of the foreign food inspection program in the 
Office of Regulatory Affairs (ORA).
    In fiscal year 2017, FDA spent $4.97 million. GO expanded the 
number of foreign onsite verifications and facility data provided by 
D&B for foreign medical device and food establishments. These specific 
commodities were chosen due to the value and impact that commercial 
onsite verifications provide these programs. For the pharmaceutical 
program, GO worked with CDER to issue grants for analysis that 
supported the development of quality scorecards for pharmaceutical 
facilities and products, which enhanced oversight by improving the Site 
Selection Model's identification of high-risk foreign facilities. For 
the foods program, GO worked with ORA to enhance the research and 
review of the inventory of high-risk facilities targeted for foreign 
inspections.
    In fiscal year 2018, FDA spent $4.50 million, as GO continued work 
with D&B to provide on-site verifications of foreign high-risk medical 
device and human food establishments. For the devices program, this 
work stream provided regulatory intelligence on complex supply chains, 
and business- to- business relationships. For the foods program, GO 
worked with ORA on the site verifications work in concert with a 
separate contract with a small-vendor to expand and validate data on 
high risk foreign facilities. Through these combined efforts, FDA 
improved the reliability of data for inspection planning, which allowed 
optimization of resource allocation and enhanced the Agency's oversight 
of foreign food firms. In the pharmaceutical program, GO worked with 
CDER to identify additional commercial services and sources for social 
and news media, such as Brand-Watch and LexisNexis, in an effort to 
increase the vitality of the Site-Selection and Risk Models and reveal 
signals about high-risk sites and products.
                                 ______
                                 
             Questions Submitted by Senator Mitch McConnell
    Question. I commend your July 2017 statement prioritizing harm 
reduction and committing to bring ``foundational rules'' to the tobacco 
regulatory process, which is long overdue and needed to provide greater 
certainty for the regulated industry. As the FDA moves forward to 
propose a substantial equivalence rule, what is the agency doing to 
ensure that the impending proposed rule reflects feedback from 
stakeholders? What steps are being taken to ensure the rule provides 
clarity on how FDA plans to regulate ``same characteristics'' and 
``questions of public health'' standards? Is it FDA's intent that this 
proposed rule will apply to all tobacco products, including so-called 
provisional products?
    Answer. FDA's comprehensive plan for tobacco and nicotine 
regulation will serve as a multi-year roadmap to better protect kids 
and significantly reduce tobacco-related disease and death. As part of 
this comprehensive plan, FDA announced that it will issue foundational 
rules to make the product review process more efficient, predictable, 
and transparent for manufacturers, while upholding the Agency's public 
health mission. Among other things, FDA intends to issue proposed 
regulations outlining what information the Agency expects to be 
included in Premarket Tobacco Product Applications (PMTAs) and 
Substantial Equivalence (SE) Reports.
    With respect to the proposed SE rule, the content has been informed 
by the Agency's experience reviewing thousands of SE reports, including 
questions and feedback received from applicants during the SE review 
process. Moreover, when the proposed rule issues, the Agency will 
solicit comments from the public on all aspects of the rule and will 
take all of the comments into consideration before issuing a final 
rule. Additionally, within the proposed SE Rule, FDA intends to pose 
questions to solicit specific comment on whether FDA should allow 
streamlined SE Reports for certain types or categories of 
modifications.
    The rule would establish requirements for SE Reports submitted 
after the effective date of the final regulation, not to those 
submitted earlier. In particular, this rule would provide greater 
clarity for industry on what information is required in these 
applications, while preserving flexibility for industry to determine 
their predicate, supporting data, and what type of application to 
submit.
    Question. As you know, the proposed regulation to limit the N-
nitrosonornicotine (NNN) levels found in smokeless tobacco products, 
which was proposed on the last day of the previous Administration, is 
of great concern to a number of my constituents who grow tobacco or 
work in tobacco manufacturing facilities in the Commonwealth. What is 
the FDA doing to ensure that any final regulation to limit NNN levels 
in smokeless tobacco products is both workable and technically 
achievable? Does the Agency have any plans to withdraw the proposed 
rule and replace it with a new regulation?
    Answer. The proposed rule would require that the mean level of NNN 
in any batch of finished smokeless tobacco products not exceed 1.0 
microgram per gram
(mg/g, 1 part per million) of tobacco (on a dry weight basis) at any 
time through the product's labeled expiration date as determined by 
product testing.
    FDA received almost 8,000 comments on the proposed rule from 
smokeless tobacco manufacturers, tobacco farmers, public health 
organizations, trade associations, academia, elected officials 
(Federal, state, local), Tribes, and individuals. The issues most 
frequently raised by commenters related to technical achievability, 
impact on tobacco growers, the effective date, and FDA's public health 
benefit analysis (``appropriate for the protection of public health''). 
FDA is currently reviewing and evaluating the comments to determine 
appropriate next steps.
                                 ______
                                 
               Questions Submitted by Senator Jerry Moran
    Question. I understand that FDA continues to work towards defining 
the term ``natural'' and regulating its use on food labeling after 
receiving public comments on a number of relevant questions. Can you 
please provide an update of FDA's ongoing work on this pre-rulemaking 
initiative?
    Answer. In late 2015, FDA sought feedback from consumers and the 
industry on whether FDA should define the word ``natural'' on food 
labeling (80 FR 69905). FDA received and reviewed more than 7,600 
comments. FDA recognizes that consumers are trusting in products 
labeled as ``natural'' without clarity around the term. Just like other 
claims made on products regulated by FDA, the Agency believes the 
``natural'' claim must be true and based on science. At the same time, 
FDA recognizes that there are widespread differences in beliefs 
regarding what criteria should apply for products termed ``natural,'' 
and that many of those criteria may not be based on public health 
considerations. This makes it quite challenging for FDA, which is first 
and foremost a public health agency. FDA will have more to say on the 
issue soon.
    Question. Despite the FDA's recent actions to solicit and review 
information on premium cigars and ultimately consider changing how it 
regulates the product, several current or pending requirements for 
premium cigar products remain in place. This includes the August 
deadlines for costly warning labels on packaging and advertising. If 
FDA is currently in a process that may change its approach to the 
premium cigar category, why does it not delay or suspend these 
deadlines and requirements until it ultimately comes to a final 
decision?
    Answer. Due to the continued interest in the regulation of 
``premium cigars,'' FDA issued an Advance Notice of Proposed Rulemaking 
on March 26, 2018, to provide an opportunity for the public to provide 
new information for the Agency to consider. In particular, FDA is 
seeking comments and scientific data related to how to define a 
``premium'' cigar and the patterns of use and resulting public health 
impacts from these products. The Agency will explore any new and 
different questions raised and consider additional data that is 
relevant to the regulatory status of premium cigars.
    In the meantime, all cigars remain subject to regulation based on 
FDA's previous determination that there was no appropriate public 
health justification to exempt ``premium'' cigars.
    The deeming rule took effect on August 8, 2016. Cigar label 
rotational warning plans were initially due to the Agency on May 10, 
2017. The Agency provided a compliance period of three additional 
months to provide industry time to come into compliance with the cigar 
warning label requirements. More than 300 companies are working toward 
complying with the August compliance date and have already submitted 
cigar warning label rotational plans to the FDA, all of which were 
reviewed by the Agency. Of the more than 300 cigar warning plans 
submitted to the Agency, almost all of them were approved.
    Question. The SBA's Office of Advocacy found fault with the FDA's 
prior rule-making on premium cigars for the FDA's failure to properly 
conduct an economic analysis on the impact of the rule on small 
businesses. What is your plan to make sure you have performed the 
necessary analysis?
    Answer. In the preamble to the proposed deeming rule, FDA sought 
comment on two options regarding the categories of cigars that would be 
covered by this rule-specifically, whether all cigars should be subject 
to deeming or if ``premium'' cigars should be excluded from deeming. 
FDA sought those comments because while the Agency recognized that all 
cigars are harmful and potentially addictive, it had been suggested 
that different kinds of cigars may have the potential for varying 
effects on public health.
    FDA carefully reviewed comments, data, and information submitted to 
the docket, including many comments from cigar users and the cigar 
industry, and concluded in the final deeming rule that deeming all 
cigars, rather than a subset, more completely protects the public 
health. Ultimately, FDA concluded that all cigars pose serious negative 
health risks, the available evidence does not provide a basis for FDA 
to conclude that the patterns of ``premium'' cigar use sufficiently 
reduce the health risks to warrant exclusion, and ``premium'' cigars 
are used by youth and young adults. FDA examined the impacts of the 
final rule, including considering the economic implications of the 
final rule for small entities and analyzing regulatory options that 
would minimize any significant impact of the rule on small entities.
    More recently, as part of the Agency's comprehensive plan for 
regulation of nicotine and tobacco, FDA stated that it would solicit 
additional comments and scientific data related to the patterns of use 
and resulting public health impacts from ``premium'' cigars and 
consider the appropriate regulatory status of ``premium'' cigars. FDA 
published an Advance Notice of Proposed Rulemaking (ANPRM) on March 26, 
2018, requesting relevant new and different information, data, and 
analysis not submitted in response to FDA's proposed deeming rule, on 
topics including, but not limited to patterns of use associated with 
``premium cigars'' generally and among youth and young adults 
specifically, public health considerations associated with ``premium 
cigars,'' and the definition of ``premium'' cigars. On June 8, 2018, 
FDA extended the comment period, and the comment period for this ANPRM 
closes on July 25, 2018. The ANPRM does not propose a specific 
regulatory action. FDA will consider the submissions, which may inform 
regulatory actions FDA might take with respect to ``premium'' cigars. A 
future regulatory action would comply with any applicable requirements 
to conduct an economic analysis.
    Question. With the Advance Notice of Proposed Rulemaking process 
underway--why does the agency continue to enforce costly requirements 
on premium cigars when it may amend how regulates the category? Are 
there steps that can be taken through enforcement discretion or 
otherwise to minimize these burdens while the FDA's review process 
takes place?
    Answer. In the preamble to the proposed deeming rule, FDA sought 
comment on two options regarding the categories of cigars that would be 
covered by this rule-specifically, whether all cigars should be subject 
to deeming or if only those cigars not considered ``premium'' should be 
subject to deeming. FDA sought those comments because it had been 
suggested that different kinds of cigars may have the potential for 
varying effects on public health.
    FDA carefully reviewed all comments, data, and information 
submitted to the docket, including many comments from cigar users and 
the cigar industry, and concluded in the final deeming rule that 
regulating all cigars, rather than a subset, more completely protects 
the public health. Ultimately, FDA concluded that all cigars pose 
serious negative health risks.
    Due to the continued interest in the regulation of ``premium 
cigars,'' on March 26, 2018, FDA issued an Advance Notice of Proposed 
Rulemaking to provide an opportunity for the public to provide new 
information for the Agency to consider. In particular, FDA is seeking 
comments and scientific data related to how to define a ``premium'' 
cigar and the patterns of use and resulting public health impacts from 
these products. The Agency will explore any new and different questions 
raised and consider additional data that is relevant to the regulatory 
status of premium cigars.
    In the meantime, all cigars remain subject to regulation based on 
FDA's previous determination that there was no appropriate public 
health justification to exempt ``premium'' cigars.
                                 ______
                                 
             Question Submitted by Senator Cindy Hyde-Smith
    Question. Commissioner Gottlieb, I am pleased that the FDA Office 
of the Chief Scientist has been working with the University of 
Mississippi Medical Center to explore ways to incorporate physiological 
modeling into the FDA's regulatory process for medical products. Can 
you please provide me with an update on that work? Is the FDA working 
to finalize an affiliation agreement with an academic institution like 
UMMC for this purpose?
    Answer. Regulatory evaluation of modeling and simulation is 
advancing alongside the power and sophistication of the tools. 
Therefore, FDA formed an Agency-wide working group on modeling and 
simulation under the auspices of the Office of the Chief Scientist with 
objectives that include aligning regulatory decisionmaking with 
modeling and simulation and, where appropriate, employing in silico 
clinical trials. Completing these objectives will advance the in silico 
clinical trial framework for the medical product Centers and will 
establish the appropriate methods and guidelines necessary to implement 
in silico clinical trials. Scientists within FDA, particularly those 
leading the Modeling and Simulation Working Group, have had numerous 
interactions with UMMC over the last year and are working to formalize 
a research collaboration. FDA intends to continue advancing these 
methodologies and techniques from both a scientific and regulatory 
perspective to best take advantage of their benefits for continued 
product innovation and more rapid introduction of life saving 
technology to U.S. patients.
                                 ______
                                 
              Questions Submitted by Senator Jeff Merkley
                         overall budget request
    Question. The overall budget request for FDA is more than $400 
million for a significant number of new investments. Can you please 
prioritize those requests?
    Answer. The President's proposed fiscal year 2019 Budget includes 
$400 million for initiatives aimed at supporting new and ongoing 
efforts to foster more investment and innovation in the development of 
therapeutics and diagnostics that target unmet medical needs; advance 
drug and device competition; stand up new domestic industries--such as 
pharmacy outsourcing facilities; and create more modern, domestically-
based manufacturing, including continuous manufacturing of drugs and 
biological products, including vaccines. These manufacturing platforms 
can bring more businesses back to the U.S., help lower drug and device 
development costs, and reduce the risk of shortages. Investing in these 
initiatives will help the FDA advance goals that we all share: improved 
treatment and diagnostic options for patients; lower healthcare costs; 
the development of new industries that will lead to U.S.-based jobs; 
and manufacturing advances that are more reliable, lower cost, and high 
quality.
    As the Agency that regulates $2.4 trillion of consumer products, 
FDA can think of no better place to make an impact. While each of the 
proposed fiscal year 2019 initiatives are important, FDA would 
highlight those that the Agency believes could be the most 
fundamentally transformational for FDA:

        Continuous Manufacturing.--The President's fiscal year 2019 
        Budget Request for FDA includes $58.2 million to promote 
        domestic manufacturing, including continuous manufacturing. 
        These technologies have great potential to accelerate new, more 
        targeted therapies, enhance product quality, and bolster 
        stability in the U.S. drug supply to meet domestic and global 
        needs. These new manufacturing platforms may be especially 
        important in the development of personalized medicines and 
        innovations in cell- and gene-based therapies and vaccines.

        New Medical Data Enterprise.--The fiscal year 2019 Budget 
        request includes $100 million to advance the use of real-world 
        experience to better inform patient care and provide more 
        efficient, robust, and potentially lower-cost ways to develop 
        clinical data that can inform product review and promote 
        innovation. Expanding FDA's capacity to utilize real-world 
        evidence to evaluate the pre- and post-market safety and 
        effectiveness of medical products will generate processes that 
        could improve the efficiency of the regulatory process, better 
        inform patients and providers about pre-and post-market safety, 
        reduce some of the burdens that drive up the time and cost 
        required to bring beneficial innovations to the market, and 
        address barriers that can make certain important safety and 
        effectiveness information around the real-world use of products 
        hard to collect and evaluate.

        Knowledge Management System for New Drug Development.--The 
        fiscal year 2019 budget request includes $57.5 million to build 
        a knowledge management system and portal to existing and 
        developing information on drug development and previous 
        regulatory decisions. This platform would enable FDA to store 
        and manage the collective experience of our medical review 
        staff to identify how decisions are made across different 
        functions, the scientific precedents established in the course 
        of the review process, and the knowledge FDA has developed.
    Question. Are they scaleable?
    Answer. Yes, these projects are scaleable.
                          cancer immunotherapy
    Question. Given the substantial clinical benefit and unique 
mechanisms of action reported for tumor immunotherapy across a large 
number of cancers, how is the FDA planning to continue its forward 
momentum in immuno-oncology drug development for patients with cancer?
    Answer. Cancer immunotherapies have demonstrated clinical benefit 
across many different types of cancer, despite different sites of 
origin, based upon their unique mechanisms of action. The first such 
approval was in May 2017 for pembrolizumab for use in MSI-high or 
mismatch repair deficient solid tumors that have progressed following 
prior treatment when there are no satisfactory alternate treatment 
options. In addition to such monoclonal antibody-based cancer 
immunotherapies, many personalized immunotherapies, including 
genetically-modified cellular therapies such as chimeric antigen 
receptor T-cells and other cellular therapies, intended for the 
treatment of cancer are either approved or in development. Those in 
development are eligible for a variety of programs intended to expedite 
their development and review, including fast track designation, 
breakthrough therapy designation, priority review, accelerated 
approval, and Regenerative Medicine Advanced Therapy (RMAT) 
designation, established under the 21st Century Cures Act.
    Information about these expedited programs, as well as 
considerations for the clinical development of regenerative medicine 
therapies, are addressed in a draft guidance on Expedited Programs for 
Regenerative Medicine Therapies for Serious Conditions, issued in 
November 2017, as part of our comprehensive regenerative medicine 
policy framework.\1\ In the draft guidance, FDA reiterates our 
commitment to working with sponsors of regenerative medicine therapies 
indicated for the treatment of cancer and encourages flexibility in 
clinical trial design. In addition, FDA recently issued six draft 
guidances related to manufacturing issues for the development of gene 
therapies. FDA believes that the issuance of these guidance documents 
will provide information to sponsors to help advance the development of 
immunotherapies. In addition, a recent guidance (Targeted Therapies in 
Low-Frequency Molecular Subsets of a Disease) provides FDA's thinking 
on the development of therapies that target uncommon specific molecular 
defects such as those that occur in cancers or genetic disorders. This 
approach is applicable to immunotherapies and other types of drugs. 
Additionally, FDA is continuing the forward momentum on site agnostic 
oncology drug development by actively engaging with stakeholders at 
professional society meetings and providing further insight on this 
drug development approach in a perspective article published in the 
``New England Journal of Medicine''.\2\
---------------------------------------------------------------------------
    \1\ Our guidance on Expedited Programs for Serious Conditions--
Drugs and Biologics, issued in May 2014, may also be helpful to 
sponsors for developing these and other drugs and biologics.
    \2\ Lemery S, Keegan P, and R Pazdur, 2017, First FDA Approval 
Agnostic of Cancer Site--When a Biomarker Defines the Indication, N 
Engl J Med, 377:1409-1412.
---------------------------------------------------------------------------
    Question. Specifically, how will the FDA address the need for 
updated clinical trial eligibility, alternative clinical and biomarker 
endpoints, innovative study designs and accelerated review programs?
    Answer. FDA has a variety of mechanisms available to expedite the 
development and review of anticancer agents, including fast track 
designation, breakthrough therapy designation, priority review, 
accelerated approval, and Regenerative Medicine Advanced Therapy (RMAT) 
designation established under the 21st Century Cures Act.
    As specified in FD&C Act authority added by the 21st Century Cures 
Act, sponsors of products that have been granted RMAT designation are 
afforded early interactions to discuss any potential surrogate or 
intermediate endpoints to be used to support accelerated approval. 
Accelerated approval for development programs with RMAT designation can 
be based either on surrogate or intermediate endpoints that are 
reasonably likely to predict long-term clinical benefit, or reliance 
upon data obtained from a meaningful number of sites, including through 
expansion to additional sites.
    In FDA's draft guidance, Expedited Programs for Regenerative 
Medicine Therapies for Serious Conditions, issued in November 2017, FDA 
encourages flexibility in clinical trial design for regenerative 
medicine therapies, and describes that FDA will consider clinical 
trials that incorporate adaptive designs, enrichment strategies, or 
novel endpoints. The guidance also describes innovative trial designs 
for these products.
    FDA held a public meeting in April 2018 on Evaluating Inclusion and 
Exclusion Criteria in Clinical Trials, which included discussion of a 
variety of topics related to eligibility criteria in clinical trials 
and their potential impact on patient access to investigational drugs, 
and how to facilitate the enrollment of a diverse patient population. 
Additionally, FDA is working on multiple draft guidances related to 
efficient trial designs and clinical endpoints to expedite the 
development of drugs and biologics.
    In March 2018, FDA conducted a workshop on the use of complex 
innovative designs (CID) in clinical trials of drugs and biological 
products to inform regulatory decisionmaking. The Agency plans to use 
the information learned at this workshop to inform the development of a 
pilot program as well as a draft guidance document on the same topic.
    FDA's annual Accelerating Anticancer Agent Development and 
Validation (AAADV) workshop was developed to expedite the development 
and validation processes for new anticancer and cancer prevention 
agents. Likewise, FDA's qualification program for drug development 
tools, including biomarkers, can help support the use of biomarkers 
across drug and biologic development programs. This can help aid in 
optimizing drug development and evaluation, potentially expediting drug 
development and review of regulatory applications.
                              added sugars
    Question. On the issue of added sugars, FDA's most recent 
suggestion to allow honey and maple syrup industry to label jars of 
pure honey or maple syrup as having ``added sugars'' with an asterisk 
and explaining text, has been described as further confusing the issue, 
and ultimately not helpful to consumers.
    Can you please provide an update on FDA's most recent and planned 
actions to ensure clarity for consumers that pure honey and maple syrup 
do not have any added sugars?
    Answer. FDA is sensitive to the honey and maple syrup industries' 
concerns regarding the declaration of added sugars on single-ingredient 
products. On June 19, 2018, FDA announced that the Agency is taking 
another look at this issue following comments received from the public 
regarding FDA's original March 2, 2018, draft guidance titled ``The 
Declaration of Added Sugars on Honey, Maple Syrup, and Certain 
Cranberry Products.'' The feedback that FDA received is that the 
approach laid out in the draft guidance does not provide the clarity 
that the Agency intended. It is important to FDA that consumers are 
able to use the new Nutrition Facts label to make informed, healthy 
dietary choices. FDA looks forward to working with stakeholders to 
devise a sensible solution.
                        medical data enterprise
    Question. The budget includes a $100 million request to ``create a 
new medical data enterprise'', specifically conducting evidence 
evaluation, including electronic health records of at least 10 million 
individuals. What specifically are we buying with this money?
    Answer. The requested funding would pay for a number of cooperative 
agreements and contracts that enable FDA to advance active surveillance 
and more modern device, drug, and biologic product evaluation.
    The development of data infrastructure will be supported through 
continuation of existing and/or new cooperative agreements. Data 
infrastructure includes support for the maturation of Coordinated 
Registry Networks (CRNs) and other data sources. Technical developments 
include harmonization of minimum core data elements for a variety of 
clinical areas. Libraries of minimum core data elements are needed to 
ensure consistency and interoperability between health information 
systems, which contribute to consistency in how data are captured and 
analyzed throughout the learning healthcare ecosystem.
    In addition, the funding would continue support of technical 
developments in structured data capture and unstructured data 
generation and analysis. This work with the clinical entities that 
provide data to registries will improve the efficiency and accuracy of 
data collection from clinical care in general, minimize duplication of 
parallel data collection that exists today (one for clinical care and 
one for research). This investment could support many Federal efforts 
which rely on data collection.
    Another cooperative agreement would be for the purpose of 
implementation of active surveillance using Coordinated Registry 
Networks (CRNs) Community of Practice and other data sources. Active 
surveillance requires registries to have high-quality linkages with 
other data sources. The cooperative agreement would require the 
participating parties to develop and/or apply methodologies and tools 
(including but not limited to, DELTA software) to enable more effective 
distinction between the role of device, operator, and patient 
characteristics as part of outlier identification of potential safety 
issues.
    The requested funding would also support a cooperative agreement to 
continue work on unique device identifier (UDI) adoption in a variety 
of electronic data sources (e.g. electronic health records, registries, 
claims data). This work is needed to scale the evaluation of the impact 
of capturing UDI in electronic data sources on advancing device-
specific studies (e.g., to address device-specific questions in the 
real-world setting). Capturing UDI in these electronic data sources is 
critical for many device studies that would use those sources because 
the UDI provides precise identification of the device being evaluated. 
FDA regulations already require inclusion of a UDI on most device 
labels. Use of the UDI in electronic healthcare information (such as 
EHRs or registries) is an essential step for the development of the 
National Evaluation System for health Technology (NEST).
    In addition, the requested funding would be used to advance the 
development and use of mobile apps and related technologies for patient 
input. The growing use of mobile apps and related technologies provides 
opportunities to improve data collection. New methods for obtaining 
patient input and informed consent and for communication between study 
participants and study sponsors could reduce the time and cost of 
studying new medical products.
    This funding would also significantly expand the FDA Sentinel 
initiative, including the Center for Biologics Evaluation and Research 
(CBER) Biologics Effectiveness and Safety (BEST) system. BEST is 
administered through contracts and consists of a small number of 
electronic health record (EHR)-based healthcare providers and partners; 
the additional funding would enable us to fund contracts to bring more 
providers and tens of millions more patient EHR records into BEST. This 
will dramatically improve our data infrastructure and capabilities to 
gather and evaluate real-world data, especially for serious and rare 
adverse events, and improve our ability to meet our public health 
mission of ensuring the safety and effectiveness of vaccines, blood 
products and new advanced therapies. Biologic products differ from 
drugs and devices and have their own unique `big healthcare data' 
needs. For instance, while most drugs in large medical databases have 
their own product codes, most biologic products do not. Furthermore, 
biologics such as blood products have their own coding system which 
needs to be added to each provider system. These nuances and others 
challenge our ability to readily identify patient uses of blood, 
advanced therapeutics and some vaccines--so the funding would support 
needed, additional EHR data sources, millions of patients, development 
of new data models, inclusion of new data fields, new tools and methods 
to specifically address these challenges.
    Lastly, this increase request would also be used by the Center for 
Veterinary Medicine to expand surveillance by the National 
Antimicrobial Resistance Monitoring System (NARMS) by funding new and 
strengthening existing cooperative agreements and interagency 
agreements. This data will help provide a more complete picture of 
antimicrobial resistance and strengthen the basis for regulatory 
decisions to address this important public health challenge.
    Question. How do you ensure patient privacy is maintained when 
doing something like this?
    Answer. Patient privacy and data security are among the highest 
priorities for the medical data enterprise. Major sources of data (such 
as Sentinel, PCORNet, and Coordinated Registry Networks) are maintained 
behind each data owners firewall and personally identifiable 
information is not shared. Analysis of the data across data sources is 
accomplished through use of distributed analytics, where analysis is 
done behind the firewall and only aggregate, non-patient level data are 
shared. Under these procedures, data that can identify an individual 
patient are not shared. All aspects of the medical data enterprise 
advanced by FDA will: (1) build on the existing privacy and security 
processes/procedures established by existing data sources; (2) comply 
with the Common Rule, as applicable; and (3) promote development and 
testing of distributed analytics and other approaches designed to 
protect the privacy and security of patients.
    Question. In what ways could this investment result in lower priced 
drugs and medical devices?
    Answer. Production of evidence to support regulatory decisionmaking 
can be an expensive and time-consuming endeavor. The purpose of the new 
medical data enterprise is to decrease the time and cost of evidence 
generation and to serve as a resource that will be available for use 
not only by FDA but also by the device and pharmaceutical industries, 
academia, and other stakeholders. According to the Medical Device 
Innovation Consortium, the new medical data enterprise has already 
demonstrated ``faster, safer, more cost-effective'' evidence generation 
using real-world data sources. These efficiencies could lead to lower 
costs of medical products by reducing the amount of investment to be 
recovered through higher sales prices. In addition, the same systems 
being used to support regulatory decisionmaking could be used to 
evaluate the net benefit of medical products.
    Question. Are there precursors that show this type of investment 
works?
    Answer. Early investments in the foundations of the National 
Evaluation System for health Technology (NEST) and in prototype studies 
have already demonstrated a return on investment (ROI). CDRH has 
documented increasing numbers of regulatory decisions that use real-
world evidence with over 50 decisions since 2015. For instance, the 
Transcatheter Valve Therapy (TVT) coordinated registry network (CRN) 
has thus far supported 23 regulatory decisions and ensured evidence-
based evaluation of the application of TVT technology. Before the use 
of the TVT CRN, the U.S. was 42nd in the world in approval of this 
breakthrough lifesaving technology. It is now first in the world in 
approving the mitral valve-in-valve application, a new intended use for 
this device.
    Documentation of value created by the TVT CRN is based on ROI and 
time saved in conducting necessary regulatory studies. For both ROI and 
time saved analyses, studies were compared that used the TVT CRN with 
those that would have been required if the registry did not exist. The 
decisions based on use of the TVT CRN generated evidence for three TVT 
device manufacturers. The ROI was estimated to be greater than 400 
percent. Time saved by using the CRN ranged from months to years. The 
CRN method is one example of evidence generation that creates value for 
manufactures and the broader device ecosystem. Claims data have been 
linked to other registries to further augment their value in assessing 
evidence of longer-term device performance. For example, Vascular 
Quality Initiative (VQI) registry was linked to claims data to create 
the Vascular Implants Surveillance and Interventional Outcomes Network 
(VISION) and the American Joint Replacement Registry (AJRR) was linked 
to claims data to contribute to Orthopedic CRN.
            modernizing generic drug development and review
    Question. The budget request includes $38 million to modernize the 
way FDA reviews generic drugs.
If this funding is provided, what changes would generic drug 
        manufacturers see when interacting with FDA?
    Answer. With additional funding, FDA will create a new review 
platform--the Knowledge-aided Assessment & Structured Application 
(KASA) platform--to modernize generic drug review from a text-based to 
a data-based assessment. The KASA will enable a structured review that 
will make the application review process more efficient and allow 
deficiencies to be spotted earlier. This will allow the FDA to provide 
earlier feedback to generic drug applicants that will, in turn, help to 
reduce multiple cycles of application review, one of our key aims and a 
primary focus of our overall efforts to speed market access to new 
generic medicines. Going through multiple review cycles is one of the 
primary reasons why the approval of generic drug applications is 
sometimes delayed many years. We anticipate the new KASA system will 
promote consistent drug product evaluations, enhance the predictability 
of regulatory decisions and facilitate generic entry by reducing the 
number of review cycles that applications undergo, and, ultimately, 
allowing more generic applications to be approved after the first 
cycle.
    The new platform will also enable more efficient and robust 
knowledge management across different aspects of the FDA's review 
process, helping reviewers capture and manage all of the information 
about products allowing for more seamless and effective product 
surveillance based upon quality and risk. This system will benefit both 
the agency and generic drug sponsors by increasing overall speed and 
efficiency of the pre- and post-market processes.
    Having a structured template that replaces the current largely 
narrative-based review will allow for more consistent and predictable 
entry and analysis of data. Current assessments require manual review 
of the entire application. KASA will enable automated analysis of some 
portions of the application, which will save time, and ensure 
consistency.
    Question. Assuming that FDA received a complete application from a 
manufacturer, how much FDA review time could be saved by using this new 
system?
    Answer. The Knowledge-aided Assessment & Structured Application 
(KASA) platform will enable a structured review that will make the 
application review process more efficient and allow deficiencies to be 
spotted earlier. This will allow the FDA to provide earlier feedback to 
generic drug makers that will, in turn, help to reduce multiple cycles 
of application review, one of our key aims and a primary focus of our 
overall efforts to speed market access to new generic medicines. Going 
through multiple review cycles is one of the primary reasons why the 
approval of generic drug applications is sometimes delayed many years. 
We anticipate the new KASA system will promote consistent drug product 
evaluations, enhance the predictability of regulatory decisions and 
facilitate generic entry by reducing the number of review cycles that 
applications undergo, and, ultimately, allowing more generic 
applications to be approved after the first cycle.
    Question. How long would this system take to develop and implement?
    Answer. The first stage of KASA development could be 1-2 years 
away, and the last stage as much as 4-5 years.
    Drug pricing continues to be hindered by industry maneuvering to 
keep generic drugs off of the market, or to make it more difficult for 
them to develop their products.
    Question. What are the major issues regarding generic drugs and 
their entry to the marketplace as soon as legally possible?
    Answer. While FDA does not have a direct role in drug pricing, when 
more than one generic version of a drug is approved and marketed, it 
can spur competition and facilitate affordable options for consumers. 
Under the Drug Competition Action Plan, we continue to review our 
practices and policies to identify areas to facilitate generic drug 
market entry at the earliest possible date.
    The Drug Competition Action Plan addresses the major issues 
regarding generic drugs and their entry into the marketplace in the 
following ways:

  --Streamlining the generic drug review process to increase efficiency 
        and effectiveness, with the ultimate goal of more approvals. By 
        ensuring that regulatory requirements are streamlined, 
        predictable, and science-based, we can help reduce the time, 
        uncertainty, and cost of drug development.
  --Supporting development and enhancing review of complex generic drug 
        products, which have traditionally been more challenging and 
        can lack generic competition, through product development 
        meetings, pre-submission meetings, and mid-review cycle 
        meetings for applicants and prospective applicants of complex 
        generic drug products.
  --Reducing the ``gaming'' that delays generic drug approvals and 
        extends brand monopolies beyond what Congress intended. One 
        example of such gaming is the increasing unavailability of 
        certain branded products for comparative testing. We also see 
        problems accessing testing samples when branded products are 
        subject to limited distribution.

    Question. We note that there are other factors that inform when a 
generic drug product enters the market after FDA's approval, including 
a generic drug sponsor's decision not to market the product due to 
business reasons, or as a result of a settlement with the brand company 
in a related patent litigation.
    How can Congress be helpful, both with funding and legislative 
needs?
    Answer. The Agency is continuously reviewing its authorities and 
regulations to ensure that we have the tools necessary to facilitate 
generic competition. We appreciate your attention to these very 
important issues, and we welcome the opportunity to work with Congress 
and provide feedback on any proposals you and your colleagues may have.
                                 ______
                                 
            Questions Submitted by Senator Dianne Feinstein
                              food safety
    Question. Over the last several months, there have been alarming 
reports of romaine lettuce contaminated with E. coli that has led to 
illnesses and even deaths throughout the United States.
    The Centers for Disease Control estimates that each year, 48 
million people get sick from a foodborne illness, 128,000 are 
hospitalized, and 3,000 die. In response to the likelihood that 
foodborne illness will continue to be a major public health concern, 
Congress passed the Food Safety Modernization Act (FSMA) in 2011. Since 
enactment, Congress has provided additional budget authority to support 
FSMA implementation, including for coordination and outreach with a 
wide cross-section of stakeholders, public health and consumer 
representatives as well as members of the agricultural and processed 
foods industries.
    In order to protect the public's health, strengthen consumer 
confidence in American food products, and ensure this law is fully 
implemented, it is necessary that FDA has the resources it needs. But 
in the fiscal year 2019 budget request, the agency didn't include 
significant increases to continue FSMA implementation.
    Can you provide a detailed justification for why the FDA believes 
the requested funding level is sufficient to continue full 
implementation of the Food Safety Modernization Act?
    Answer. FDA appreciates Congress's support of its FSMA 
implementation efforts. As of fiscal year 2018, FDA has received 
approximately $327 million in funding to directly support 
implementation.
    FDA has dedicated a substantial portion of these resources to 
ensuring industry has tools to properly prepare for implementation of 
the seven foundational FSMA rules and has supported state partners in 
preparing for FSMA implementation. The Agency has made significant 
progress in these efforts, including the following:

  --Established and funded public-private alliances to provide training 
        for the Preventive Controls for Human Food (PCHF) and 
        Preventive Controls for Animal Food (PCAF) rules, as well as 
        jointly funding with the U.S. Department of Agriculture (USDA) 
        produce safety and sprouts alliances to offer training on the 
        Produce Safety Rule (PSR).
  --Provided multi-year funding for state agencies (including funding 
        43 states in fiscal year 2018) to develop programs for helping 
        to implement the PSR, including outreach and education to meet 
        the specific and unique needs of their farmers and growing 
        communities.
  --Established a Produce Safety Network of FDA experts, located 
        throughout the country, to provide technical assistance and 
        outreach to industry and state partners.
  --Issued draft guidances on the PCHF, PCAF, and Foreign Supplier 
        Verification Programs (FSVP) rules to assist industry in 
        meeting FSMA requirements.
  --Released an online Food Safety Plan Builder to help industry create 
        the food safety plans that are a cornerstone of the PCHF rule.
  --Issued a Current Good Manufacturing Practice (CGMP) draft guidance 
        to help industry understand and comply with relevant provisions 
        of the PCAF rule.
  --Issued draft guidances to assist industry in meeting certain supply 
        chain requirements of the PCHF and FSVP rules.
  --Initiated and continue to conduct inspectional activities under the 
        modernized CGMP provisions for both human and animal food, 
        PCHF, and FSVP.

    Question. The President's fiscal year 2019 Budget allows the Agency 
to maintain the progress FDA has achieved. The Agency will continue to 
provide tools for successful FSMA implementation and, as always, FDA 
will leverage available resources for maximum impact to achieve its 
public health goals.How is FDA coordinating with states to ensure that 
farmers are able to understand and comply with the regulations that FDA 
has issued pursuant to FSMA?
    Answer. Since FSMA was passed in fiscal year 2011, FDA has devoted 
significant resources to collaborations with public and private 
partners in state, Federal, tribal, and foreign governments, industry, 
and academia to help ensure produce farmers can successfully implement 
the FSMA Produce Safety Rule, which the Agency published in November 
2015. FDA has particularly focused on developing and funding various 
mechanisms to offer small and very small farms and other small 
businesses information on how to understand, implement, and comply with 
applicable FSMA rules, including how to satisfy the requirements for 
the qualified exemptions. Two of these mechanisms specifically involve 
FDA's coordination with state partners: the State Cooperative Agreement 
Program (CAP) and the educational On Farm Readiness Reviews (OFRR) 
conducted by states through the National Association of State 
Departments of Agriculture (NASDA).
    FDA has provided funds to state agencies to develop produce safety 
programs. The state agencies involved in the CAP have been funded to 
help implement the Produce Safety Rule, and a portion of these funds 
are being used to conduct education and outreach to produce farmers, as 
well as providing technical assistance to help them understand and 
comply with the Produce Safety Rule. Under the CAP, each state grantee 
is developing and implementing outreach and education programs that 
address the specific and unique needs of its farmers and growing 
community to ensure that they are educated and prepared for compliance.
    FDA also has funded NASDA to develop programs and resources to 
assist State Departments of Agriculture to help implement the Produce 
Safety Rule. A portion of these funds are being used to develop and 
conduct the OFRRs that help produce farmers assess how prepared their 
produce farm is to comply with the Produce Safety Rule before routine 
regulatory inspections begin. This voluntary OFRR program was developed 
by the State Departments of Agriculture and Land Grant University 
Cooperative Extension Specialists, via the leadership of NASDA with a 
portion of funds provided by FDA.
    Finally, FDA established the Produce Safety Network (PSN) 
comprising 25 regionally-based FDA personnel to support the efforts of 
farmers, Federal, state and local regulators, and other key 
stakeholders to implement the Produce Safety Rule. The PSN works with 
farmers to address their education needs by connecting them with 
educational resources provided by the state and other sources.
    Question. I believe there is more the FDA can do to restore 
consumer confidence in the recall process, especially given that the 
majority of recalls are voluntary. It is critical that food recalls are 
quickly initiated and effectively carried out.Does the FDA regularly 
collect and publish the information about recalls included in the OIG 
Report (Report No. A-12-16-01502), such as the amount of time that 
elapsed from when FDA learned about a contamination problem to when a 
recall was initiated?
    Answer. FDA is committed to continuously improving how the Agency 
manages situations where either contaminated or potentially 
contaminated foods are in the food supply, which includes FDA's 
handling of food recalls. FDA routinely makes information about 
specific recalls available to consumers and provides annual statistics 
associated with recalls.
    FDA tracks several data points related to recalls, including recall 
initiation date (by fiscal year), FDA product type, recall 
classification, recall status, recalling state, and classification 
date. FDA tracks recall initiation dates, as those reflect the timing 
when the adequate information has been compiled to support a recall 
determination and Agency recall activities. Prior to the recall 
initiation date, situations can be very fluid, with information coming 
into FDA from multiple sources, some of which cannot be verified or may 
contradict other information coming into FDA. Due to these issues, FDA 
does not generally track the time period prior to the recall initiation 
date.
    The recall data are publicly available on the FDA website at the 
FDA Data Dashboard in aggregated form and can be filtered according to 
the data points listed above. In addition to the dashboard, FDA also 
creates a publicly available annual enforcement statistics report, a 
comprehensive source of information about a variety of food related 
activities, including recalls, recall classifications, recalled 
products, food import debarments, warning letters, injunctions, and 
seizures. The annual report is also available on FDA's website.
    FDA also provides consumers timely information about specific 
recalls to help them determine whether they may have been exposed to 
the product or if the recalled food may be in their home. Among other 
things, FDA reposts on its website press releases issued by companies 
regarding their recalls and posts information about recalls on the 
weekly FDA Enforcement Report that lists the Agency's recalls and the 
classification of the level of health hazard, as well as linking 
relevant recall notices to foodborne outbreak web postings. During an 
outbreak, FDA routinely posts information about the investigation, 
which can typically include significant dates in the investigation, 
relevant epidemiologic details, traceback linking a particular source 
or establishment, and the date a firm takes action. Taken together, 
FDA's tools for making specific recall information and aggregate recall 
data publicly available have helped to maintain consumer confidence in 
the recall process.
    Question. How many times has the FDA initiated the mandatory recall 
process before a company decided to voluntarily recall its product?
    Answer. FDA has initiated use of its mandatory recall authority 
three times since the Agency was granted mandatory recall authority by 
the FDA Food Safety Modernization Act of 2011. Two times, the firms 
voluntarily initiated recall after receiving a letter from FDA 
initiating the mandatory recall process. A third instance occurred 
earlier this year when Triangle Pharmanaturals, LLC failed to respond 
to FDA's letter affording an opportunity to voluntarily initiate a 
recall related to the ongoing outbreak investigation of Salmonella-
contaminated kratom products. On April 2, 2018, FDA proceeded to the 
issuance of the final order requiring mandatory recall.
    Question. An annual report of this type would help ensure that the 
deficiencies identified in the OIG report do not persist.
    Is the FDA willing to commit to providing to this Subcommittee and 
to the public, an annual report detailing the Agency's food recall 
activities?
    Answer. FDA already routinely makes information about specific 
recalls available to consumers, as well as annual statistics associated 
with recalls. The FDA Data Dashboard contains compliance statistics, 
which includes data on recalls. Data on the dashboard can be filtered 
by fiscal year, FDA product type, recall classification, recall status, 
recalling state, and classification date. The Dashboard can be accessed 
on the FDA website. In addition to the dashboard, FDA also maintains a 
publicly available annual enforcement statistics report, which is a 
comprehensive source of information about a variety of food related 
activities, including recalls, recall classifications, recalled 
products, food import debarments, warning letters, injunctions, and 
seizures. The annual report is also available on FDA's website. In 
addition, FDA prepares annual reports on the use of mandatory recalls, 
pursuant to section 206 of the Food Safety Modernization Act. This can 
be accessed on the FDA website.
    FDA would be happy to meet with Subcommittee staff to discuss these 
data and to share information provided to OIG in response to its 
report. The Agency continues to work with OIG to provide information 
about improvements associated with the recommendations in OIG Report A-
12-16-01502 on FDA's food recall process.
                         antibiotic resistance
    Question. I strongly support the FDA's focus in recent years on the 
challenges of antibiotic use in animal agriculture and the need to 
address outstanding barriers to effective stewardship. With Guidance 
for Industry #209 and Guidance for Industry #213 now fully in effect, 
efforts to end production uses of medically important antibiotics, 
encourage voluntary removal of production claims by drug sponsors, and 
strengthen the involvement of skilled veterinarians in animal 
production through the mandating veterinary oversight represent a giant 
leap forward.
    However, there are still significant problems. First, FDA announced 
in September 2016 that it was seeking comments on antibiotics used in 
feed or water that lack a defined duration of use on their label. The 
comment period closed over a year ago.
    Please provide an update on the status of this important focus area 
and how you plan to make progress on these drug label duration issues 
in the coming year.
    Answer. FDA is developing additional actions to ensure judicious 
use of medically important antimicrobials. Last January, FDA published 
its key initiatives for the next 5 years, which include the following: 
(1) Align antimicrobial drug products with the principles of 
antimicrobial stewardship in veterinary settings; (2) Support efforts 
to foster stewardship of antimicrobials in veterinary settings; (3) 
Assess the impact of strategies intended to curb the emergence of 
antimicrobial resistance associated with the use of antimicrobial drugs 
in veterinary settings.
    To further build on progress and ensure judicious use of 
antimicrobial drugs in veterinary settings, FDA is working to 
incorporate these key initiatives into a more detailed multi-year plan 
to be published later in 2018. This plan includes steps for addressing 
concerns about products that lack defined durations of use.
    FDA received numerous substantive comments in response to its 
request for public comment on duration of use. The Agency has evaluated 
the comments and is in the process of developing a specific strategy 
for addressing this issue. Any changes to such use conditions will be 
based on sound science and available evidence.
    This continues to be an agency priority, as it will support overall 
efforts to foster stewardship of medically important antimicrobial 
drugs in food-producing animals and help preserve the effectiveness of 
these antimicrobials in animal and human medicine.
    Question. Second, we still do not have sufficient data to determine 
if the changes in FDA guidance are significantly reducing the use of 
medically important antimicrobials in agriculture. In response to 
questions from Senator Udall at the hearing, you noted that more data 
is always better in order to understand and respond to a public health 
concern.
    Can you provide an update as to what actions the FDA is planning on 
taking this year related to enhancing efforts to collect on-farm data, 
both through the National Antimicrobial Resistance Monitoring System 
(NARMS) and through joint efforts with the Centers for Disease Control 
and the U.S. Department of Agriculture?
    Answer. FDA is committed to reducing the rate of development of 
antibiotic resistance by fostering the judicious use of antimicrobial 
drugs in animals. The Agency has issued a number of important guidance 
documents and regulations to support its judicious use strategy and has 
actively engaged in outreach efforts to support effective 
implementation.
    The National Antimicrobial Resistance Monitoring System (NARMS) is 
a critical interagency collaboration between FDA, U.S. Department of 
Agriculture (USDA), and the Centers for Disease Control and Prevention 
(CDC), for tracking antimicrobial resistance in foodborne bacteria in 
the U.S. In June 2017, FDA's Science Board recommended activities to 
enhance NARMS following the One Health framework. One recommendation 
was to explore a possible on-farm component implemented by the USDA-
APHIS National Animal Health Monitoring System (NAHMS). NAHMS is 
currently exploring partnerships to conduct longitudinal studies to 
collect on-farm data on antimicrobial use and resistance. In addition, 
a meeting of USDA, FDA and CDC officials was held in May 2017 in 
Ithaca, NY to discuss how resistance surveillance in animal pathogens 
can be established, with a view to benefit animal and human health.
    FDA and USDA continue to work in close collaboration to foster 
antimicrobial stewardship in veterinary settings and enhance data 
collection on antimicrobial use and resistance. FDA has provided input 
to USDA's Center for Epidemiology and Animal Health on surveys to 
collect information on antimicrobial use in animal agriculture. 
Additionally, FDA continues to fund two cooperative agreements to 
support collection of data on antimicrobial use in U.S. animal 
agriculture, specifically in the poultry and swine industries and on-
farm use data for dairy and feedlot cattle. FDA expects these pilots to 
provide part of the baseline information about on-farm antimicrobial 
use practices and assist in developing long-term functional and 
efficient antimicrobial use monitoring and reporting systems for food 
animal production settings.
                          dietary supplements
    Question. I am concerned by the lack of resources dedicated to 
oversight of the safety of dietary supplements.
    Given the growing demand for and use of dietary supplements, does 
the FDA have plans to request increased resources for the Office of 
Dietary Supplement Policy?
    Answer. FDA appreciates the Committee's continued interest in the 
oversight of dietary supplements. The dietary supplement industry has 
grown steadily since enactment of the Dietary Supplement Health and 
Education Act of 1994 (DSHEA), when Congress found that an estimated 
600 dietary supplement manufacturers in the United States produced 
approximately 4,000 products, with total annual sales of those products 
reaching at least $4 billion. Today, nearly 25 years later, the dietary 
supplement market is worth in excess of $40 billion, with current 
estimates ranging from 50,000 to 80,000 different products produced 
through a global supply chain that includes approximately 7,000 
facilities. The market has grown in scope, as well as size, and now 
encompasses a range of products far broader than it was when DSHEA was 
enacted.
    FDA created the Office of Dietary Supplement Programs (ODSP) in 
December 2015, elevating the program from its previous status as a 
division within the Center for Food Safety and Nutrition (CFSAN), 
reflecting the Agency's recognition that this evolution required a 
higher priority for dietary supplement regulation if FDA is to 
effectively fulfill its public health mission. In doing this, CFSAN 
realigned resources within the base to expand ODSP from 19 to 26 FTEs.
    Although dietary supplement safety is a priority, there are 
currently no plans to request additional resources towards the dietary 
supplement program.
    Question. Does the FDA plan on scaling up outreach and technical 
assistance to dietary supplement manufacturers to ensure compliance 
with the Dietary Supplement Health and Education Act?
    Answer. Although FDA is not currently planning to scale up outreach 
to dietary supplement manufacturers, FDA is committed to continued 
engagement with stakeholders, including dietary supplement 
manufacturers, both through proactive outreach and by responding to 
inquiries to help firms understand how to comply with the Dietary 
Supplement Health and Education Act of 1994 (DSHEA) and related 
regulations. As a matter of practice, FDA regularly grants meeting 
requests from stakeholders, accepts invitations to participate in 
industry training and educational events, and strives to respond in a 
timely and meaningful manner to requests for technical assistance.
       mammography quality standards on breast density reporting
    Question. It was encouraging to see that the Food and Drug 
Administration has recognized the importance of patients receiving 
their own medical information regarding breast density when they have a 
mammogram by identifying the need to modernize mammography standards as 
part of the FDA's major goals in the Unified Agenda, as well as 
Commissioner Gottlieb's recognition of breast density as a risk factor 
for breast cancer.
    What is your timeline for announcing amendments proposed in the 
Unified Agenda to update the regulations issued under the Mammography 
Quality Standards Act of 1992, particularly those related to breast 
density reporting directly to patients?
    Answer. FDA announced in OMB's Spring 2018 Unified Agenda an 
estimated August 2018 publication date for its proposed amendments to 
the implementing regulations of the Mammography Quality Standards Act 
of 1992. FDA is taking this action to address changes in mammography 
technology and mammography processes that have occurred since the 
regulations were published in 1997 and to address breast density 
reporting to patients and healthcare providers.
    Question. Will you commit to amending regulations to allow patients 
to receive their own personal medical information by including 
appropriate information about breast density on the patient's 
mammography summary, including, at a minimum, a qualitative assessment 
of the patient's personal breast density, an explanation of the effect 
of breast density in masking the presence of breast cancer on a 
mammogram, and a reminder to patients that individuals with dense 
breast tissue should talk with their providers if they have any 
questions or concerns about their summary?
    Answer. FDA is committed to ensuring that patients and their 
healthcare providers receive all the information available from 
mammograms in the lay summaries and medical reports they receive, to be 
able to make informed breast healthcare decisions. FDA has drafted 
proposed amendments to the implementing regulations of the Mammography 
Quality Standards Act of 1992 that, among other updates, address breast 
density reporting, and has announced in OMB's Spring 2018 Unified 
Agenda an estimated August 2018 publication date for the proposed 
amendments.
                               phthalates
    Question. Two years ago, 11 national health and consumer 
organizations filed a petition with the FDA requesting a ban on the use 
of phthalate chemicals in food contact substances due to significant 
health concerns. The FDA has yet to respond to this petition.
    When will FDA publicly respond to this petition?
    Answer. FDA continues to actively review the subject Food Additive 
Petition (FAP 6B4815). The petition was filed on April 12, 2016. In the 
Federal Register of May 20, 2016 (81 FR 31877), FDA published a notice 
of filing that invited comments on the petition. The Federal Register 
notice established July 19, 2016 as the end of the comment period. On 
August 8, 2016, in response to a request for an extension of the 
comment period, FDA reopened the comment period until September 19, 
2016. On October 16, 2016, FAP 6B4815 was placed in abeyance. Abeyance 
is an administrative category of petitions that are filed but non-
active because of deficiencies that were identified during FDA's 
review. A petition remains in abeyance until either the petitioner 
provides OFAS with the required information, requests a final decision 
based on the data currently in the petition, or requests withdrawal of 
the petition. When the petitioner provides the information required to 
address all deficiencies, the petition may be refiled resulting in a 
new filing date.
    On March 12, 2018, FDA removed the petition from abeyance, and the 
petition is currently under review.
    Question. Will FDA consider the impact of low-dose, long-term 
exposure of phthalate chemicals on human health when evaluating the 
safety of use in food contact substances?
    Answer. When FDA evaluates the safety of the use of a food contact 
substance, FDA considers the impact of the dietary exposure to the 
additive and calculates exposure as an estimated daily intake which 
occurs over the life-time of the consumer.
    Question. Will the safety evaluation go beyond short-term 
toxicology and fully consider other impacts such as on the endocrine 
and reproductive systems?
    Answer. When FDA evaluates the safety of a food contact substance, 
FDA considers a wide range of toxicological findings, including 
potential toxicity of a substance that could result from impacts on the 
endocrine and reproductive systems.
                 improving diversity in clinical trials
    Question. The fiscal year 18 Omnibus included Senate report 
language on Improving Diversity in Clinical Trials and Safety Studies. 
Specifically, the Committee encouraged FDA action to achieve greater 
inclusion of racially and ethnically diverse populations in genome-wide 
association studies, clinical trials, and safety analysis; more 
complete data reporting in Clinical Drug Trials Snapshots; and Spanish-
language reporting forms in the MedWatch system to address adverse 
events and safety concerns.
    What is your timeline and plan to address each of the requested 
actions?
    Answer. There is the potential for varying effects of treatment 
among demographic subgroups. Women may respond differently to treatment 
as compared to men, while elderly patients may be more or less 
sensitive to a drug. With this realization, FDA is committed to 
ensuring safe and effective use of medical products across the 
demographic spectrum. The assessment of varying treatment effects 
across patient subgroups from clinical studies is important to provide 
the best information for patients and prescribers to make treatment 
decisions. This assessment includes quantifying the heterogeneity of 
the treatment effects and determining effect modifiers and the 
characteristics associated with these effect modifiers.
    Multiple units in the Agency are collaborating to provide 
additional information to the public about demographics in clinical 
trials, through Drug Trial Snapshots and other sources. These groups 
are exploring the use of innovative methodology, where applicable, to 
better inform treatment decisions related to subgroups of patients. 
Drug Trial Snapshots provide consumers with information about who 
participated in the clinical trials and include information on study 
designs, effectiveness and safety, and whether there were differences 
in efficacy and side effects among subgroups.
    Since the beginning of 2017, Drug Trials Snapshots have reported on 
sex, age, race and ethnicity of trial participants as well as on the 
geographic distribution of the trial sites (proportion of participants 
from U.S. trial sites). Ethnicity is presented in Snapshots as 
``Hispanic,'' ``not-Hispanic,'' and ``not reported. The ``not 
reported'' category provides additional explanation if available in the 
submitted application. For example, it may note that data were missing 
or not collected during the clinical trial. In the latter case, it may 
provide additional clarification for why that data were not collected. 
In some cases, regulatory authorities in certain countries do not 
permit collecting ethnicity data from their clinical trial sites.
    FDA is also taking additional steps related to assessing clinical 
trial inclusion and exclusion criteria and increasing diversity in 
clinical trial participation, as required under the FDA Reauthorization 
Act of 2017 (FDARA). Sec. 610 of FDARA requires FDA to publish a draft 
guidance to discuss eligibility criteria for clinical trials and make 
recommendations of methodological approaches for a manufacturer or 
sponsor of an investigation of a new drug. The draft guidance will 
focus on three themes, as required by the statute: broadening 
eligibility criteria, increasing trial recruitment, and using 
eligibility criteria for the benefit of drugs intended for the 
treatment of rare diseases or conditions. Development of the guidance 
is on schedule to be published by July 15, 2019.
    On March 16, 2018, FDA published an information collection notice 
in the Federal Register: Agency Information Collection Activities; 
Proposed Collection; Comment Request; MedWatch: The Food and Drug 
Administration Medical Products Reporting Program. The following 
statement concerning translation of MedWatch forms was included: ``The 
Agency welcomes comments about translation of Form FDA 3500B (consumer) 
into Spanish and other languages.'' The comment period on this notice 
closed on June 15, 2018. FDA continues to work on improving ways to 
submit MedWatch forms in Spanish and other languages.
                                 ______
                                 
                Question Submitted by Senator Tom Udall
    Question. Dr. Gottlieb, we appreciate FDA's focus in recent years 
on the challenges of antibiotic use in animal agriculture and the need 
to address outstanding barriers to effective stewardship. Your efforts 
to end production uses of medically important antibiotics, encourage 
voluntary removal of production claims by drug sponsors, and strengthen 
the involvement of skilled veterinarians in animal production through 
the mandating veterinary oversight has meaningfully advanced our common 
objective to enhance stewardship among animal producers. But you've 
also acknowledged that more work is needed and that there are 
outstanding challenges we still need to address. In particular, FDA 
announced in September, 2016 that you planned to focus on antibiotics 
used in feed or water that lack a defined duration of use. You sought 
public feedback on this effort, and you developed a cross-functional 
working group to determine next steps. Can you update us on the status 
of this important focus area and how you plan to make progress on these 
drug label duration issues in the coming year? Please reply in writing 
and share a concrete, stepwise plan with this Subcommittee to address 
this issue in a timely manner.
    Answer. FDA is developing additional actions to ensure judicious 
use of medically important antimicrobials. Last January, FDA published 
its key initiatives for the next 5 years, which include the following: 
(1) Align antimicrobial drug products with the principles of 
antimicrobial stewardship in veterinary settings; (2) Support efforts 
to foster stewardship of antimicrobials in veterinary settings; (3) 
Assess the impact of strategies intended to curb the emergence of 
antimicrobial resistance associated with the use of antimicrobial drugs 
in veterinary settings.
    To further build on progress and ensure judicious use of 
antimicrobial drugs in veterinary settings, FDA is working to 
incorporate these key initiatives into a more detailed multi-year plan 
to be published later in 2018. This plan includes steps for addressing 
concerns about products that lack defined durations of use.
    FDA received numerous substantive comments in response to its 
request for public comment on the duration of use issue. The Agency has 
evaluated the comments and is in the process of developing a specific 
strategy for addressing this issue. Any changes to such use conditions 
will be based on sound science and available evidence.
    This continues to be an agency priority, as it will support overall 
efforts to foster stewardship of medically important antimicrobial 
drugs in food-producing animals and help preserve the effectiveness of 
these antimicrobials in animal and human medicine.
                                 ______
                                 
            Questions Submitted by Senator Patrick J. Leahy
                           drug affordability
    Question. We have discussed the frustration we both share about the 
anti-competitive tactics used by brand drug companies to deny the sale 
of samples to generic manufacturers. This is a problem that has been 
around for a long time and it is my understanding that the FDA has 
limited ability to police this behavior.
    Does the FDA have the clear and explicit authority to order a brand 
drug company to sell samples of its product to a generic manufacturer, 
even if the agency have found that the generic manufacturer can safely 
handle that sample?
    Answer. FDA has never asserted authority to order a brand drug 
company to sell samples of its product to a generic manufacturer. FDA 
has issued letters stating that the Agency will not consider it to be a 
violation of the applicable Risk Evaluation and Mitigation Strategies 
(REMS) for the brand drug company to provide samples to a particular 
generic company for generic development.
    Question. Has FDA ever actually ordered a brand drug company to 
sell samples to a generic manufacturer?
    Answer. No. FDA has issued letters stating that the Agency will not 
consider it to be a violation of the applicable REMS for the brand drug 
company to provide samples to a particular generic company for generic 
development, but we have not ordered a brand company to provide samples 
to a generic company.
    Question. It's my understanding that the FDA has some authority to 
levy civil monetary penalties when the agency determines a brand drug 
company is using the existence of a REMS program to block or delay a 
generic applicant. Is that correct?
    Answer. FDA has authority to levy civil monetary penalties for 
violations of section 505-1 of the Federal Food, Drug, and Cosmetic Act 
(FD&C Act), which (among other things) prohibits holders of brand (and 
generic) applications from using any REMS element to assure safe use 
(ETASU) to block or delay approval of either a generic or 505(b)(2) 
application. FDA notes that a significant number of the products about 
which FDA has received RLD access inquiries are not subject to a REMS 
with ETASU.
    Question. Has the FDA ever used that authority?
    Answer. FDA has not used this civil monetary penalty (CMP) 
authority for violations of section 505-1 of the FD&C Act.
    Question. Would the FDA be required to develop a lengthy record 
prior to any action?
    Answer. To obtain a CMP, the FDA Center with principal jurisdiction 
over the matter must file an administrative complaint and bears the 
burden of proving a violation of section 505-1 of the FD&C Act. Prior 
to filing a complaint, that Center would need to develop a record 
establishing each element of the violation. An entity against whom a 
CMP is sought may request an administrative hearing. The parties (the 
FDA Center and the drug company) may serve requests for production of 
documents on each other and must submit written direct testimony of 
their witnesses pre-hearing. At the hearing, the parties may cross-
examine the other party's witnesses. Following the hearing and possibly 
post-hearing briefing, the presiding officer determines whether the 
Center has met its burden of proving the drug company's liability and 
determines the appropriateness of the penalty amount proposed by the 
Center. Either party may appeal an adverse decision to the Department 
of Health and Human Services' Departmental Appeals Board (Board). 
Appeals involve briefing and possibly oral argument before the Board. 
The brand company can appeal an adverse Board decision to the Federal 
Court of Appeals. CMP cases, therefore, are resource-intensive and 
often become protracted, multi-year proceedings.
    Question. Would the agency need to compile evidence that the 
brand's actions were designed to block or delay the generic 
application?
    Answer. Yes. FDA would be required to compile evidence necessary to 
establish each of the elements of 505-1. FDA notes that because FDA is 
not privy to the details of business transactions between brand and 
generic companies, much of the evidence required to prove such 
violations is not within FDA's possession or control.
    Question. Would this require FDA's time and resources?
    Answer. Yes. As described above, CMP cases often become protracted, 
multi-year proceedings, requiring the Agency to expend significant time 
and resources on the litigation of each individual CMP case.
    Question. And does the authority only apply to drugs that are 
behind a REMS and not drugs subject to restrictive contracting 
agreements?
    Answer. FDA may seek to impose CMPs in circumstances where holders 
of brand (and generic) applications have used a REMS ETASU to block or 
delay approval of either a generic or 505(b)(2) application.
    Question. Even if the FDA is successful in levying civil monetary 
penalties, does the FDA have the explicit authority to order a brand 
drug company to sell samples of its product to a generic manufacturer?
    Answer. FDA has never asserted authority to order a brand drug 
company to sell samples of its product to a generic manufacturer.
                              added sugar
    Question. I appreciated hearing how your family has enjoyed tapping 
your own trees, but for you and your daughters that is a fun hobby. For 
many Vermont families, their livelihoods depend on maple syrup and 
maintaining consumer confidence. It is clear from the public comments 
submitted for the `Draft Guidance for Industry: Declaration of Added 
Sugars on Honey, Maple Syrup, and Certain Cranberry Products' published 
on March 2, 2018, that maple and honey producers remain worried about 
this requirement, and that your offer to use an ``obelisk'' will not 
resolve the confusion for consumers for maple syrup or honey. This 
would alter consumer perceptions and buying habits, likely leading to 
consumers replacing the small amount of maple syrup used today with 
other refined sugar and corn sweeteners, thus encouraging poorer 
dietary practices rather than healthier ones.
    You have said that the rational and rule for the new nutrition fact 
label and declaration of added sugar are ``driven by the statute that 
is prescriptive in some places.'' However, the Federal Food and 
Cosmetics Act does offer some flexibility and exemptions. For instance 
Section 403(q)(2)(B) of the Federal Food and Cosmetics Act states that 
``If the Secretary determines that the information relating to a 
nutrient required by subparagraph (1)(C), (1)(D), or (1)(E) or clause 
(A) of this subparagraph to be included in the label or labeling of 
food is not necessary to assist consumers in maintaining healthy 
dietary practices, the Secretary may by regulation remove information 
relating to such nutrient from such requirement.''
    Applying the added sugar labeling to bottles of pure maple syrup, 
which makes up less than 5 percent of the table syrup market, would not 
assist consumers in maintaining healthy dietary practices, and could 
instead lead to poorer dietary practices. Have you or your staff 
reviewed Section 403(q)(2)(B) of the Federal Food and Cosmetics Act to 
determine whether it gives you the necessary authority to maintain 
listing total sugars on the label, but removing the added sugar 
information from pure maple syrup or honey packages?
    Answer. The Dietary Guidelines recommends consuming no more than 10 
percent of daily calories from added sugars. There is strong and 
consistent evidence that healthy dietary patterns, characterized, in 
part, by lower intakes of sugar-sweetened foods and beverages relative 
to less healthy patterns, are associated with a reduced risk of 
cardiovascular disease. Additionally, there is strong and consistent 
evidence that it is difficult to meet nutrient needs within calorie 
limits when more than 10 percent of daily calories comes from added 
sugars. In general, declaring added sugars on the Nutrition Facts label 
provides consumers with information based on the latest science and 
empowers them to make informed and healthy food choices.
    However, FDA is sensitive to the honey and maple syrup industries' 
concerns regarding the declaration of added sugars on single-ingredient 
products. On June 19, 2018, FDA announced that the Agency is taking 
another look at this issue following comments received from the public 
regarding FDA's original March 2, 2018 draft guidance titled ``The 
Declaration of Added Sugars on Honey, Maple Syrup, and Certain 
Cranberry Products.'' The feedback that FDA received is that the 
approach laid out in the draft guidance does not provide the clarity 
that the Agency intended. It is important to FDA that consumers are 
able to effectively use the new Nutrition Facts label to make informed, 
healthy dietary choices. FDA looks forward to working with stakeholders 
to devise a sensible solution.
    Question. Do you believe a change in the law is needed to alter 
this requirement for these two pure natural products, of which maple 
has considerable nutritional value, contains antioxidants, and may have 
additional health advantages?
    Answer. FDA believes that the Agency can work in the context of its 
current regulatory framework to develop a solution to address maple 
syrup and honey producers' concerns regarding the declaration of added 
sugars on single-ingredient products. FDA published a draft guidance 
titled ``The Declaration of Added Sugars on Honey, Maple Syrup, and 
Certain Cranberry Products: Guidance for Industry'' on March 2, 2018. 
The guidance states FDA's current thinking to allow manufacturers of 
specific products to use a symbol immediately after the added sugars 
Daily Value, directing consumers to language that provides truthful and 
not misleading contextual information about ``added sugars'' and what 
it means for each of these specific products.
    The draft guidance is out for public comment, and FDA recently 
extended the comment period by 45 days to close on June 15, 2018. 
Although the comment period is still open, the Agency has received 
comments asking for consideration of alternative approaches to what was 
proposed in the draft guidance to address added sugars labeling for 
these products. FDA will consider all proposed options once the comment 
period closes and will consider the feedback received in determining 
how best to go forward.
                                 ______
                                 
              Questions Submitted by Senator Tammy Baldwin
    Question. I am pleased that FDA announced its intention to revise 
the draft MOU between FDA and the states concerning pharmacy 
compounding published in 2015. I have heard from constituents, 
including family-owned compounding pharmacies in Wisconsin that have a 
reputation for quality, who have serious concerns that the draft MOU 
defines ``distribution'' to include ``dispensing,'' which are typically 
considered separate and distinct activities. Further, I have heard 
concerns that states may be reluctant to sign the MOU due to concerns 
that it would be overly burdensome to enforce without adequate funding. 
Under the law, for states that don't enter into the MOU, FDA will 
enforce a 5 percent limit for compounding pharmacies on interstate 
distribution of compounded products. I am concerned that without proper 
clarification of the definition of ``distribution'' in a revised draft 
MOU, access would be restricted for patients who depend on compounding 
pharmacies in other states for unique medical needs and those who 
travel during the year. This would be particularly acute should a state 
not sign the MOU.
    Will you commit to clarifying the definition of distribution in a 
manner that maintains sufficient patient access to the compounded 
medications they need?
    Answer. FDA takes seriously the concerns that some stakeholders 
have raised about the implications of the statutory limitation on 
distribution of compounded drugs out of the State in which they are 
compounded found in section 503A(b)(3)(B)(ii) of the FD&C Act. This 
section provides one of the conditions to qualify for the exemptions in 
section 503A, which is that if a drug product is compounded in a state 
that has not entered into an MOU with FDA addressing the distribution 
of inordinate amounts of compounded drugs interstate and providing for 
the investigation of complaints, the compounder does not distribute 
compounded drugs out of the state in which they are compounded in 
excess of 5 percent of its total prescription orders dispensed or 
distributed. Stakeholders expressed concern about maintaining patient 
access to drugs compounded by pharmacies located in states that may 
decide not to enter into the MOU with FDA, once the MOU is final and 
offered for signature. FDA anticipates that the revisions it intends to 
make to the draft MOU will make it more feasible for states to enter 
into the MOU once it is final.
    Question. What modifications does the agency plan to make to 
address these issues in the revised draft?
    Answer. As FDA works to develop and issue a revised draft MOU for 
public comment in the coming months, the Agency is considering the 
concerns and recommendations conveyed in the 3,000 comments submitted 
on the 2015 draft MOU, including comments regarding the definition of 
``distribution'' and the challenges states might face in meeting the 
terms of the draft MOU.
    Question. Please describe what FDA is doing to consult with 
stakeholders, including compounding pharmacies and state boards of 
pharmacy, in developing a revised draft and will you open the draft to 
public comment?
    Answer. FDA believes that the revisions that it is making in the 
revised draft MOU, developed in consultation with the National 
Association of Boards of Pharmacy, will address many of the concerns 
that stakeholders, including certain states, had raised regarding the 
draft issued in 2015. FDA will further take into consideration any 
comments received during the public comment period for the revised 
draft MOU.
    Question. As FDA considers how to best redefine ``healthy'' on food 
packages, I am interested to know what considerations are being made to 
ensure fruits like cranberries are appropriately recognized by any new 
proposed definition. Cranberries are naturally tart, nutrient dense 
fruits with a de minimis amount of natural sugars. As such, sugar is 
added for palatability and processing. What are you doing to ensure 
that any new definition of ``healthy'' appropriately accounts for 
naturally tart, nutrient dense fruits that are sweetened to levels 
similar to products with natural sugars, but still deliver high levels 
of nutrients and other unique health benefits?
    Answer. FDA recognizes that the claim ``healthy'' is ready for an 
update to be more consistent with the 2015-2020 Dietary Guidelines for 
Americans and current nutrition science. In September 2016, FDA 
published a request for information (RFI) on the use of the term 
``healthy'' in food labeling. FDA also held a public meeting in March 
2017 to discuss the use of the term ``healthy'' in the labeling of food 
and beverage products. The Agency received nearly 1,200 comments in the 
docket for the RFI and public meeting. FDA will take into consideration 
the latest Dietary Guidelines and nutrition science, including 
recommendations regarding added sugar consumption as part of a healthy 
eating pattern, as well as stakeholders' comments, as it determines how 
best to update the definition of ``healthy.''
    Question. Additionally, as FDA begins to modernize how the Agency 
reviews and establishes health claims on food packages, do you 
anticipate any near-term changes that would impact petitions now under 
consideration? How is that different from the current approach and what 
are the long-term goals for changes?
    Answer. As part of FDA's Nutrition Innovation Strategy, the Agency 
intends to develop a comprehensive framework to modernize our approach 
on how we look at health claims to support industry initiatives already 
underway and encourage other companies to introduce products that meet 
the growing consumer demand for healthier products. FDA is looking to 
streamline its process for reviewing health claims it receives from 
industry to enhance the efficiency of the review process. The Agency is 
at the beginning stages of this process and, therefore, does not 
anticipate near-term impact on petitions currently under consideration.
    FDA plans to have extensive engagement with stakeholders to seek 
input and further explore how to best promote public health in the 
evolving food and beverage marketplace. Part of this public engagement 
includes holding a public meeting this summer on the Nutrition 
Innovation Strategy. The Agency will announce the meeting details and 
open a docket for public comment in the Federal Register.

                          SUBCOMMITTEE RECESS

    Senator Hoeven. We are adjourned.
    [Whereupon, at 3:20 p.m., Tuesday, April 24, the 
subcommittee was recessed, to reconvene subject to the call of 
the Chair.]